Over the last 5 years, national policy has encouraged general practices to serve populations of >30 000 people (called 'working at scale') by collaborating with other practices.
To describe the ...number of English general practices working at scale, and their patient populations.
Observational study of general practices in England.
Data published by the NHS on practices' self-reports of working in groups were supplemented with data from reports by various organisations and practice group websites. Practices were categorised by the extent to which they were working at scale; within these categories, the age distribution of the practice population, level of socioeconomic deprivation, rurality, and prevalence of longstanding illness were then examined.
Approximately 55% of English practices (serving 33.5 million patients) were working at scale, individually or collectively serving populations of >30 000 people. Organisational models representing close collaboration for the purposes of core general practice services were identifiable for approximately 5% of practices; these comprised large practices, superpartnerships, and multisite organisations. Approximately 50% of practices were working in looser forms of collaboration, focusing on services beyond core general practice; for example, primary care in the evenings and at weekends. Data on organisational models and the purpose of the collaboration were very limited for this group.
In early 2018, approximately 5% of general practices were working closely at scale; approximately half of practices were working more loosely at scale. However, data were incomplete. Better records of what is happening at practice level should be collected so that the effect of working at scale on patient care can be evaluated.
Scholars from many different intellectual disciplines have attempted to measure, estimate, or quantify resilience. However, there is growing concern that lack of clarity on the operationalization of ...the concept will limit its application. In this paper, we discuss the theory, research development and quantitative approaches in ecological and community resilience. Upon noting the lack of methods that quantify the complexities of the linked human and natural aspects of community resilience, we identify several promising approaches within the ecological resilience tradition that may be useful in filling these gaps. Further, we discuss the challenges for consolidating these approaches into a more integrated perspective for managing social-ecological systems.
•Resilience is a key strategy for assessing and managing emerging global challenges.•Developing approaches for quantifying community resilience is of great importance.•Research on resilience should account for scale and cross-scale interactions.•We suggest approaches for quantitative assessments of community resilience.
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Salivary pellicles i.e., thin films formed upon selective adsorption of saliva, protect oral surfaces against chemical and mechanical insults. Pellicles are also excellent aqueous ...lubricants. It is generally accepted that reconstituted pellicles have a two-layer structure, where the outer layer is mainly composed of MUC5B mucins. We hypothesized that by comparing the effect of ionic strength on reconstituted pellicles and MUC5B films we could gain further insight into the pellicle structure.
Salivary pellicles and MUC5B films reconstituted on solid surfaces were investigated at different ionic strengths by Force Spectroscopy, Quartz Crystal Microbalance with Dissipation, Null Ellipsometry and Neutron Reflectometry.
Our results support the two-layer structure for reconstituted salivary pellicles. The outer layer swelled when ionic strength decreased, indicating a weak polyelectrolyte behavior. While initially the MUC5B films exhibited a similar tendency, this was followed by a drastic collapse indicating an interaction between exposed hydrophobic domains. This suggests that mucins in the pellicle outer layer form complexes with other salivary components that prevent this interaction. Lowering ionic strength below physiological values also led to a partial removal of the pellicle inner layer. Overall, our results highlight the importance that the interactions of mucins with other pellicle components play on their structure.
Abstract
Background
Respiratory syncytial virus (RSV) infection is the primary cause of lower respiratory tract infections in children <5 years of age. Monocytes, especially in the respiratory tract, ...are suggested to contribute to RSV pathology, but their role is incompletely understood. With transcriptomic profiling of blood and airway monocytes, we describe the role of monocytes in severe RSV infection.
Methods
Tracheobronchial aspirates and blood samples were collected from control patients (n = 9) and those infected with RSV (n = 14) who were admitted to the pediatric intensive care unit. Monocytes (CD14+) were sorted and analyzed by RNA sequencing for transcriptomic profiling.
Results
Peripheral blood and airway monocytes of patients with RSV demonstrated increased expression of antiviral and interferon-responsive genes as compared with controls. Cytokine signaling showed a shared response between blood and airway monocytes while displaying responses that were more pronounced according to the tissue of origin. Airway monocytes upregulated additional genes related to migration and inflammation.
Conclusions
We found that the RSV-induced interferon response extends from the airways to the peripheral blood. Moreover, RSV induces a migration-promoting transcriptional program in monocytes. Unraveling the monocytic response and its role in the immune response to RSV infection could help the development of therapeutics to prevent severe disease.
Dermatomyositis has been modeled as an autoimmune disease largely mediated by the adaptive immune system, including a local humorally mediated response with B and T helper cell muscle infiltration, ...antibody and complement‐mediated injury of capillaries, and perifascicular atrophy of muscle fibers caused by ischemia. To further understand the pathophysiology of dermatomyositis, we used microarrays, computational methods, immunohistochemistry and electron microscopy to study muscle specimens from 67 patients, 54 with inflammatory myopathies, 14 with dermatomyositis. In dermatomyositis, genes induced by interferon‐α/β were highly overexpressed, and immunohistochemistry for the interferon‐α/β inducible protein MxA showed dense staining of perifascicular, and, sometimes all myofibers in 8/14 patients and on capillaries in 13/14 patients. Of 36 patients with other inflammatory myopathies, 1 patient had faint MxA staining of myofibers and 3 of capillaries. Plasmacytoid dendritic cells, potent CD4+ cellular sources of interferon‐α, are present in substantial numbers in dermatomyositis and may account for most of the cells previously identified as T helper cells. In addition to an adaptive immune response, an innate immune response characterized by plasmacytoid dendritic cell infiltration and interferon‐α/β inducible gene and protein expression may be an important part of the pathogenesis of dermatomyositis, as it appears to be in systemic lupus erythematosus. Ann Neurol 2005;57:664–678
Over a quarter of drugs that enter clinical development fail because they are ineffective. Growing insight into genes that influence human disease may affect how drug targets and indications are ...selected. However, there is little guidance about how much weight should be given to genetic evidence in making these key decisions. To answer this question, we investigated how well the current archive of genetic evidence predicts drug mechanisms. We found that, among well-studied indications, the proportion of drug mechanisms with direct genetic support increases significantly across the drug development pipeline, from 2.0% at the preclinical stage to 8.2% among mechanisms for approved drugs, and varies dramatically among disease areas. We estimate that selecting genetically supported targets could double the success rate in clinical development. Therefore, using the growing wealth of human genetic data to select the best targets and indications should have a measurable impact on the successful development of new drugs.
Sterol regulatory element-binding proteins (SREBPs) are membrane-bound transcription factors that increase the synthesis of fatty acids as well as cholesterol in animal cells. All three SREBP ...isoforms (SREBP-1a, -1c, and -2) are subject to feedback regulation by cholesterol, which blocks their proteolytic release from membranes. Previous data indicate that the SREBPs are also negatively regulated by unsaturated fatty acids, but the mechanism is uncertain. In the current experiments, unsaturated fatty acids decreased the nuclear content of SREBP-1, but not SREBP-2, in cultured human embryonic kidney (HEK)-293 cells. The potency of unsaturated fatty acids increased with increasing chain length and degree of unsaturation. Oleate, linoleate, and arachidonate were all effective, but the saturated fatty acids palmitate and stearate were not effective. Down-regulation occurred at two levels. The mRNAs encoding SREBP-1a and SREBP-1c were markedly reduced, and the proteolytic processing of these SREBPs was inhibited. When SREBP-1a was produced by a cDNA expressed from an independent promoter, unsaturated fatty acids reduced nuclear SREBP-1a without affecting the mRNA level. There was no effect when the cDNA encoded a truncated version that was not membrane-bound. When administered together, sterols and unsaturated fatty acids potentiated each other in reducing nuclear SREBP-1. In the absence of fatty acids, sterols did not cause a sustained reduction of nuclear SREBP-1, but they did reduce nuclear SREBP-2. We conclude that unsaturated fatty acids, as well as sterols, can down-regulate nuclear SREBPs and that unsaturated fatty acids have their greatest inhibitory effects on SREBP-1a and SREBP-1c, whereas sterols have their greatest inhibitory effects on SREBP-2.
Re–Os dating of synsedimentary to early diagenetic pyrite from carbonaceous shale that straddles the boundary between the Rooihoogte and Timeball Hill formations, Transvaal Supergroup, South Africa, ...provides a precise isochron age of 2316±7 Ma (±4 statistical uncertainty if error on decay constant is excluded) and a chondritic initial
187Os/
188Os ratio of 0.1121±0.0012. These units were deposited between what are interpreted as the second and third of three Paleoproterozoic global glacial events, and thus provide minimum and maximum ages, respectively, for these events. The Rooihoogte Formation is correlative with the Duitschland Formation, which records previously undated carbon isotope excursions. Because the pyrite samples show no evidence of mass independent fractionation of sulfur and have highly negative
δ
34S values, the rise of atmospheric oxygen most likely began prior to 2.32 Ga. The chondritic initial
187Os/
188Os ratio requires that primitive hydrothermal sources of Os dominated the Os budget of seawater at 2.32 Ga. Os is mobile only under oxidizing conditions. Therefore, the chondritic initial
187Os/
188Os ratio may reflect atmospheric oxygen levels too low to introduce sufficient riverine flux of dissolved radiogenic Os to offset the primitive hydrothermal/magmatic flux. Even if atmospheric oxygen levels had increased significantly by 2.32 Ga, anoxic conditions throughout the Archean most likely limited Os enrichment in Archean marine shales, so that their subsequent exposure and weathering was unable to provide a significant amount of radiogenic Os to Paleoproterozoic seawater.
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