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Background We aimed to estimate the public health impact of booster vaccination against COVID-19 in the UK during an Omicron-predominant period. Research design and methods A dynamic transmission model was developed to compare public health outcomes for actual and alternative UK booster vaccination programs. Input sources were publicly available data and targeted literature reviews. Base case analyses estimated outcomes from the UK’s Autumn–Winter 2021–2022 booster program during January–March 2022, an Omicron-predominant period. Scenario analyses projected outcomes from Spring and in Autumn 2022 booster programs over an extended time horizon from April 2022–April 2023, assuming continued Omicron predominance, and explored hypothetical program alternatives with modified eligibility criteria and/or increased uptake. Results Estimates predicted that the Autumn–Winter 2021–2022 booster program averted approximately 12.8 million cases, 1.1 million hospitalizations, and 290,000 deaths. Scenario analyses suggested that Spring and Autumn 2022 programs would avert approximately 6.2 million cases, 716,000 hospitalizations, and 125,000 deaths; alternatives extending eligibility or targeting risk groups would improve these benefits, and increasing uptake would further strengthen impact. Conclusions Boosters were estimated to provide substantial benefit to UK public health during Omicron predominance. Benefits of booster vaccination could be maximized by extending eligibility and increasing uptake.

This article assesses how the adoption of a range of digital technologies affects firm productivity. It combines cross-country firm-level data on productivity and industry-level data on digital technology adoption in an empirical framework that accounts for firm heterogeneity. The results provide robust evidence that digital adoption in an industry is associated to productivity gains at the firm level. Effects are relatively stronger in manufacturing and routine-intensive activities. They also tend to be stronger for more productive firms and weaker in the presence of skill shortages, which may relate to the complementarities between digital technologies and other forms of capital (e.g. skills, organisation, or other intangibles). As a result, digital technologies may have contributed to the growing dispersion in productivity performance across firms. Hence, policies to support digital adoption should go hand in hand with creating the conditions to enable the catch-up of lagging firms, notably by easing access to skills.

Background: Simulation modeling facilitates the estimation of long-term health and economic outcomes to inform healthcare decision-making. Objective: To develop a framework to simulate progression of Parkinson’s disease (PD), capturing motor and non-motor symptoms, clinical outcomes, and associated costs over a lifetime. Methods: A patient-level simulation was implemented accounting for individual variability and interrelated changes in common disease progression scales. Predictive equations were developed to model progression for newly diagnosed patients and were combined with additional sources to inform long-term progression. Analyses compared a hypothetical disease-modifying therapy (DMT) with a standard of care to explore the drivers of cost-effectiveness. Results: The equations captured the dependence between the various measures, leveraging prior values and rates of change to obtain realistic predictions. The simulation was built upon several interrelated equations, validated by comparison with observed values for the Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) and UPDRS subscales over time. In a case study, disease progression rates, patient utilities, and direct non-medical costs were drivers of cost-effectiveness. Conclusions: The developed equations supported the simulation of early PD. This model can support conducting simulations to inform internal decision-making, trial design, and strategic planning early in the development of new DMTs entering clinical trials.

Mumps outbreaks, especially in adolescents and young adults, have been reported in the Czech Republic. The aim of the presented study was to determine the seroprevalence of specific IgG antibodies against mumps in the adult population of the Czech Republic. The study was designed as a multicenter serological survey of adults aged 18 years and over. Specific IgG antibodies against mumps were detected in blood samples using an enzyme-linked immunosorbent assay (ELISA). A total of 1,911 serum samples were examined. The overall seropositivity reached 55.3%. In individual age groups, the highest seropositivity 63% (63.5–65.2%) was recorded in adults aged 40 years and over; the lowest seropositivity was found in adults aged 18–29 years (27.4%). The difference in seropositivity rate between the 18–29 years age group and the 40 years and over age groups was statistically significant (p < 0.001). Only the 18–29 years age group included both vaccinated and unvaccinated (born in the pre-vaccine era) individuals. In vaccinated individuals, seropositivity was reported in only 19.1% of persons; in unvaccinated individuals, seropositivity reached 48.2%. Our results demonstrate the long-term persistence of antibodies following natural infection and the decrease in seropositivity that occurs after vaccination over time. This immunity waning may account for the higher susceptibility of adolescents and young adults to mumps. Therefore, the current vaccination program in the Czech Republic could be considered as less effective. It will be modified with the shifting of the second dose of vaccine from two years of age to the preschool age.

In recent years, Europe has recorded an increase in the number of measles outbreaks despite the implementation of vaccination into the National Immunization Programs. The Czech Republic introduced vaccination against measles into National Immunization Program in 1969. The aim of this study was to determine seroprevalence of IgG antibodies against measles in adults.Our study was designed as a prospective, multicenter cohort study. Samples of blood were taken from adults aged 18 years and over. Specific IgG antibodies were determined by ELISA method.A number of 1911 sera samples were obtained. The total seropositivity reached 83.3%, 14.3% of the results were negative and 2.4% were borderline. When comparing the individual age groups, the highest antibody seropositivity (> 96%) was detected in persons aged 50 years and over who were naturally infected in pre-vaccine era. The lowest seropositivity was recorded in the age groups 30-39 years (61.5%), 40-49 years (77.5%) and 18-29 years (81.1%).A long term high rate of seropositivity persists after natural measles infection. By contrast, it decreases over time after vaccination. Similarly, the concentrations of antibodies in persons with measles history persist for a longer time at a higher level than in vaccinated persons. Our results indicate possible gap in measles protection in adults born after implementation of vaccination into the National Immunization Programs. There are two probable reasons, decrease of measles antibody seropositivity in time after vaccination in setting of limited natural booster and one-dose vaccination schedule used in the first years after implementation.

Chronic hepatitis C is curable disease. Low detection rate could be one of the reasons of poor treatment uptake. It is important to identify HCV prevalence and anti-hepatitis C virus (HCV) positive patients in population by effective screening strategy such as risk-based or birth cohort screening programs. There are no national population-based estimates of the HCV prevalence in the Czech Republic (CZ). The most recent seroprevalence survey determined a prevalence of positive anti-HCV antibodies of 0.2% (in 2001). The aim of the study was to determine the seroprevalence of HCV, HCV viraemia and HCV genotype in the CZ adult population. We also estimated the number of persons living with chronic hepatitis C in CZ. The examined group included 3000 adults, 18-90 years of age enrolled in 2015. All serum samples were examined to determined anti-HCV antibodies positivity, HCV-RNA positivity and genotypes. Of the 3000 samples, 50 were found to be anti-HCV-positive, for a seroprevalence of 1.67% (2.39% in males, 0.98% in females). The overall prevalence of positive HCV RNA was 0.93%: 1.5% in males, 0.39% in females. HCV genotype (GT) 1a was determined in 25%, GT 1b in 25% and GT 3a in 46%. Since 2001, the HCV seroprevalence has increased 8-fold. The highest HCV seroprevalence occurred in males aged 30-44 years. We can estimate that there are more than 140,000 people with HCV antibodies and more than 80,000 people with chronic hepatitis C living in the CZ. The introduction of birth cohort HCV screening could be beneficial for the country.

Aluminium brazing is a method for joining Al-parts in close proximity by introducing liquid alloys which melt above 577 °C. On the basis of an applied heat source, conventional (flame) and energy-beam brazing (laser) can be distinguished. The laser is capable to result in rapid local melting around the surface to be joined. In spite of the high energy density (represented by laser irradiation) the melting of Al is often unsuccessful. The reason is the low absorption ability of Al at around the wavelength characteristic to the CO2 laser. Coatings with a high absorption ability have to be used in order to facilitate the energy absorption. In the present study the change in absorption ability of Al surfaces due to NOCOLOK© Flux coatings will be presented.

When quantifying therapeutic drugs using LC-MS/MS instrumentation in clinical laboratories, batch-mode analysis with a calibration curve consisting of 6–10 concentrations for each analyte is the most widely used approach. However, this is an inefficient use of this technology since it increases cost, delays result availability and precludes random instrument access. Various alternative methods to reduce the calibrator use and improve efficiency without compromising analytical quality have been investigated, and a single-point calibration has been reported to be the simplest, least expensive and the quickest approach.This study compares a single and a multi-point calibration method using LC-MS/MS with 5-fluorouracil (5-FU) as a model drug. The method was validated for quantitative analysis of 5-FU over a concentration range of 0.05–50 mg/L. Patients undergoing cancer treatment with intravenous 5-FU had plasma 5-FU concentrations measured, and their dose adjusted in real time based on the calculated area under the time-concentration curve (AUC). Subsequently, a single point calibration method using a concentration at 0.5 mg/L was compared to the multi-point calibration method in terms of accuracy and precision. A Bland-Altman bias plot and a Passing-Bablok regression analysis showed a good agreement between the two methods (mean difference = −1.87 %, slope = 1.002, respectively) when comparing patient plasma 5-FU concentrations. The calibration method did not impact the AUC results nor the decision on 5-FU dose adjustments. Our study demonstrated that a single point calibration method produced analytically and clinically comparable results to those produced by a multi-point method when quantifying 5-FU and is feasible to be used clinically.

The increasing prominence of digital tools for city-scale solar analysis emphasizes the need for validation methodologies, which include urban environmental monitoring and data quality control. This study addresses this gap by introducing a quality control scheme for solar irradiance measurements, using a typical street canyon in Geneva (Switzerland) as a case study. The developed quality control scheme is replicable and effectively addresses challenges posed by the built environment, distinguishing it from existing methods that mostly apply to measurements from unobstructed sensors. The experimental data used in this study were retrieved from the monitoring system installed on two opposing facades of the street canyon case study, as well as a nearby weather station. Measurements were recorded from December 22nd, 2022, to December 19th, 2023, at a one-minute time resolution. Five quality checks – nighttime check, range limit tests, precipitation check, shadow detection, and consistency check - were defined to identify the potential flaws and disturbances in the dataset so that these data points could be flagged accordingly. The results consist of reliable solar irradiance data over one year, which can be used in the future for validating a new component for modeling façade solar potential within the Grand Geneva Area Solar Cadaster.

Wound healing represents a complex and evolutionarily conserved process across vertebrates, encompassing a series of life-rescuing events. The healing process runs in three main phases: inflammation, proliferation, and maturation/remodelling. While acute inflammation is indispensable for cleansing the wound, removing infection, and eliminating dead tissue characterised by the prevalence of neutrophils, the proliferation phase is characterised by transition into the inflammatory cell profile, shifting towards the prevalence of macrophages. The proliferation phase involves development of granulation tissue, comprising fibroblasts, activated myofibroblasts, and inflammatory and endothelial cells. Communication among these cellular components occurs through intercellular contacts, extracellular matrix secretion, as well as paracrine production of bioactive factors and proteolytic enzymes. The proliferation phase of healing is intricately regulated by inflammation, particularly interleukin-6. Prolonged inflammation results in dysregulations during the granulation tissue formation and may lead to the development of chronic wounds or hypertrophic/keloid scars. Notably, pathological processes such as autoimmune chronic inflammation, organ fibrosis, the tumour microenvironment, and impaired repair following viral infections notably share morphological and functional similarities with granulation tissue. Consequently, wound healing emerges as a prototype for understanding these diverse pathological processes. The prospect of gaining a comprehensive understanding of wound healing holds the potential to furnish fundamental insights into modulation of the intricate dialogue between cancer cells and non-cancer cells within the cancer ecosystem. This knowledge may pave the way for innovative approaches to cancer diagnostics, disease monitoring, and anticancer therapy.

As worldwide obesity rates increase the number of patients with an elevated BMI requiring urological surgery will increase. Although obesity has previously been considered a relative contra-indication to laparoscopic surgery, here we present a case of successful laparoscopic nephrectomy performed due to renal cancer in a patient with a BMI >60 kg/m2 together with a review of the associated challenges.

BackgroundSchistosomes are highly efficient evaders of human immunity, as evident by their ability to survive in human blood for years. How they protect themselves against the constant attack by a key element of innate immunity, the complement system, has remained unclear. In this study, new light is shed on the interaction between distinct life-cycle stages of Schistosoma mansoni and the human complement system.ResultsWe demonstrate that schistosomula, the young stage assumed immediately after cercaria penetration of the skin, are extremely vulnerable towards complement-mediated killing as only 10-20% survive. The survival rate increases to 70% already within 30 minutes and reaches close to 100% within two hours. Pathway-specific complement inhibitors revealed the alternative pathway of complement activation as the main contributor to killing and damage of the schistosomula. Moreover, the complement regulator factor H is recruited by the schistosomula in this early stage to evade killing. Surviving parasites appear fully viable despite the ongoing complement attack, as demonstrated by the deposition of C3 fragments. However, when exposed to the widely used schistocidal drug praziquantel, the vulnerability of 24 h-old schistosomula towards complement-mediated killing is notably increased; no such effect was observed for mefloquine or oxamniquine. Similar to the younger life-cycle stages, adult worms remain under complement attack. C3 fragments were found all over the outer surface (tegument), deposited mostly on the ridges and not on the tubercles.ConclusionThe recruitment of factor H merits more detailed studies that pinpoint the molecules involved and elucidate the novel possibilities to intercept the uncovered immune evasion therapeutically. That praziquantel and complement work in synergy is surprising and may in the future result in enhanced understanding of the drug’s mechanism of action.

Abstract Quorum sensing (QS) is a communication form between bacteria via small signal molecules that enables global gene regulation as a function of cell density. We applied a microfluidic mother machine to study the kinetics of the QS response of Pseudomonas aeruginosa bacteria to additions and withdrawals of signal molecules. We traced the fast buildup and the subsequent considerably slower decay of a population-level and single-cell-level QS response. We applied a mathematical model to explain the results quantitatively. We found significant heterogeneity in QS on the single-cell level, which may result from variations in quorum-controlled gene expression and protein degradation. Heterogeneity correlates with cell lineage history, too. We used single-cell data to define and quantitatively characterize the population-level quorum state. We found that the population-level QS response is well-defined. The buildup of the quorum is fast upon signal molecule addition. At the same time, its decay is much slower following signal withdrawal, and the quorum may be maintained for several hours in the absence of the signal. Furthermore, the quorum sensing response of the population was largely repeatable in subsequent pulses of signal molecules.

Abstract Both hypoxia and the complement lectin pathway (CLP) are involved in atherosclerosis and atherosclerosis-related stroke and acute myocardial infarction (AMI). We have previously shown that mannose-binding lectin-associated serine protease-1 (MASP-1), the most abundant enzyme of CLP, induces an inflammatory phenotype of endothelial cells (ECs) by cleaving protease activated receptors (PARs). In the absence of data, we aimed to investigate whether hypoxia and MASP-1 interact at the level of ECs, to better understand their role in atherosclerosis-related diseases. Hypoxia attenuated the wound healing ability of ECs, increased ICAM-1 and decreased ICAM-2 expression and upregulated PAR2 gene expression. Hypoxia and MASP-1 increased GROα and IL-8 production, and endothelial permeability without potentiating each other’s effects, whereas they cooperatively disrupted vascular network integrity, activated the Ca2+, CREB and NFκB signaling pathways, and upregulated the expression of E-selectin, a crucial adhesion molecule in neutrophil homing. VCAM-1 expression was not influenced either by hypoxia, or by MASP-1. In summary, hypoxia potentiates the effect of MASP-1 on ECs, at least partially by increasing PAR expression, resulting in interaction at several levels, which may altogether exacerbate stroke and AMI progression. Our findings suggest that MASP-1 is a potential drug target in the acute phase of atherosclerosis-related diseases.

A ferences rendtartományok első olyan összeírását, mely az egyes provinciák mellett immár név szerint felsorolja azok őrségeit és kolostorait is, Paulinus Venetus pozzuoli püspök készítette el 1340 körül. A lajstrom a magyar rendtartomány kötelékében 8 őrséget és összesen 45 kolostort említ, s bár a felsorolás nem hiánytalan, mégis átfogó képet nyújt a magyar provincia 14. századi szervezetéről. Több magyar kolostor első említése éppen ebből az összeállításából ismert. A tanulmány a forrás magyar vonatkozásait vizsgálja, kiemelve annak kritikus pontjait, egyúttal mérlegre helyezi a kérdéskört érintő, máig mérvadónak tekintett szakirodalmat.

MYC family oncoproteins regulate the expression of a large number of genes and broadly stimulate elongation by RNA polymerase II (RNAPII). While the factors that control the chromatin association of MYC proteins are well understood, much less is known about how interacting proteins mediate MYC’s effects on transcription. Here, we show that TFIIIC, an architectural protein complex that controls the three-dimensional chromatin organisation at its target sites, binds directly to the amino-terminal transcriptional regulatory domain of MYCN. Surprisingly, TFIIIC has no discernible role in MYCN-dependent gene expression and transcription elongation. Instead, MYCN and TFIIIC preferentially bind to promoters with paused RNAPII and globally limit the accumulation of non-phosphorylated RNAPII at promoters. Consistent with its ubiquitous role in transcription, MYCN broadly participates in hubs of active promoters. Depletion of TFIIIC further increases MYCN localisation to these hubs. This increase correlates with a failure of the nuclear exosome and BRCA1, both of which are involved in nascent RNA degradation, to localise to active promoters. Our data suggest that MYCN and TFIIIC exert an censoring function in early transcription that limits promoter accumulation of inactive RNAPII and facilitates promoter-proximal degradation of nascent RNA.

Supportive robotic solutions take over mundane, but essential tasks from human workforce in biomedical research and development laboratories. The newest technologies in collaborative and mobile robotics enable the utilization in the human-centered and low-structured environment. Their adaptability, however, is hindered by the additional complexity that they introduce. In our paper we aim to entangle the convoluted laboratory robot integration architectures. We begin by hierarchically decomposing the laboratory workflows, and mapping the activity representations to layers and components of the automation control architecture. We elaborate the framework in detail on the example of pick-and-place labware transportation - a crucial supportive step, which we identified as the number one area of interest among experts of the field. Our concept proposal serves as a reference architecture model, the key principles of which were used in reference implementations, and are in line with international standardization efforts.

Background: Fatigue is a prominent symptom in many diseases and is strongly associated with impaired daily function. The measurement of daily function is currently almost always done with questionnaires, which are subjective and imprecise. With the recent advances of digital wearable technologies, novel approaches to evaluate daily function quantitatively and objectively in real-life conditions are increasingly possible. This also creates new possibilities to measure fatigue-related changes of daily function using such technologies. Summary: This review examines which digitally assessable parameters in immune-mediated inflammatory and neurodegenerative diseases may have the greatest potential to reflect fatigue-related changes of daily function. Key Messages: Results of a standardized analysis of the literature reporting about perception-, capacity-, and performance-evaluating assessment tools indicate that changes of the following parameters: physical activity, independence of daily living, social participation, working life, mental status, cognitive and aerobic capacity, and supervised and unsupervised mobility performance have the highest potential to reflect fatigue-related changes of daily function. These parameters thus hold the greatest potential for quantitatively measuring fatigue in representative diseases in real-life conditions, e.g., with digital wearable technologies. Furthermore, to the best of our knowledge, this is a new approach to analysing evidence for the design of performance-based digital assessment protocols in human research, which may stimulate further systematic research in this area.

Abstract In pancreatic ductal adenocarcinoma (PDAC), endogenous MYC is required for S-phase progression and escape from immune surveillance. Here we show that MYC in PDAC cells is needed for the recruitment of the PAF1c transcription elongation complex to RNA polymerase and that depletion of CTR9, a PAF1c subunit, enables long-term survival of PDAC-bearing mice. PAF1c is largely dispensable for normal proliferation and regulation of MYC target genes. Instead, PAF1c limits DNA damage associated with S-phase progression by being essential for the expression of long genes involved in replication and DNA repair. Surprisingly, the survival benefit conferred by CTR9 depletion is not due to DNA damage, but to T-cell activation and restoration of immune surveillance. This is because CTR9 depletion releases RNA polymerase and elongation factors from the body of long genes and promotes the transcription of short genes, including MHC class I genes. The data argue that functionally distinct gene sets compete for elongation factors and directly link MYC-driven S-phase progression to tumor immune evasion.

Agrimonia eupatoria L. (AE) has a rich tradition of use in wound healing improvement across various cultures worldwide. In previous studies, we revealed that Agrimonia eupatoria L. water extract (AE) possesses a rich polyphenolic composition, displaying remarkable antioxidant properties. Our investigations also demonstrated that lipophosphonoxin (LPPO) exhibited antibacterial efficacy in vitro while preserving the proliferation and differentiation of fibroblasts and keratinocytes. Building upon our prior findings, in this study, we intended to examine whether a combination of AE and LPPO could enhance skin wound healing while retaining antibacterial attributes. The antibacterial activity of AE/LPPO against Staphylococcus aureus was evaluated, alongside its effects on fibroblast-to-myofibroblast transition, the formation of extracellular matrix (ECM), and endothelial cells and keratinocyte proliferation/phenotype. We also investigated AE/LPPO’s impact on TGF-β1 and VEGF-A signaling in keratinocytes/fibroblasts and endothelial cells, respectively. Additionally, wound healing progression in rats was examined through macroscopic observation and histological analysis. Our results indicate that AE/LPPO promotes myofibroblast-like phenotypic changes and augments ECM deposition. Clinically relevant, the AE/LPPO did not disrupt TGF-β1 and VEGF-A signaling and accelerated wound closure in rats. Notably, while AE and LPPO individually exhibited antibacterial activity, their combination did not lead to synergism, rather decreasing antibacterial activity, warranting further examination. These findings underscore substantial wound healing improvement facilitated by AE/LPPO, requiring further exploration in animal models closer to human physiology.

This paper presents a robust and efficient method for validating the accuracy of orientation sensors commonly used in practical applications, leveraging measurements from a commercial robotic manipulator as a high-precision reference. The key concept lies in determining the rotational transformations between the robot’s base frame and the sensor’s reference, as well as between the TCP (Tool Center Point) frame and the sensor frame, without requiring precise alignment. Key advantages of the proposed method include its independence from the exact measurement of rotations between the reference instrumentation and the sensor, systematic testing capabilities, and the ability to produce repeatable excitation patterns under controlled conditions. This approach enables automated, high-precision, and comparative evaluation of various orientation sensing devices in a reproducible manner. Moreover, it facilitates efficient calibration and analysis of sensor errors, such as drift, noise, and response delays under various motion conditions. The method’s effectiveness is demonstrated through experimental validation of an Inertial Navigation System module and the SLAM-IMU fusion capabilities of the HTC VIVE VR headset, highlighting its versatility and reliability in addressing the challenges associated with orientation sensor validation.

Diabetic cardiomyopathy (DCM) is a severe secondary complication of type 2 diabetes mellitus (T2DM) that is diagnosed as a heart disease occurring in the absence of any previous cardiovascular pathology in diabetic patients. Although it is still lacking an exact definition as it combines aspects of both pathologies – T2DM and heart failure, more evidence comes forward that declares DCM as one complex disease that should be treated separately. It is the ambiguous pathological phenotype, symptoms or biomarkers that makes DCM hard to diagnose and screen for its early onset. This re-view provides an updated look on the novel advances in DCM diagnosis and treatment in the experimental and clinical settings. Management of patients with DCM proposes a challenge by itself and we aim to help navigate and advice clinicians with early screening and pharmacotherapy of DCM.

The contribution is devoted to the issue of hybrid threats in connection with the level of education achieved. Hybrid threats represent coordinated activities by which different interest groups try to influence people in other areas. The research subjects are the respondents divided according to their levels of education. Data for the research were collected through the questionnaire method. The study was based on predetermined hypotheses, subsequently verified by statistical tests. The research was conducted with 157 respondents. The research results reveal that the level of education impacts the knowledge of the concept of hybrid threats. The verified hypothesis confirms this conclusion, the result of which is at the level of value p = 0.0482. The second hypothesis proves the danger of hybrid threats and their relationship with achieved education, calculated at the level of p=0.0334. The research also focused on the area related to information sharing and its subsequent verification. The hypothesis, aimed at verifying information from multiple sources, did not confirm the differences between university-educated respondents and respondents with secondary education. The verified hypothesis represented the value level of p = 0.039. To eliminate hybrid threats, effective and efficient measures would be used to prevent the spread of negative impacts on society. In this context, the hypothesis was established for examining the differences between educational attainment and protection methods against hybrid threats. The result of the verified hypothesis at the level of p = 0.04 confirms the differences between the level of education. It shows that people with higher education consider an effective educational process to protect against misinformation, compared to people with secondary education who favour repressive measures and various forms of control by the government.

Abstract The climate effects of atmospheric aerosol particles serving as cloud condensation nuclei (CCN) depend on chemical composition and hygroscopicity, which are highly variable on spatial and temporal scales. Here we present global CCN measurements, covering diverse environments from pristine to highly polluted conditions. We show that the effective aerosol hygroscopicity, κ, can be derived accurately from the fine aerosol mass fractions of organic particulate matter (ϵ org) and inorganic ions (ϵ inorg) through a linear combination, κ = ϵ org ⋅ κ org + ϵ inorg ⋅ κ inorg. In spite of the chemical complexity of organic matter, its hygroscopicity is well captured and represented by a global average value of κ org = 0.12 ± 0.02 with κ inorg = 0.63 ± 0.01 as the corresponding value for inorganic ions. By showing that the sensitivity of global climate forcing to changes in κ org and κ inorg is small, we constrain a critically important aspect of global climate modelling.

Abstract N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ionotropic glutamate receptors that mediate a calcium-permeable component to fast excitatory neurotransmission. NMDARs are heterotetrameric assemblies of two obligate GluN1 subunits (GRIN1) and two GluN2 subunits (GRIN2A-GRIN2D). Sequencing data shows that 43% (297/679) of all currently known NMDAR disease-associated genetic variants are within the GRIN2A gene, which encodes the GluN2A subunit. Here, we show that unlike missense GRIN2A variants, individuals affected with disease-associated null GRIN2A variants demonstrate a transient period of seizure susceptibility that begins during infancy and diminishes near adolescence. We show increased circuit excitability and CA1 pyramidal cell output in juvenile mice of both Grin2a +/− and Grin2a −/− mice. These alterations in somatic spiking are not due to global upregulation of most Grin genes (including Grin2b). Deeper evaluation of the developing CA1 circuit led us to uncover age- and Grin2a gene dosing-dependent transient delays in the electrophysiological maturation programs of parvalbumin (PV) interneurons. We report that Grin2a +/+ mice reach PV cell electrophysiological maturation between the neonatal and juvenile neurodevelopmental timepoints, with Grin2a +/− mice not reaching PV cell electrophysiological maturation until preadolescence, and Grin2a −/− mice not reaching PV cell electrophysiological maturation until adulthood. Overall, these data may represent a molecular mechanism describing the transient nature of seizure susceptibility in disease-associated null GRIN2A patients.

Abstract No previous studies have investigated the systemic absorption of bupivacaine when used topically for posttonsillectomy pain. The present study was undertaken to investigate the pharmacokinetics of bupivacaine after administration by a swab in the tonsillar fossae over 4 min after tonsillectomy. Eleven adult patients undergoing elective tonsillectomy were recruited. After removal of both tonsils, each of the two tonsillar fossae was covered with a swab moistened with 2 mL of bupivacaine 5 mg/mL, that is, a total of 20 mg bupivacaine. Blood samples were drawn after 0, 5, 10, 20, 30, 45, and 60 min. Bupivacaine was analyzed with an ultra‐high‐performance liquid chromatography–tandem mass spectrometry method. The highest single measured bupivacaine serum concentration was 23.2 ng/mL and took place 10 min after drug administration. Mean (±SD) Cmax was 11.4 ± 6.0 ng/mL and mean tmax was 11.3 ± 4.7 min. Mean t1/2 was 31.6 ± 9.3 min. As the toxic concentration threshold has been reported to be in the interval 1500–4500 ng/mL, the concentrations measured were well below 2% of the lowest cited toxic threshold. In conclusion, this study shows that applying 4 mL of bupivacaine 5 mg/mL by a swab in the tonsillar fossae posttonsillectomy yields very low plasma concentrations, suggesting its safe application without any risk of systemic toxic effects.

Abstract Cancer medicines often have narrow therapeutic windows; toxicity can be severe and sometimes fatal, but inadequate dose intensity reduces efficacy and survival. Determining the optimal dose for each patient is difficult, with body‐surface area used most commonly for chemotherapy and flat dosing for tyrosine kinase inhibitors, despite accumulating evidence of a wide range of exposures in individual patients with many receiving a suboptimal dose with these strategies. Therapeutic drug monitoring (measuring the drug concentration in a biological fluid, usually plasma) (TDM) is an accepted and well validated method to guide dose adjustments for individual patients to improve this. However, implementing TDM in routine care has been difficult outside a research context. The development of genotyping of various proteins involved in drug elimination and activity has gained prominence, with several but not all Guideline groups recommending dose reductions for particular variant genotypes. However, there is increasing concern that dosing recommendations are based on limited data sets and may lead to unnecessary underdosing and increased cancer mortality. This Review discusses the evidence surrounding genotyping and TDM to guide decisions around best practice.

The world today is ceaselessly under the influence of changing conditions and threats. The contemporary digital age enables the provision of information that serves not only as common information but also as disinformation and hoaxes. This risk is high, specifically on social networks, dramatically impacting society. The paper's main objective is to point out the danger of misusing social networks to spread disinformation as a hybrid threat to influence people's thinking and behaviour, thus endangering democratic processes in developed democratic countries. The study, which focused on the risks of misusing social networks, was conducted using the questionnaire method and was subsequently assessed using statistical tests. The results indicate no link between age and the ability to distinguish desinformation, and that age does not influence the effects of disinformation. However, we did find the opposite result in terms of education, where people with lower education share hoaxes and disinformation more. Alternative media, whose posts are shared by more than 20% of social network users, have a relatively strong presence in our environment. The possibilities of spreading disinformation are also evident in the social impacts on users, who, according to our study, fear lowering their economic well-being. The study focuses on the effects of social networks on individuals' thinking and behaviour. Because we consider this issue insufficiently studied thus far, attention must also be paid to it in the future.

The paper's chief goal is to determine the impact of COVID-19 on consumer purchasing behaviour and purchasing decisions concerning selected factors affecting consumers when buying food products in chain stores. The research was conducted in V4 countries, and data were obtained from a questionnaire. Essential research methods, such as analysis, synthesis, comparison, induction and deduction, were used in the presented research. Selected basic methods of descriptive statistics, normality tests and correlation coefficients were also applied. After evaluating the results of the questionnaire and verifying the research hypotheses, the expected conclusion regarding the apparent impact of COVID-19 on consumer purchasing and decision-making was confirmed. The hypothesis focused on buying behaviour in relation to gender (p = 0.03665), and economic status (p = 0.0407) was confirmed, manifesting a statistically significant relationship between these factors. A statistically significant relationship between age and buying behaviour during the COVID-19 pandemic was not confirmed (p > 0.05). The research's benefit is identifying changes in buying behaviour and consumer decision-making during the COVID-19 pandemic, which is crucial information, especially for entrepreneurs who can thus adjust their business activities to the current customer needs.