Systematic review of studies generating individual participant data on the efficacy of drugs for treating soil-transmitted helminthiases and the case for data-sharing

Preventive chemotherapy and transmission control (PCT) by mass drug administration is the cornerstone of the World Health Organization (WHO)’s policy to control soil-transmitted helminthiases (STHs) caused by Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm) and hookworm species (Necator americanus and Ancylostama duodenale) which affect over 1 billion people globally. Despite consensus that drug efficacies should be monitored for signs of decline that could jeopardise the effectiveness of PCT, systematic monitoring and evaluation is seldom implemented. Drug trials mostly report aggregate efficacies in groups of participants, but heterogeneities in design complicate classical meta-analyses of these data. Individual participant data (IPD) permit more detailed analysis of drug efficacies, offering increased sensitivity to identify atypical responses potentially caused by emerging drug resistance

Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression

Tumour-associated angiogenesis is partly regulated by the hypoxia-inducible factor (HIF) pathway. Endocrine tumours are highly vascularised and the molecular mechanisms of their angiogenesis are not fully delineated. The aim of this study is to evaluate angiogenesis and expression of HIF-related molecules in a series of patients with pancreatic endocrine tumours (PETs). The expression of vascular endothelial growth factor (VEGF), HIF-1α, HIF-2α and carbonic anhydrase 9 (CA9) was examined by immunohistochemistry in 45 patients with PETs and compared to microvascular density (MVD), endothelial proliferation, tumour stage and survival. Microvascular density was very high in PETs and associated with a low endothelial index of proliferation. Microvascular density was significantly higher in benign PETs than in PETs of uncertain prognosis, well-differentiated and poorly differentiated carcinomas (mean values: 535, 436, 252 and 45 vessels mm−2, respectively, P<0.0001). Well-differentiated tumours had high cytoplasmic VEGF and HIF-1α expression. Poorly differentiated carcinomas were associated with nuclear HIF-1α and membranous CA9 expression. Low MVD (P=0.0001) and membranous CA9 expression (P=0.0004) were associated with a poorer survival. Contrary to other types of cancer, PETs are highly vascularised, but poorly angiogenic tumours. As they progress, VEGF expression is lost and MVD significantly decreases. The regulation of HIF signalling appears to be specific in pancreatic endocrine tumours

Clinical-pathological study on β-APP, IL-1β, GFAP, NFL, Spectrin II, 8OHdG, TUNEL, miR-21, miR-16, miR-92 expressions to verify DAI-diagnosis, grade and prognosis

Traumatic brain injury (TBI) is one of the most important death and disability cause, involving substantial costs, also in economic terms, when considering the young age of the involved subject. Aim of this paper is to report a series of patients treated at our institutions, to verify neurological results at six months or survival; in fatal cases we searched for βAPP, GFAP, IL-1β, NFL, Spectrin II, TUNEL and miR-21, miR-16, and miR-92 expressions in brain samples, to verify DAI diagnosis and grade as strong predictor of survival and inflammatory response. Concentrations of 8OHdG as measurement of oxidative stress was performed. Immunoreaction of β-APP, IL-1β, GFAP, NFL, Spectrin II and 8OHdG were significantly increased in the TBI group with respect to control group subjects. Cell apoptosis, measured by TUNEL assay, were significantly higher in the study group than control cases. Results indicated that miR-21, miR-92 and miR-16 have a high predictive power in discriminating trauma brain cases from controls and could represent promising biomarkers as strong predictor of survival, and for the diagnosis of postmortem traumatic brain injury

Resummation of the hadronic tau decay width with the modified Borel transform method

A modified Borel transform of the Adler function is used to resum the hadronic tau decay width ratio. In contrast to the ordinary Borel transform, the integrand of the Borel integral is renormalization--scale invariant. We use an ansatz which explicitly accounts for the structure of the leading infrared renormalon. Further, we use judiciously chosen conformal transformations for the Borel variable, in order to map sufficiently away from the origin the other ultraviolet and infrared renormalon singularities. In addition, we apply Pade approximants for the corresponding truncated perturbation series of the modified Borel transform, in order to further accelerate the convergence. Comparing the results with the presently available experimental data on the tau hadronic decay width ratio, we obtain $\alpha_s(M^z) = 0.1192 +- 0.0007_{exp.} +- 0.0010_{EW+CKM} +- 0.0009_{th.} +- 0.0003_{evol.}$. These predictions virtually agree with those of our previous resummations where we used ordinary Borel transforms instead.Comment: 32 pages, 2 eps-figures, revtex; minor changes in the formulations; a typo in Eq.(47) corrected; version as appearing in Phys. Rev.

Some Consequences of Thermosolutal Convection: The Grain Structure of Castings

The essential principles of thermosolutal convection are outlined, and how convection provides a transport mechanism between the mushy region of a casting and the open bulk liquid is illustrated. The convective flow patterns which develop assist in heat exchange and macroscopic solute segregation during solidification; they also provide a mechanism for the transport of dendritic fragments from the mushy region into the bulk liquid. Surviving fragments become nuclei for equiaxed grains and so lead to blocking of the parental columnar, dendritic growth front from which they originated. The physical steps in such a sequence are considered and some experimental data are provided to support the argument

The impact of hypoxia on B cells in COVID-19

Background: Prominent early features of COVID-19 include severe, often clinically silent, hypoxia and a pronounced reduction in B cells, the latter important in defence against SARS-CoV-2. This presentation resembles the phenotype of mice with VHL-deficient B cells, in which Hypoxia-Inducible Factors are constitutively active, suggesting hypoxia might drive B cell abnormalities in COVID-19. Methods: Detailed B cell phenotyping was undertaken by flow-cytometry on longitudinal samples from patients with COVID-19 across a range of severities (NIHR Cambridge BioResource). The impact of hypoxia on the transcriptome was assessed by single-cell and whole blood RNA sequencing analysis. The direct effect of hypoxia on B cells was determined through immunisation studies in genetically modified and hypoxia-exposed mice. Findings: We demonstrate the breadth of early and persistent defects in B cell subsets in moderate/severe COVID-19, including reduced marginal zone-like, memory and transitional B cells, changes also observed in B cell VHL-deficient mice. These findings were associated with hypoxia-related transcriptional changes in COVID-19 patient B cells, and similar B cell abnormalities were seen in mice kept in hypoxic conditions. Interpretation: Hypoxia may contribute to the pronounced and persistent B cell pathology observed in acute COVID-19 pneumonia. Assessment of the impact of early oxygen therapy on these immune defects should be considered, as their correction could contribute to improved outcomes. Funding: Evelyn Trust, Addenbrooke's Charitable Trust, UKRI/NIHR, Wellcome Trus

Preparation and characterization of carbon nanofluid by a plasma arc nanoparticles synthesis system

Heat dissipation from electrical appliances is a significant issue with contemporary electrical devices. One factor in the improvement of heat dissipation is the heat transfer performance of the working fluid. In this study, we used plasma arc technology to produce a nanofluid of carbon nanoparticles dispersed in distilled water. In a one-step synthesis, carbon was simultaneously heated and vaporized in the chamber, the carbon vapor and particles were then carried to a collector, where cooling furnished the desired carbon/water nanofluid. The particle size and shape were determined using the light-scattering size analyzer, SEM, and TEM. Crystal morphology was examined by XRD. Finally, the characterization include thermal conductivity, viscosity, density and electric conductivity were evaluated by suitable instruments under different temperatures. The thermal conductivity of carbon/water nanofluid increased by about 25% at 50°C compared to distilled water. The experimental results demonstrated excellent thermal conductivity and feasibility for manufacturing of carbon/water nanofluids

Renal tubular HIF-2α expression requires VHL inactivation and causes fibrosis and cysts.

The Hypoxia-inducible transcription Factor (HIF) represents an important adaptive mechanism under hypoxia, whereas sustained activation may also have deleterious effects. HIF activity is determined by the oxygen regulated α-subunits HIF-1α or HIF-2α. Both are regulated by oxygen dependent degradation, which is controlled by the tumor suppressor "von Hippel-Lindau" (VHL), the gatekeeper of renal tubular growth control. HIF appears to play a particular role for the kidney, where renal EPO production, organ preservation from ischemia-reperfusion injury and renal tumorigenesis are prominent examples. Whereas HIF-1α is inducible in physiological renal mouse, rat and human tubular epithelia, HIF-2α is never detected in these cells, in any species. In contrast, distinct early lesions of biallelic VHL inactivation in kidneys of the hereditary VHL syndrome show strong HIF-2α expression. Furthermore, knockout of VHL in the mouse tubular apparatus enables HIF-2α expression. Continuous transgenic expression of HIF-2α by the Ksp-Cadherin promotor leads to renal fibrosis and insufficiency, next to multiple renal cysts. In conclusion, VHL appears to specifically repress HIF-2α in renal epithelia. Unphysiological expression of HIF-2α in tubular epithelia has deleterious effects. Our data are compatible with dedifferentiation of renal epithelial cells by sustained HIF-2α expression. However, HIF-2α overexpression alone is insufficient to induce tumors. Thus, our data bear implications for renal tumorigenesis, epithelial differentiation and renal repair mechanisms