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Background: By March, 2023, 54 countries, areas, and territories (hereafter CAT) in the WHO European Region had reported more than 2·2 million COVID-19-related deaths to the WHO Regional Office for Europe. Here, we estimated how many lives were directly saved by vaccinating adults in the WHO European Region from December, 2020, to March, 2023., Methods: In this retrospective surveillance study, we estimated the number of lives directly saved by age group, vaccine dose, and circulating variant-of-concern (VOC) period, regionally and nationally, using weekly data on COVID-19 mortality and infection, COVID-19 vaccination uptake, and SARS-CoV-2 virus characterisations by lineage downloaded from The European Surveillance System on June 11, 2023, as well as vaccine effectiveness data from the literature. We included data for six age groups (25-49 years, 50-59 years, ≥60 years, 60-69 years, 70-79 years, and ≥80 years). To be included in the analysis, CAT needed to have reported both COVID-19 vaccination and mortality data for at least one of the four older age groups. Only CAT that reported weekly data for both COVID-19 vaccination and mortality by age group for 90% of study weeks or more in the full study period were included. We calculated the percentage reduction in the number of expected and reported deaths., Findings: Between December, 2020, and March, 2023, in 34 of 54 CAT included in the analysis, COVID-19 vaccines reduced deaths by 59% overall (CAT range 17-82%), representing approximately 1·6 million lives saved (range 1·5-1·7 million) in those aged 25 years or older: 96% of lives saved were aged 60 years or older and 52% were aged 80 years or older; first boosters saved 51% of lives, and 60% were saved during the Omicron period., Interpretation: Over nearly 2·5 years, most lives saved by COVID-19 vaccination were in older adults by first booster dose and during the Omicron period, reinforcing the importance of up-to-date vaccination among the most at-risk individuals. Further modelling work should evaluate indirect effects of vaccination and public health and social measures., Funding: US Centers for Disease Control and Prevention., Competing Interests: Declaration of interests GD reports that the predecessor of the organisation he works for, Public Health England, received an unrestricted grant from GSK to undertake a study on the outcome of patients who received parenteral zanamavir. The funder received data and interim reports from Public Health England but did not influence analysis and reporting of the study. GD had no involvement in the GSK-funded study on parenteral zanamavir. Furthermore, the currently submitted work was part of the public health response activities to COVID-19 and had no relationship to GSK or the study on parenteral zanamivir. EP has received a personal grant from the Finnish Medical Foundation for PhD studies. JM declares that Public Health Scotland received funding from the EU Horizon 2020 programme for work in describing the epidemiology of COVID-19 and its impact on primary and secondary care as a partner in the IMOVE-COVID-19 project. MK declares having received consulting fees from Gilead Sciences for advising on development of a clinical module for collection of patient-reported outcome data from people living with HIV, and having received an honoraria from GESIDA for speaking at an annual conference on patient-reported outcome measures for people with HIV. All other authors declare no competing interests., (Copyright © 2024 World Health Organization. Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Human tyrosine hydroxylase (hTH) has key role in the production of catecholamine neurotransmitters. The structure, function and regulation of hTH has been extensively researched area and the possibility of enzyme replacement therapy (ERT) involving hTH through nanocarriers has been raised as well. However, our understanding on how hTH may interact with nanocarriers is still lacking. In this work, we attempted to investigate the immobilization of hTH on magnetic nanoparticles (MNPs) with various surface linkers in quantitative and mechanistic detail. Our results showed that the activity of hTH was retained after immobilization via secondary and covalent interactions as well. The colloidal stability of hTH could be also enhanced proved by Dynamic light scattering and Zeta potential analysis and a homogenous enzyme layer could be achieved, which was investigated by Raman mapping. The covalent attachment of hTH on MNPs via aldehyde or epoxy linkers provide irreversible immobilization and 38.1 % and 16.5 % recovery (ER). The hTH-MNPs catalyst had 25 % ER in average in simulated nasal electrolyte solution (SNES). This outcome highlights the relevance of immobilization applying MNPs as a potential formulation tool of sensitive therapeutic enzymes offering new opportunities for ERT related to neurodegenerative disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Wetlands are fragile, dynamic systems, transient at larger temporal scales and strongly affected by long-term human activities. Sustaining at least some aspects of human management, particularly traditional grazing, would be especially important as a way of maintaining the "necessary" disturbances for many endangered species. Traditional ecological knowledge represents an important source of information for erstwhile management practices. Our objective was to review historical traditional knowledge on wetland grazing and the resulting vegetation response in order to assess their relevance to biodiversity conservation. We studied the Pannonian biogeographic region and its neighborhood in Central Europe and searched ethnographic, local historical, early botanical, and agrarian sources for historical traditional knowledge in online databases and books. The findings were analyzed and interpreted by scientist, nature conservationist and traditional knowledge holder (herder) co-authors alike. Among the historical sources reviewed, we found 420 records on traditional wetland grazing, mainly from the period 1720-1970. Data showed that wetlands in the region served as basic grazing areas, particularly for cattle and pigs. We found more than 500 mentions of habitat categories and 383 mentions of plants consumed by livestock. The most important reasons for keeping livestock on wetlands were grazing, stock wintering, and surviving forage gap periods in early spring or mid-late summer. Besides grazing, other commonly mentioned effects on vegetation were trampling and uprooting. The important outcomes were vegetation becoming patchy and remaining low in height, tall-growing dominant species being suppressed, litter being removed, and microhabitats being created, such as open surfaces of mud and water. These historical sources lay firm foundations for developing innovative nature conservation management methods. Traditional herders still holding wetland management knowledge could contribute to this process when done in a participatory way, fostering knowledge co-production., (Copyright © 2019. Published by Elsevier B.V.)

The principal task of acute critical care is to avoid or correct oxygen debt by increasing oxygen delivery (DO2) and/or decreasing oxygen consumption (VO2). The most commonly used methods to assess the relationship of adequate delivery and consumption are mixed venous oxygen saturation and its surrogate, central venous oxygen saturation (ScvO2). The purpose of this article is to review the values and limitations of the two parameters and evaluate the clinical use of ScvO2 in certain clinical scenarios, such as anaemia and transfusion, hypovolaemia, major surgery, septic shock, and in difficult-to-wean patients., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Infertile men with low sperm concentration and/or less motile spermatozoa have an increased risk of producing aneuploid spermatozoa. Selecting spermatozoa by hyaluronic acid (HA) binding may reduce genetic risks such as chromosomal rearrangements and numerical aberrations. Fluorescence in-situ hybridization (FISH) has been used to evaluate the presence of aneuploidies. This study examined spermatozoa of 10 oligozoospermic, 9 asthenozoospermic, 9 oligoasthenozoospermic and 17 normozoospermic men by HA binding and FISH. Mean percentage of HA-bound spermatozoa in the normozoospermic group was 81%, which was significantly higher than in the oligozoospermic (P<0.001), asthenozoospermic (P<0.001) and oligoasthenozoospermic (P<0.001) groups. Disomy of sex chromosomes (P=0.014) and chromosome 17 (P=0.0019), diploidy (P=0.03) and estimated numerical chromosome aberrations (P=0.004) were significantly higher in the oligoasthenozoospermic group compared with the other groups. There were statistically significant relationships (P<0.001) between sperm concentration and HA binding (r=0.658), between sperm concentration and estimated numerical chromosome aberrations (r=-0.668) and between HA binding and estimated numerical chromosome aberrations (r=-0.682). HA binding and aneuploidy studies of spermatozoa in individual cases allow prediction of reproductive prognosis and provision of appropriate genetic counselling. Infertile men with normal karyotypes and low sperm concentrations and/or less motile spermatozoa have significantly increased risks of producing aneuploid (diminished mature) spermatozoa. Selecting spermatozoa by hyaluronic acid (HA) binding, based on a binding between sperm receptors for zona pellucida and HA, may reduce the potential genetic risks such as chromosomal rearrangements and numerical aberrations. In the present study we examined sperm samples of 45 men with different sperm parameters by HA-binding assay and fluorescence in-situ hybridization (FISH). Mean percentage of HA-bound spermatozoa in the normozoospermic group was significantly higher than the oligozoospermic, the asthenozoospermic and the oligoasthenozoospermic groups. Using FISH, disomy of sex chromosomes and chromosome 17, diploidy and estimated numerical chromosome aberration frequencies were significantly higher in the oligoasthenozoospermic group compared with the three other groups. A significant positive correlation was found between the sperm concentration and the HA-binding capacity, and significant negative correlations between the sperm concentration and the estimated numerical chromosomes aberrations as well as between the HA-binding ability and the estimated numerical chromosome aberrations were identified. We conclude that HA-binding assay and sperm aneuploidy study using FISH may help to predict the reproductive ability of selected infertile male patients and to provide appropriate genetic counselling., (Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.)

Rodents and primates both show considerable variation in the overall size, the radial and tangential dimensions, folding and subdivisions into distinct areas of their cerebral cortex. Our current understanding of brain development is based on a handful of model systems. A detailed comparative analysis of the cellular and molecular mechanisms that regulate neural progenitor production, cell migration, and circuit assembly can provide much needed insights into the working of neocortical evolution. From the limited comparative data currently available, it is apparent that the emergence and variation of the neuronal progenitor cells have led to the production of increased neuronal populations and the evolution of the cortex. Further diversification and compartmentalization of the germinal zone together with changing proportions of radial glia in the ventricular zone and various intermediate progenitors in the subventricular zone may have been the driving force behind increased cell numbers in larger brains both in rodents and primates. Radial and tangential migratory patterns are both present in rodents and primates, but in different proportions. There are apparent differences between mouse and human in the generation and elaboration of the interneuronal subtypes and also in gene expression patterns associated with the appearance of distinct cortical areas. The increased cortical dimensions and the formation of a more elaborate cortical architecture in primates require a larger and more compartmentalized transient subplate zone during development. More comparative analysis in rodent and primate species with large, small, and smooth and folded brains is needed to reveal the biological significance of the alterations in these cortical developmental programs., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The effects of orexin-monoaminergic compound interactions on vasopressin release were studied in 14-day neurohypophyseal cell cultures from adult rats, prepared by an enzymatic dissociation technique. The vasopressin contents of the supernatants were determined by radioimmunoassay. Following administration of either orexin-A or orexin-B in increasing doses, significant changes were not observed in the vasopressin levels of the supernatant media. The vasopressin level substantially increased after epinephrine, norepinephrine, serotonin, histamine, dopamine or K(+) treatment. Preincubation with either orexin-A or orexin-B reduced the epinephrine-, histamine- or serotonin-induced increases in vasopressin level, but the vasopressin concentrations of the supernatant media remained above the control level. There was no significant difference in decreasing effect between orexin-A and orexin-B. Neither orexin-A nor orexin-B induced changes in vasopressin release following monoaminergic compound treatment. The results indicate that the changes in vasopressin secretion induced by the monoaminergic system can be directly influenced by orexin system. It may be presumed that the orexins can play a physiological role in the regulation of the water metabolism by reducing the effect of increased vasopressin release caused by monoaminergic compounds. The interactions between the monoaminergic and orexin systems regarding vasopressin secretion occur at both the hypothalamic and the neurohypophyseal level., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The nature of cerebral cortical circuitry has been increasingly clarified by markers for the identification of precise cell types with specific morphology, connectivity and distinct physiological properties. Molecular markers are not only helpful in dissecting cortical circuitry, but also give insight into the mechanisms of cortical neuronal specification and differentiation. The two principal neuronal types of the cerebral cortex are the pyramidal and GABAergic cells. Pyramidal cells are excitatory and project to distant targets, while GABAergic neurons are mostly inhibitory non-pyramidal interneurons. Reliable markers for specific subtypes of interneurons are available and have been employed in the classification and functional analysis of cortical circuitry. Until recently, cortical pyramidal neurons have been considered a homogeneous class of cells. This concept is now changing as the powerful tools of molecular biology and genetics identify molecular tags for subtypes of pyramidal cells such as: Otx-1 [Frantz, G.D., Bohner, A.P., Akers, R.M., McConnell, S.K., 1994. Regulation of the POU domain gene SCIP during cerebral cortical development. J. Neurosci. 14, 472-485; Weimann, J.M., Zhang, Y.A., Levin, M.E., Devine, W.P., Brulet, P., McConnell, S.K., 1999. Cortical neurons require Otx1 for the refinement of exuberant axonal projections to subcortical targets. Neuron 24, 819-831]; SMI-32, N200 and FNP-7 [Voelker, C.C., Garin, N., Taylor, J.S., Gahwiler, B.H., Hornung, J.P., Molnár, Z., 2004. Selective neurofilament (SMI-32, FNP-7 and N200) expression in subpopulations of layer V pyramidal neurons in vivo and in vitro. Cereb. Cortex 14, 1276-1286]; ER81 [Hevner, R.F., Daza, R.A., Rubenstein, J.L., Stunnenberg, H., Olavarria, J.F., Englund, C., 2003. Beyond laminar fate: toward a molecular classification of cortical projection/pyramidal neurons. Dev. Neurosci. 25 (2-4), 139-151; Yoneshima, H., Yamasaki, S., Voelker, C., Molnár, Z., Christophe, E., Audinat, E., Takemoto, M., Tsuji, S., Fujita, I., Yamamoto, N., 2006. ER81 is expressed in a subpopulation of layer 5 projection neurons in rodent cerebral cortices. Neuroscience, 137, 401-412]; Lmo4 [Bulchand, S., Subramanian, L., Tole, S., 2003. Dynamic spatiotemporal expression of LIM genes and cofactors in the embryonic and postnatal cerebral cortex. Dev. Dyn. 226, 460-469; Arlotta, P., Molyneaux, B.J., Chen, J., Inoue, J., Kominami, R., Macklis, J.D., 2005. Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. Neuron 45 (2), 207-221]; CTIP2 [Arlotta, P., Molyneaux, B.J., Chen, J., Inoue, J., Kominami, R., Macklis, J.D., 2005. Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. Neuron 45 (2), 207-221]; Fez1 [Molyneaux, B.J., Arlotta, P., Hirata, T., Hibi, M., Macklis, J.D., 2005. Fez1 is required for the birth and specification of corticospinal motor neurons. Neuron 47 (6), 817-831; Chen, B., Schaevitz, L.R., McConnell, S.K., 2005. Fez1 regulates the differentiation and axon targeting of layer 5 subcortical projection neurons in cerebral cortex. Proc. Natl. Acad. Sci. U.S.A. 102 (47), 17184-17189]. These genes outline the numerous subtypes of pyramidal cells and are increasingly refining our previous classifications. They also indicate specific developmental programs operate in cell fate decisions. This review will describe the progress made on the correlation of these markers to each other within a specific subtype of layer V neurons with identified, stereotypic projections. Further work is needed to link these data with observations on somatodendritic morphology and physiological properties. The integrated molecular, anatomical and physiological characterisation of pyramidal neurons will lead to a much better appreciation of functional cortical circuits.

Recombinant human-activated protein C (rhAPC) has been suggested to treat sepsis. We present the case of a 19-year-old pregnant patient at the 18th week of gestation with septic shock syndrome that originated from urinary tract infection and was successfully treated with rhAPC.

The deep layers of the mammalian cerebral cortex contain pyramidal neurons that project predominantly to subcortical targets. To understand the mechanisms that determine the identity of deeper layer neurons, a PCR based subtractive hybridisation was performed to isolate genes that are specifically expressed during the specification of these neurons. One of the genes we isolated was the rat homologue of the mouse Slap-1. SLAP-1 is an adaptor protein containing SH2-SH3 domains and it participates in the signalling of Receptor Tyrosine Kinases. In situ hybridisation studies have shown that Slap-1 is not substantially expressed before E17. At later stages, it is specifically and selectively expressed by deeper layer neurons and by neurons of layers II/III in the developing cortex. The specific timing and location of its expression, suggests that this gene may play a role in the differentiation of these neurons.

Embryology is the interface of genetic inheritance and phenotypic expression in adult forms, and as such is uniquely positioned to illuminate both. Embryonic cell migration pattern, transient connectivity, axonal growth kinetics and fasciculation patterns can clearly be substantially impacted at the striatocortical junction, which appears to be critical for telencephalic development. Similarly, the big questions concerning pallial evolution in amniotes all involve the pivotal region at the pallial-subpallial boundary, an area where complex developmental cross-currents may be involved in the specification of multiple structures that are thus related to each other. We review some of the positions based on recent genetic data and/or hodology, then suggest that comparative studies of intervening, embryological events may resolve some of the apparent conflicts and illuminate the evolutionary scenario. We propose a new hypothesis, the collopallial field hypothesis, which specifies that the anterior dorsal ventricular ridge of sauropsids and a set of structures in mammals--the lateral neocortex, basolateral amygdalar complex, and claustrum-endopiriform nucleus formation--are homologous to each other as derivatives of a common embryonic field. We propose that in mammals the laterally lying collopallium splits, or differentiates, into deep (claustroamygdalar) and superficial (neocortical) components, whereas in sauropsids, this split does not occur.