Abstract Background Budget impact analyses (BIAs) are an essential part of a comprehensive economic assessment of a health care intervention and are increasingly required by reimbursement authorities ...as part of a listing or reimbursement submission. Objectives The objective of this report was to present updated guidance on methods for those undertaking such analyses or for those reviewing the results of such analyses. This update was needed, in part, because of developments in BIA methods as well as a growing interest, particularly in emerging markets, in matters related to affordability and population health impacts of health care interventions. Methods The Task Force was approved by the International Society for Pharmacoeconomics and Outcomes Research Health Sciences Policy Council and appointed by its Board of Directors. Members were experienced developers or users of BIAs; worked in academia and industry and as advisors to governments; and came from several countries in North America and South America, Oceania, Asia, and Europe. The Task Force solicited comments on the drafts from a core group of external reviewers and, more broadly, from the membership of the International Society for Pharmacoeconomics and Outcomes Research. Results The Task Force recommends that the design of a BIA for a new health care intervention should take into account relevant features of the health care system, possible access restrictions, the anticipated uptake of the new intervention, and the use and effects of the current and new interventions. The key elements of a BIA include estimating the size of the eligible population, the current mix of treatments and the expected mix after the introduction of the new intervention, the cost of the treatment mixes, and any changes expected in condition-related costs. Where possible, the BIA calculations should be performed by using a simple cost calculator approach because of its ease of use for budget holders. In instances, however, in which the changes in eligible population size, disease severity mix, or treatment patterns cannot be credibly captured by using the cost calculator approach, a cohort or patient-level condition-specific model may be used to estimate the budget impact of the new intervention, accounting appropriately for those entering and leaving the eligible population over time. In either case, the BIA should use data that reflect values specific to a particular decision maker’s population. Sensitivity analysis should be of alternative scenarios chosen from the perspective of the decision maker. The validation of the model should include at least face validity with decision makers and verification of the calculations. Data sources for the BIA should include published clinical trial estimates and comparator studies for the efficacy and safety of the current and new interventions as well as the decision maker’s own population for the other parameter estimates, where possible. Other data sources include the use of published data, well-recognized local or national statistical information, and, in special circumstances, expert opinion. Reporting of the BIA should provide detailed information about the input parameter values and calculations at a level of detail that would allow another modeler to replicate the analysis. The outcomes of the BIA should be presented in the format of interest to health care decision makers. In a computer program, options should be provided for different categories of costs to be included or excluded from the analysis. Conclusions We recommend a framework for the BIA, provide guidance on the acquisition and use of data, and offer a common reporting format that will promote standardization and transparency. Adherence to these good research practice principles would not necessarily supersede jurisdiction-specific BIA guidelines but may support and enhance local recommendations or serve as a starting point for payers wishing to promulgate methodology guidelines.
Abstract
Background
Advanced age is a well-known risk factor for poor prognosis in COVID-19. However, few studies have specifically focused on very old inpatients with COVID-19. This study aims to ...describe the clinical characteristics of very old inpatients with COVID-19 and identify risk factors for in-hospital mortality at admission.
Methods
We conducted a nationwide, multicenter, retrospective, observational study in patients ≥ 80 years hospitalized with COVID-19 in 150 Spanish hospitals (SEMI-COVID-19) Registry (March 1–May 29, 2020). The primary outcome was in-hospital mortality. A uni- and multivariate logistic regression was performed to assess predictors of mortality at admission.
Results
A total of 2772 consecutive patients (49.4% men, median age 86.3 years) were analyzed. Rates of atherosclerotic cardiovascular disease, diabetes mellitus, dementia, and Barthel Index < 60 were 30.8%, 25.6%, 30.5%, and 21.0%, respectively. The overall case-fatality rate was 46.9% (n: 1301) and increased with age (80–84 years: 41.6%; 85–90 years: 47.3%; 90–94 years: 52.7%; ≥95 years: 54.2%). After analysis, male sex and moderate-to-severe dependence were independently associated with in-hospital mortality; comorbidities were not predictive. At admission, independent risk factors for death were: oxygen saturation < 90%; temperature ≥ 37.8°C; quick sequential organ failure assessment (qSOFA) score ≥ 2; and unilateral–bilateral infiltrates on chest x-rays. Some analytical findings were independent risk factors for death, including estimated glomerular filtration rate < 45 mL/min/1.73 m2; lactate dehydrogenase ≥ 500 U/L; C-reactive protein ≥ 80 mg/L; neutrophils ≥ 7.5 × 103/μL; lymphocytes < 0.8 × 103/μL; and monocytes < 0.5 × 103/μL.
Conclusions
This first large, multicenter cohort of very old inpatients with COVID-19 shows that age, male sex, and poor preadmission functional status—not comorbidities—are independently associated with in-hospital mortality. Severe COVID-19 at admission is related to poor prognosis.
African swine fever (ASF) is a complex disease of swine, caused by a large DNA virus belonging to the family Asfarviridae. The disease shows variable clinical signs, with high case fatality rates, up ...to 100%, in the acute forms. ASF is currently present in Africa and Europe where it circulates in different scenarios causing a high socio-economic impact. In most affected regions, control has not been effective in part due to lack of a vaccine. The availability of an effective and safe ASFV vaccines would support and enforce control-eradication strategies. Therefore, work leading to the rational development of protective ASF vaccines is a high priority. Several factors have hindered vaccine development, including the complexity of the ASF virus particle and the large number of proteins encoded by its genome. Many of these virus proteins inhibit the host's immune system thus facilitating virus replication and persistence. We review previous work aimed at understanding ASFV-host interactions, including mechanisms of protective immunity, and approaches for vaccine development. These include live attenuated vaccines, and "subunit" vaccines, based on DNA, proteins, or virus vectors. In the shorter to medium term, live attenuated vaccines are the most promising and best positioned candidates. Gaps and future research directions are evaluated.
•Recent advances in coating techniques of alginate capsules are provided.•Ionic and covalent cross-linking between alginate and coating materials are highlighted.•Coating techniques to improve the ...mechanical and chemical stability of capsules are addressed.•Potential applications in cell encapsulation are discussed.
Cell encapsulation is used as a biotechnology tool to solve the technological problems derived from handling and application of cells in a great range of fields. This involves immobilization of the cells within a polymeric gel that permits the preservation of their metabolic activity. Alginate is widely established as the most suitable polymer for cell encapsulation. However, alginate gel capsules suffer several disadvantages because of their lack of mechanical and chemical stability. This review summarizes results of recent advances in coating techniques that include ionic and covalent cross-linking between alginate and coating materials for cell encapsulation as a strategy to solve the disadvantages mentioned before. Throughout this review, physicochemical properties of coated-alginate capsules and the effect of coating process on metabolic activity and viability of immobilized cells have been specially discussed.
The role of alternative splicing is one of the great unanswered questions in cellular biology. There is strong evidence for alternative splicing at the transcript level, and transcriptomics ...experiments show that many splice events are tissue specific. It has been suggested that alternative splicing evolved in order to remodel tissue-specific protein-protein networks. Here we investigated the evidence for tissue-specific splicing among splice isoforms detected in a large-scale proteomics analysis. Although the data supporting alternative splicing is limited at the protein level, clear patterns emerged among the small numbers of alternative splice events that we could detect in the proteomics data. More than a third of these splice events were tissue-specific and most were ancient: over 95% of splice events that were tissue-specific in both proteomics and RNAseq analyses evolved prior to the ancestors of lobe-finned fish, at least 400 million years ago. By way of contrast, three in four alternative exons in the human gene set arose in the primate lineage, so our results cannot be extrapolated to the whole genome. Tissue-specific alternative protein forms in the proteomics analysis were particularly abundant in nervous and muscle tissues and their genes had roles related to the cytoskeleton and either the structure of muscle fibres or cell-cell connections. Our results suggest that this conserved tissue-specific alternative splicing may have played a role in the development of the vertebrate brain and heart.
Interleukin 35 (IL-35) is a heterodimeric cytokine involved in the development of atherosclerosis. The aim of the present study was to establish if the polymorphisms of IL-12A and EBI3 genes that ...encode the IL-35 subunits are associated with the development of premature coronary artery disease (CAD) in Mexican individuals. The IL-12A and EBI3 polymorphisms were determined in 1162 patients with premature CAD and 873 controls. Under different models, the EBI3 rs428253 (OR = 0.831, P a d d = 0.036; OR = 0.614, P r e c = 0.033; OR = 0.591, P c o d 2 = 0.027) and IL-12A rs2243115 (OR = 0.674, P a d d = 0.010; OR = 0.676, P d o m = 0.014; OR = 0.698, P h e t = 0.027; OR = 0.694, P c o d 1 = 0.024) polymorphisms were associated with decreased risk of developing premature CAD. Some polymorphisms were associated with clinical and metabolic parameters. Significant different levels of IL-35 were observed in EBI3 rs4740 and rs4905 genotypes only in the group of healthy controls. In summary, our study suggests that the EBI3 and IL-12A polymorphisms play an important role in decreasing the risk of developing premature CAD; it also demonstrates the relationship of the EBI3 rs4740 and rs4905 genotypes with IL-35 levels in healthy individuals.
Amplification and diversification of transcriptional regulators that control development is a driving force of morphological evolution. A major source of protein diversity is alternative splicing, ...which leads to the generation of different isoforms from a single gene. The mechanisms and timing of intron evolution nonetheless remain unclear, and the functions of alternative splicing-generated protein isoforms are rarely studied. In Solanum tuberosum, the BRANCHED1a (BRC1a) gene encodes a TCP transcription factor that controls lateral shoot outgrowth. Here, we report the recent evolution in Solanum of an alternative splice site in BRC1a that leads to the generation of two BRC1a protein isoforms with distinct C-terminal regions, BRC1aLong and BRC1aShort, encoded by unspliced and spliced mRNA, respectively. The BRC1aLong C-terminal region has a strong activation domain, whereas that of BRC1aS lacks an activation domain and is predicted to form an amphipathic helix, the H domain, which prevents protein nuclear targeting. BRC1aShort is thus mainly cytoplasmic, while BRC1aLong is mainly nuclear. BRC1aLong functions as a transcriptional activator, whereas BRC1aShort appears to have no transcriptional activity. Moreover, BRC1aShort can heterodimerize with BRC1aLong and act as a dominant-negative factor; it increases BRC1aLong concentration in cytoplasm and reduces its transcriptional activity. This alternative splicing mechanism is regulated by hormones and external stimuli that control branching. The evolution of a new alternative splicing site and a novel protein domain in Solanum BRC1a led to a multi-level mechanism of post-transcriptional and post-translational BRC1a regulation that effectively modulates its branch suppressing activity in response to environmental and endogenous cues.
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•In the Solanum clade, an alternative splice site evolved in the BRC1a gene•Alternative splicing of potato BRC1a renders two proteins with antagonistic functions•BRC1aLong isoform is a transcription factor that prevents shoot and stolon branching•BRC1aShort isoform interacts with and limits BRC1aLong nuclear targeting
Nicolas et al. show that a splice site evolved in Solanum adds a novel regulatory level to BRC1a branching function. In potato, BRC1aL is a transcription factor that prevents shoot and stolon branching. In contrast, BRC1aS is cytoplasmic, does not have transcriptional activity, and sequesters BRC1aL to the cytoplasm to antagonize its activity.
Plasmid-mediated quinolone resistance: an update Rodríguez-Martínez, José Manuel; Velasco, Carmen; Pascual, Álvaro ...
Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy,
04/2011, Letnik:
17, Številka:
2
Journal Article
Recenzirano
Abstract In 1998, the first plasmid-mediated gene involved in quinolone resistance (currently named qnrA1 ) was reported. Extra qnr -like plasmid-mediated genes ( qnrB , qnrS , qnrC , qnrD ) and ...their chromosomal homologues have also been characterized. These genes code for a pentapeptide repeat protein that protects type II topoisomerases from quinolones. Since then, there have been reports of two other plasmid-mediated resistance mechanisms: the modification of quinolones with a piperazinyl substituent by the acetyltransferase, Aac(6′)-Ib-cr; and active efflux by QepA and OqxAB, pumps related to major facilitator superfamily (MFS) transporters. These genes have a wide geographic distribution (mainly in Enterobacteriaceae ). Because of the difficulties of phenotypic detection of this type of resistance, its real prevalence is only partially known. One important point is that although these mechanisms cause only low-level resistance, they favor and complement the selection of other resistance mechanisms.
Hydrocephalic hyh mutant mice undergo a programmed loss of the neuroepithelium/ependyma followed by a reaction of periventricular astrocytes, which form a new cell layer covering the denuded ...ventricular surface. We present a comparative morphological and functional study of the newly formed layer of astrocytes and the multiciliated ependyma of hyh mice. Transmission electron microscopy, immunocytochemistry for junction proteins (N-cadherin, connexin 43) and proteins involved in permeability (aquaporin 4) and endocytosis (caveolin-1, EEA1) were used. Horseradish peroxidase (HRP) and lanthanum nitrate were used to trace the intracellular and paracellular transport routes. The astrocyte layer shares several cytological features with the normal multiciliated ependyma, such as numerous microvilli projected into the ventricle, extensive cell–cell interdigitations and connexin 43-based gap junctions, suggesting that these astrocytes are coupled to play an unknown function as a cell layer. The ependyma and the astrocyte layers also share transport properties: (1) high expression of aquaporin 4, caveolin-1 and the endosome marker EEA1; (2) internalization into endocytic vesicles and early endosomes of HRP injected into the ventricle; (3) and a similar paracellular route of molecules moving between CSF, the subependymal neuropile and the pericapillary space, as shown by lanthanum nitrate and HRP. A parallel analysis performed in human hydrocephalic foetuses indicated that a similar phenomenon would occur in humans. We suggest that in foetal-onset hydrocephalus, the astrocyte assembly at the denuded ventricular walls functions as a CSF–brain barrier involved in water and solute transport, thus contributing to re-establish lost functions at the brain parenchyma–CSF interphase.
Abstract
Seventeen years after the sequencing of the human genome, the human proteome is still under revision. One in eight of the 22 210 coding genes listed by the Ensembl/GENCODE, RefSeq and ...UniProtKB reference databases are annotated differently across the three sets. We have carried out an in-depth investigation on the 2764 genes classified as coding by one or more sets of manual curators and not coding by others. Data from large-scale genetic variation analyses suggests that most are not under protein-like purifying selection and so are unlikely to code for functional proteins. A further 1470 genes annotated as coding in all three reference sets have characteristics that are typical of non-coding genes or pseudogenes. These potential non-coding genes also appear to be undergoing neutral evolution and have considerably less supporting transcript and protein evidence than other coding genes. We believe that the three reference databases currently overestimate the number of human coding genes by at least 2000, complicating and adding noise to large-scale biomedical experiments. Determining which potential non-coding genes do not code for proteins is a difficult but vitally important task since the human reference proteome is a fundamental pillar of most basic research and supports almost all large-scale biomedical projects.
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