Comparative analysis of variation in the quality and completeness of local outbreak control plans for SARS-CoV-2 in English local authorities.

BACKGROUND: Local outbreak control plans (LOCPs) are statutory documents produced by local authorities (LAs) across England. LOCPs outline LAs' response to Coronavirus Disease 19 (COVID19) outbreaks and the coordination of local resources, data and communication to support outbreak response. LOCPs are therefore crucial in the nation's response to COVID-19. However, there has been no previous systematic assessment of these documents. We performed this study to systematically assess the quality of LOCPs and to offer recommendations of good practice. METHODS: All published LOCPs were assessed for basic characteristics. A framework based on Department of Health and Social Care guidelines was used to assess a random sample of LOCPs. Qualitative analysis was undertaken for LOCPs with highest completeness. RESULTS: Hundred and thirty-seven of 150 LAs publicly published a full LOCP; 9 were drafts. Statistical analysis demonstrated the significant difference between reporting of mainstream schools, care homes and the homeless population and other educational settings, high-risk settings and other vulnerable groups. LOCPs varied in approach when structuring outbreak response information and focused on different areas of outbreak management. CONCLUSIONS: The majority of LAs are publicly accessible. There is significant variation between the reporting of high-risk settings and groups. Suggested recommendations may help to improve future LOCP updates

Regulatory actions of 3',5'-cyclic adenosine monophosphate on osteoclast function: possible roles of Epac-mediated signaling.

Alterations in cellular levels of the second messenger 3',5'-cyclic adenosine monophosphate ([cAMP]i ) regulate a wide range of physiologically important cellular signaling processes in numerous cell types. Osteoclasts are terminally differentiated, multinucleated cells specialized for bone resorption. Their systemic regulator, calcitonin, triggers morphometrically and pharmacologically distinct retraction (R) and quiescence (Q) effects on cell-spread area and protrusion-retraction motility, respectively, paralleling its inhibition of bone resorption. Q effects were reproduced by cholera toxin-mediated Gs -protein activation known to increase [cAMP]i , unaccompanied by the [Ca2+ ]i changes contrastingly associated with R effects. We explore a hypothesis implicating cAMP signaling involving guanine nucleotide-exchange activation of the small GTPase Ras-proximate-1 (Rap1) by exchange proteins directly activated by cAMP (Epac). Rap1 activates integrin clustering, cell adhesion to bone matrix, associated cytoskeletal modifications and signaling processes, and transmembrane transduction functions. Epac activation enhanced, whereas Epac inhibition or shRNA-mediated knockdown compromised, the appearance of markers for osteoclast differentiation and motility following stimulation by receptor activator of nuclear factor kappa-Β ligand (RANKL). Deficiencies in talin and Rap1 compromised in vivo bone resorption, producing osteopetrotic phenotypes in genetically modified murine models. Translational implications of an Epac-Rap1 signaling hypothesis in relationship to N-bisphosphonate actions on prenylation and membrane localization of small GTPases are discussed.Medical Research Counci

Cardiac electrophysiological adaptations in the equine athlete-Restitution analysis of electrocardiographic features.

Exercising horses uniquely accommodate 7-8-fold increases in heart rate (HR). The present experiments for the first time analysed the related adaptations in action potential (AP) restitution properties recorded by in vivo telemetric electrocardiography from Thoroughbred horses. The horses were subjected to a period of acceleration from walk to canter. The QRS durations, and QT and TQ intervals yielded AP conduction velocities, AP durations (APDs) and diastolic intervals respectively. From these, indices of active, λ = QT/(QRS duration), and resting, λ0 = TQ/(QRS duration), AP wavelengths were calculated. Critical values of QT and TQ intervals, and of λ and λ0 at which plots of these respective pairs of functions showed unity slope, were obtained. These were reduced by 38.9±2.7% and 86.2±1.8%, and 34.1±3.3% and 85.9±1.2%, relative to their resting values respectively. The changes in λ were attributable to falls in QT interval rather than QRS duration. These findings both suggested large differences between the corresponding critical (129.1±10.8 or 117.4±5.6 bpm respectively) and baseline HRs (32.9±2.1 (n = 7) bpm). These restitution analyses thus separately identified concordant parameters whose adaptations ensure the wide range of HRs over which electrophysiological activation takes place in an absence of heart block or arrhythmias in equine hearts. Since the horse is amenable to this in vivo electrophysiological analysis and displays a unique wide range of heart rates, it could be a novel cardiac electrophysiology animal model for the study of sudden cardiac death in human athletes

Prediction of Gene Expression Patterns With Generalized Linear Regression Model

Cell reprogramming has played important roles in medical science, such as tissue repair, organ reconstruction, disease treatment, new drug development, and new species breeding. Oct4, a core pluripotency factor, has especially played a key role in somatic cell reprogramming through transcriptional control and affects the expression level of genes by its combination intensity. However, the quantitative relationship between Oct4 combination intensity and target gene expression is still not clear. Therefore, firstly, a generalized linear regression method was constructed to predict gene expression values in promoter regions affected by Oct4 combination intensity. Training data, including Oct4 combination intensity and target gene expression, were from promoter regions of genes with different cell development stages. Additionally, the quantitative relationship between gene expression and Oct4 combination intensity was analyzed with the proposed model. Then, the quantitative relationship between gene expression and Oct4 combination intensity at each stage of cell development was classified into high and low levels. Experimental analysis showed that the combination height of Oct4-inhibited gene expression decremented by a temporal exponential value, whereas the combination width of Oct4-promoted gene expression incremented by a temporal logarithmic value. Experimental results showed that the proposed method can achieve goodness of fit with high confidence

Arrhythmic effects of Epac-mediated ryanodine receptor activation in Langendorff-perfused murine hearts are associated with reduced conduction velocity.

Recent papers have attributed arrhythmic substrate in murine RyR2-P2328S hearts to reduced action potential (AP) conduction velocities (CV), reflecting acute functional inhibition and/or reduced expression of sodium channels. We explored for acute effects of direct exchange protein directly activated by cAMP (Epac)-mediated ryanodine receptor-2 (RyR2) activation on arrhythmic substrate and CV. Monophasic action potential (MAP) recordings demonstrated that initial steady (8 Hz) extrinsic pacing elicited ventricular tachycardia (VT) in 0 of 18 Langendorff-perfused wild-type mouse ventricles before pharmacological intervention. The Epac activator 8-CPT (8-(4-chlorophenylthio)-2′-O-methyladenosine-3′,5′-cyclic monophosphate) (VT in 1 of 7 hearts), and the RyR2 blocker dantrolene, either alone (0 of 11) or with 8-CPT (0 of 9) did not then increase VT incidence (P>.05). Both progressively increased pacing rates and programmed extrasystolic (S2) stimuli similarly produced no VT in untreated hearts (n=20 and n=9 respectively). 8-CPT challenge then increased VT incidences (5 of 7 and 4 of 8 hearts respectively; P.05). 8-CPT but not dantrolene, whether alone or combined with 8-CPT, correspondingly increased AP latencies (1.14±0.04 (n=7), 1.04±0.03 (n=10), 1.09±0.05 (n=8) relative to respective control values). In contrast, AP durations, conditions for 2:1 conduction block and ventricular effective refractory periods remained unchanged throughout. We thus demonstrate for the first time that acute RyR2 activation reversibly induces VT in specific association with reduced CV.We thank the Medical Research Council (UK) (CLH), Wellcome Trust (UK) (CLH), British Heart Foundation (UK) (CLH), McVeigh Benefaction (CLH and AG), and Sudden Arrhythmic Death Syndrome (SADS) UK (CLH and AG) for support

Monitoring Drought through the Lens of Landsat: Drying of Rivers during the California Droughts

Water scarcity during severe droughts has profound hydrological and ecological impacts on rivers. However, the drying dynamics of river surface extent during droughts remains largely understudied. Satellite remote sensing enables surveys and analyses of rivers at fine spatial resolution by providing an alternative to in-situ observations. This study investigates the seasonal drying dynamics of river extent in California where severe droughts have been occurring more frequently in recent decades. Our methods combine the use of Landsat-based Global Surface Water (GSW) and global river bankful width databases. As an indirect comparison, we examine the monthly fractional river extent (FrcSA) in 2071 river reaches and its correlation with streamflow at co-located USGS gauges. We place the extreme 2012–2015 drought into a broader context of multi-decadal river extent history and illustrate the extraordinary change between during- and post-drought periods. In addition to river extent dynamics, we perform statistical analyses to relate FrcSA with the hydroclimatic variables obtained from the National Land Data Assimilation System (NLDAS) model simulation. Results show that Landsat provides consistent observation over 90% of area in rivers from March to October and is suitable for monitoring seasonal river drying in California. FrcSA reaches fair (>0.5) correlation with streamflow except for dry and mountainous areas. During the 2012–2015 drought, 332 river reaches experienced their lowest annual mean FrcSA in the 34 years of Landsat history. At a monthly scale, FrcSA is better correlated with soil water in more humid areas. At a yearly scale, summer mean FrcSA is increasingly sensitive to winter precipitation in a drier climate; and the elasticity is also reduced with deeper ground water table. Overall, our study demonstrates the detectability of Landsat on the river surface extent in an arid region with complex terrain. River extent in catchments of deficient water storage is likely subject to higher percent drop in a future climate with longer, more frequent droughts

Thymoquinone reduces cardiac damage caused by hypercholesterolemia in apolipoprotein E-deficient mice

Abstract Background Hypercholesterolemia is a well-established risk factor for cardiac damage, which can lead to cardiovascular diseases. Many studies have shown that thymoquinone protected rats from doxorubicin-induced cardiotoxicity and cardiac damage. The aim of this study was to investigate the possible protective effects of thymoquinone against cardiac damage in apolipoprotein E knockout (ApoE−/−) mice. Methods Eight-week-old male ApoE−/− mice were randomly divided into three groups: control group fed a normal diet (ND group), a high cholesterol diet (HD group) or HD mixed with thymoquinone (HD + TQ group). All groups were fed the different diets for 8 weeks. Blood samples were obtained from the inferior vena cava and collected in serum tubes. The samples were then stored at − 80 °C until used. Coronal sections of heart tissues were fixed in 10% formalin and then embedded in paraffin for histological evaluation. The remainder of the heart tissues was snap-frozen in liquid nitrogen for mRNA or immunohistochemical analysis. Results The metabolic characteristics of total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c), and high-sensitivity C-reactive protein (hs-CRP) were lower in ApoE−/−HD + TQ mice than in ApoE−/− HD mice. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) gene and protein expression was lower in the heart tissue of ApoE−/−HD + TQ mice than in those of ApoE−/−HD mice. Furthermore, the levels of macrophages and pro-inflammatory cytokines were lower in the cardiac tissues of ApoE−/−HD + TQ mice than in those of ApoE−/−HD mice. Conclusions These results indicate that thymoquinone may provide a potential therapeutic target for cardiac damage caused by hypercholesterolemia