Inhibitors are antibodies directed against haemophilia treatment products which interfere with their function. Factor VIII (FVIII) inhibitors in haemophilia A and factor IX (FIX) inhibitors in ...haemophilia B are significant clinically when they require a change in a patient's treatment regimen. Their persistence may increase morbidity and mortality. Multiple laboratory tests are now available for detecting and understanding inhibitors in haemophilia. Inhibitors are traditionally measured by their interference in clotting or chromogenic factor assays. They may also be detected using immunologic assays, such as enzyme‐linked immunosorbent assay or fluorescence immunoassay. Anti‐FVIII or anti‐FIX antibodies of IgG4 subclass best correlate with the presence of functional inhibitors. Improvements in inhibitor measurement have been recently introduced. Preanalytical heat treatment of patient specimens allows testing of patients without delaying treatment. Use of chromogenic and immunologic assays may aid in identification of false‐positive results, which are frequent among low‐titre inhibitors. Validated reagent substitutions can be used to reduce assay cost. New methods for defining assay positivity and reporting low‐titre inhibitors have been suggested. Challenges remain in the areas of quality control, assay standardization, monitoring of patients undergoing immune tolerance induction therapy and testing in the presence of modified and novel treatment products.
The interventions and outcomes in the ongoing COVID-19 pandemic are highly varied. The disease and the interventions both impose costs and harm on society. Some interventions with particularly high ...costs may only be implemented briefly. The design of optimal policy requires consideration of many intervention scenarios. In this paper we investigate the optimal timing of interventions that are not sustainable for a long period. Specifically, we look at at the impact of a single short-term non-repeated intervention (a "one-shot intervention") on an epidemic and consider the impact of the intervention's timing. To minimize the total number infected, the intervention should start close to the peak so that there is minimal rebound once the intervention is stopped. To minimise the peak prevalence, it should start earlier, leading to initial reduction and then having a rebound to the same prevalence as the pre-intervention peak rather than one very large peak. To delay infections as much as possible (as might be appropriate if we expect improved interventions or treatments to be developed), earlier interventions have clear benefit. In populations with distinct subgroups, synchronized interventions are less effective than targeting the interventions in each subcommunity separately.
Chemokines from a Structural Perspective Miller, Michelle C; Mayo, Kevin H
International journal of molecular sciences,
10/2017, Volume:
18, Issue:
10
Journal Article
Peer reviewed
Open access
Chemokines are a family of small, highly conserved cytokines that mediate various biological processes, including chemotaxis, hematopoiesis, and angiogenesis, and that function by interacting with ...cell surface G-Protein Coupled Receptors (GPCRs). Because of their significant involvement in various biological functions and pathologies, chemokines and their receptors have been the focus of therapeutic discovery for clinical intervention. There are several sub-families of chemokines (e.g., CXC, CC, C, and CX3C) defined by the positions of sequentially conserved cysteine residues. Even though all chemokines also have a highly conserved, three-stranded β-sheet/α-helix tertiary structural fold, their quarternary structures vary significantly with their sub-family. Moreover, their conserved tertiary structures allow for subunit swapping within and between sub-family members, thus promoting the concept of a "chemokine interactome". This review is focused on structural aspects of CXC and CC chemokines, their functional synergy and ability to form heterodimers within the chemokine interactome, and some recent developments in structure-based chemokine-targeted drug discovery.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of the Coronavirus Disease 2019 (COVID-19) disease, has moved rapidly around the globe, infecting millions and ...killing hundreds of thousands. The basic reproduction number, which has been widely used-appropriately and less appropriately-to characterize the transmissibility of the virus, hides the fact that transmission is stochastic, often dominated by a small number of individuals, and heavily influenced by superspreading events (SSEs). The distinct transmission features of SARS-CoV-2, e.g., high stochasticity under low prevalence (as compared to other pathogens, such as influenza), and the central role played by SSEs on transmission dynamics cannot be overlooked. Many explosive SSEs have occurred in indoor settings, stoking the pandemic and shaping its spread, such as long-term care facilities, prisons, meat-packing plants, produce processing facilities, fish factories, cruise ships, family gatherings, parties, and nightclubs. These SSEs demonstrate the urgent need to understand routes of transmission, while posing an opportunity to effectively contain outbreaks with targeted interventions to eliminate SSEs. Here, we describe the different types of SSEs, how they influence transmission, empirical evidence for their role in the COVID-19 pandemic, and give recommendations for control of SARS-CoV-2.
Reliable tables of glycemic indexes (GIs) and glycemic loads (GLs) are critical to research examining the relationship between glycemic qualities of carbohydrate in foods, diets, and health. In the ...12 years since the last edition of the tables, a large amount of new data has become available.
To systematically review and tabulate published and unpublished sources of reliable GI values, including an assessment of the reliability of the data.
This edition of the tables lists over 4000 items, a 61% increase in the number of entries compared to the 2008 edition. The data have been separated into 2 lists. The first represents more precise values derived using the methodology recommended by the International Standards Organization (∼2100 items). The second list contains values determined using less robust methods, including using limited numbers of healthy subjects or with a large SEM (∼1900 food items).
Dairy products, legumes, pasta, and fruits were usually low-GI foods (≤55 on the 100-point glucose scale) and had consistent values around the world. Cereals and cereal products, however, including whole-grain or whole-meal versions, showed wide variation in GI values, presumably arising from variations in manufacturing methods. Breads, breakfast cereals, rice, savory snack products, and regional foods were available in high-, medium-, and low-GI versions. Most varieties of potato were high-GI foods, but specific low-GI varieties have now been identified.
The availability of new data on the GIs of foods will facilitate wider research and application of the twin concepts of GI and GL. Although the 2021 edition of the tables improves the quality and quantity of GI data available for research and clinical practice, GI testing of regional foods remains a priority. This systematic review was registered in PROSPERO as #171204.
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Widely regarded as an imminent threat to our oceans, ocean acidification has been documented in all oceanic basins. Projected changes in seawater chemistry will have catastrophic biotic effects due ...to ocean acidification hindering biogenic carbonate production, which will in turn lead to substantial changes in marine ecosystems. However, previous attempts to quantify the effect of acidification on planktonic calcifying organisms has relied on laboratory based studies with substantial methodological limitations. This has been overcome by comparing historic plankton tows from the seminal HMS Challenger Expedition (1872-1876) with the recent Tara Oceans expedition material (2009-2016). Nano CT-scans of selected equatorial Pacific Ocean planktonic foraminifera, have revealed that all modern specimens had up to 76% thinner shells than their historic counterparts. The "Challenger Revisited" project highlights the potential of historic ocean collections as a tool to investigate ocean acidification since the early Industrial Revolution. Further analyses of such biotic archives will enable researchers to quantify the effects of anthropogenic climate change across the globe.
In the dog, primary intracranial neoplasia represents ~2–5% of all cancers and is especially common in certain breeds including English and French bulldogs and Boxers. The most common types of ...primary intracranial cancer in the dog are meningioma, glioma, and choroid plexus tumors, generally occurring in middle aged to older dogs. Much work has recently been done to understand the characteristic imaging and clinicopathologic features of these tumors. The gross and histologic landscape of these tumors in the dog compare favorably to their human counterparts with many similarities noted in histologic patterns, subtype, and grades. Data informing the underlying molecular abnormalities in the canine tumors have only begun to be unraveled, but reveal similar pathways are mutated between canine and human primary intracranial neoplasia. This review will provide an overview of the clinicopathologic features of the three most common forms of primary intracranial cancer in the dog, delve into the comparative aspects between the dog and human neoplasms, and provide an introduction to current standard of care while also highlighting novel, experimental treatments that may help bridge the gap between canine and human cancer therapies.
The phenomenon of RNAi, in which the introduction of dsRNA into a cell triggers the destruction of the corresponding mRNA resulting in a gene silencing effect, is conserved across a wide array of ...plant and animal phyla. However, the mechanism by which the dsRNA enters a cell, allowing the RNAi effect to occur throughout a multicellular organism (systemic RNAi), has only been studied extensively in certain plants and the nematode Caenorhabditis elegans. In recent years, RNAi has become a popular reverse genetic technique for gene silencing in many organisms. Although many RNAi techniques in non-traditional model organisms rely on the systemic nature of RNAi, little has been done to analyze the parameters required to obtain a robust systemic RNAi response. The data provided here show that the concentration and length of dsRNA have profound effects on the efficacy of the RNAi response both in regard to initial efficiency and duration of the effect in Tribolium castaneum. In addition, our analyses using a series of short dsRNAs and chimeric dsRNA provide evidence that dsRNA cellular uptake (and not the RNAi response itself) is the major step affected by dsRNA size in Tribolium. We also demonstrate that competitive inhibition of dsRNA can occur when multiple dsRNAs are injected together, influencing the effectiveness of RNAi. These data provide specific information essential to the design and implementation of RNAi based studies, and may provide insight into the molecular basis of the systemic RNAi response in insects.
The Impact of Sex and Gender on Stroke Rexrode, Kathryn M; Madsen, Tracy E; Yu, Amy Y X ...
Circulation research,
02/2022, Volume:
130, Issue:
4
Journal Article
Peer reviewed
Open access
Women face a disproportionate burden of stroke mortality and disability. Biologic sex and sociocultural gender both contribute to differences in stroke risk factors, assessment, treatment, and ...outcomes. There are substantial differences in the strength of association of stroke risk factors, as well as female-specific risk factors. Moreover, there are differences in presentation, response to treatment, and stroke outcomes in women. This review outlines current knowledge of impact of sex and gender on stroke, as well as delineates research gaps and areas for future inquiry.
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