High Accuracy Determination of Rheological Properties of Drilling Fluids Using the Marsh Funnel

Efficient and safe drilling operations require precise determination of rheological properties in drilling fluids, encompassing dynamic viscosity for Newtonian fluids, and apparent viscosity, plastic viscosity, and yield point for non-Newtonian fluids. Conventional viscometers like vibrating wire, ZNN-D6, and Fann-35 offer high accuracy but are limited by cost and complexity in small-scale industries and labs. To address this, our research presents a novel mathematical model based on the Herschel-Bulkley model, aiming to accurately characterise drilling fluids' rheological properties using the Marsh funnel as an alternative device -- an economical, operator-friendly, and power-independent equipment. Drawing inspiration from seminal works by Li et al. (2020), Sedaghat (2017), and Guria et al. (2013), this innovative framework establishes a universal inverse linear relationship between a fluid's flow factor and final discharge time. For any fluid, it utilises its density and flow factor (or final discharge time) to determine all its rheological properties. Specifically, it evaluates dynamic viscosity for Newtonian fluids, apparent viscosity, plastic viscosity, and yield point for weighted non-Newtonian fluids, and apparent viscosity for non-weighted non-Newtonian fluids, with average systematic errors (against Fann-35 measurements) of 0.39%, 3.52%, 2.17%, 18.38%, and 5.84%, respectively, surpassing the precision of alternative mathematical models found in the aforementioned literature. Furthermore, while our framework's precision in plastic viscosity and yield point assessment of non-weighted non-Newtonian fluids slightly lags behind the framework of Li et al. (2020), it outperforms the model of Sedaghat (2017). In conclusion, despite minor limitations, our proposed mathematical model holds huge promise for drilling fluid rheology in petroleum, drilling, and related industries.Comment: 57 pages, 1 figure, and 10 tables. Funding for this research work was provided through the IIChE Research Grant for the academic year 2022-23, granted by the Indian Institute of Chemical Engineers (IIChE

E-cadherin can limit the transforming properties of activating β-catenin mutations

Wnt pathway deregulation is a common characteristic of many cancers. But only Colorectal Cancer predominantly harbours mutations in APC, whereas other cancer types (hepatocellular carcinoma, solid pseudopapillary tumours of pancreas) have activating mutations in β-catenin (CTNNB1). We have compared the dynamics and the potency of β-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of β-catenin took much longer to achieve a Wnt deregulation and acquire a crypt-progenitor-cell (CPC) phenotype than Apc or Gsk3 loss. Within the colon, a single activating mutation of β-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of β-catenin mutation to differentially transform the SI versus the colon correlated with significantly higher expression of the β-catenin binding partner E-cadherin. This increased expression is associated with a higher number of E-cadherin:β-catenin complexes at the membrane. Reduction of E-cadherin synergised with an activating mutation of β-catenin so there was now a rapid CPC phenotype within the colon and SI. Thus there is a threshold of β-catenin that is required to drive transformation and E-cadherin can act as a buffer to prevent β-catenin accumulation

Evolutionary history of human colitis-associated colorectal cancer

Objective: IBD confers an increased lifetime risk of developing colorectal cancer (CRC), and colitis-associated CRC (CA-CRC) is molecularly distinct from sporadic CRC (S-CRC). Here we have dissected the evolutionary history of CA-CRC using multiregion sequencing. Design: Exome sequencing was performed on fresh-frozen multiple regions of carcinoma, adjacent non-cancerous mucosa and blood from 12 patients with CA-CRC (n=55 exomes), and key variants were validated with orthogonal methods. Genome-wide copy number profiling was performed using single nucleotide polymorphism arrays and low-pass whole genome sequencing on archival non-dysplastic mucosa (n=9), low-grade dysplasia (LGD; n=30), high-grade dysplasia (HGD; n=13), mixed LGD/HGD (n=7) and CA-CRC (n=19). Phylogenetic trees were reconstructed, and evolutionary analysis used to reveal the temporal sequence of events leading to CA-CRC. Results: 10/12 tumours were microsatellite stable with a median mutation burden of 3.0 single nucleotide alterations (SNA) per Mb, ~20% higher than S-CRC (2.5 SNAs/Mb), and consistent with elevated ageing-associated mutational processes. Non-dysplastic mucosa had considerable mutation burden (median 47 SNAs), including mutations shared with the neighbouring CA-CRC, indicating a precancer mutational field. CA-CRCs were often near triploid (40%) or near tetraploid (20%) and phylogenetic analysis revealed that copy number alterations (CNAs) began to accrue in non-dysplastic bowel, but the LGD/HGD transition often involved a punctuated ‘catastrophic’ CNA increase. Conclusions: Evolutionary genomic analysis revealed precancer clones bearing extensive SNAs and CNAs, with progression to cancer involving a dramatic accrual of CNAs at HGD. Detection of the cancerised field is an encouraging prospect for surveillance, but punctuated evolution may limit the window for early detection

Three-dimensional spectral domain optical coherence tomography and light microscopy of an intravitreal parasite

BACKGROUND: Various imaging modalities play a role in diagnosing parasitic infections of the eye. We describe the spectral domain optical coherence tomography (SD-OCT) findings of an intravitreal parasite with subsequent evaluation by light microscopy. FINDINGS: This is a case report of a 37-year-old Ecuadorian man who presented with uveitic glaucoma and a new floater in his left eye for 1 week’s duration. Full ophthalmic examination revealed an intravitreal parasite. Color fundus photography, fluorescein angiography (FA), ocular ultrasonography (US), and SD-OCT were performed. The parasite was removed via 23-gauge pars plana vitrectomy and sent to pathology for evaluation. Color fundus photography and ocular ultrasonography demonstrated an elongated foreign body within the vitreous above the retina. FA demonstrated minimal vascular changes in the vicinity of the parasite. SD-OCT was utilized to visualize the parasite and to create a three-dimensional (3D) image. The parasite was determined to be most consistent with Gnathostoma spp. by morphologic analysis. CONCLUSIONS: This is the first reported case of SD-OCT of an intravitreal parasite with corresponding evaluation by pathology. SD-OCT allows non-invasive, high-resolution visualization and 3D reconstruction of parasitic anatomy which may help establish tomographic criteria for species identification. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12348-015-0064-x) contains supplementary material, which is available to authorized users

Evolutionary history of human colitis-associated colorectal cancer

Objective IBD confers an increased lifetime risk of developing colorectal cancer (CRC), and colitis-associated CRC (CA-CRC) is molecularly distinct from sporadic CRC (S-CRC). Here we have dissected the evolutionary history of CA-CRC using multiregion sequencing. Design Exome sequencing was performed on fresh-frozen multiple regions of carcinoma, adjacent non-cancerous mucosa and blood from 12 patients with CA-CRC (n=55 exomes), and key variants were validated with orthogonal methods. Genome-wide copy number profiling was performed using single nucleotide polymorphism arrays and low-pass whole genome sequencing on archival non-dysplastic mucosa (n=9), low-grade dysplasia (LGD; n=30), high-grade dysplasia (HGD; n=13), mixed LGD/HGD (n=7) and CA-CRC (n=19). Phylogenetic trees were reconstructed, and evolutionary analysis used to reveal the temporal sequence of events leading to CA-CRC. Results 10/12 tumours were microsatellite stable with a median mutation burden of 3.0 single nucleotide alterations (SNA) per Mb, ~20% higher than S-CRC (2.5 SNAs/Mb), and consistent with elevated ageing-associated mutational processes. Non-dysplastic mucosa had considerable mutation burden (median 47 SNAs), including mutations shared with the neighbouring CA-CRC, indicating a precancer mutational field. CA-CRCs were often near triploid (40%) or near tetraploid (20%) and phylogenetic analysis revealed that copy number alterations (CNAs) began to accrue in non-dysplastic bowel, but the LGD/HGD transition often involved a punctuated ‘catastrophic’ CNA increase. Conclusions Evolutionary genomic analysis revealed precancer clones bearing extensive SNAs and CNAs, with progression to cancer involving a dramatic accrual of CNAs at HGD. Detection of the cancerised field is an encouraging prospect for surveillance, but punctuated evolution may limit the window for early detection

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Control of intestinal progenitor cell fate by the microenvironment

The conventional model of intestinal epithelial architecture describes a unidirectional tissue organisational hierarchy with stem cells situated at the crypt base and daughter cells proliferating and terminally differentiating as they progress along the vertical (crypt-luminal) axis. In this model, the fate of a cell that has left the niche is determined and its lifespan limited. I look at evidence to suggest that stem cell control and daughter cell fate determination is not solely an intrinsic, cell autonomous property but is heavily influenced by the microenvironment. Selective pressures that disrupt the homeostatic balance, such as intestinal inflammation or morphogen dysregulation, can cause committed progenitor cells and even some differentiated cells to regain stem cell properties. Disruption of cell fate determination can lead to somatic mutation and neoplastic transformation of cells situated outside the crypt base stem cell niche. The Wnt, BMP and Hedgehog pathways are explored in terms of epithelial and mesenchymal compartmentalisation and cross-talk, both in homeostasis and inflammation. Interactions between BMP and Hedgehog pathways are studied in vivo and in vitro. The BMP antagonist GREM1 is discussed, and the effect of a compartmental switch in its expression in humans (Hereditary Mixed Polyposis Syndrome) and in mouse models. This leads to ectopic crypts with supposed stem cell activity, and evidence for stem cell activity is interrogated using lineage tracing models and organoid cultures. The functionality of Sox9, a marker of ectopic crypts, is explored. An epithelial Sox9 knockout model is studied in terms of its effect on ectopic crypt formation. The role of Sox9 in intestinal restitution is also examined by using a chemical colitis model and a biopsy wounding model.</p

Control of intestinal progenitor cell fate by the microenvironment

The conventional model of intestinal epithelial architecture describes a unidirectional tissue organisational hierarchy with stem cells situated at the crypt base and daughter cells proliferating and terminally differentiating as they progress along the vertical (crypt-luminal) axis. In this model, the fate of a cell that has left the niche is determined and its lifespan limited. I look at evidence to suggest that stem cell control and daughter cell fate determination is not solely an intrinsic, cell autonomous property but is heavily influenced by the microenvironment. Selective pressures that disrupt the homeostatic balance, such as intestinal inflammation or morphogen dysregulation, can cause committed progenitor cells and even some differentiated cells to regain stem cell properties. Disruption of cell fate determination can lead to somatic mutation and neoplastic transformation of cells situated outside the crypt base stem cell niche. The Wnt, BMP and Hedgehog pathways are explored in terms of epithelial and mesenchymal compartmentalisation and cross-talk, both in homeostasis and inflammation. Interactions between BMP and Hedgehog pathways are studied in vivo and in vitro. The BMP antagonist GREM1 is discussed, and the effect of a compartmental switch in its expression in humans (Hereditary Mixed Polyposis Syndrome) and in mouse models. This leads to ectopic crypts with supposed stem cell activity, and evidence for stem cell activity is interrogated using lineage tracing models and organoid cultures. The functionality of Sox9, a marker of ectopic crypts, is explored. An epithelial Sox9 knockout model is studied in terms of its effect on ectopic crypt formation. The role of Sox9 in intestinal restitution is also examined by using a chemical colitis model and a biopsy wounding model.</p