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Does the age of pharmaceuticals matter? Undetectable hydrate seeds impact hydration behaviour
No full textA study on the hydration behaviour of fluconazole demonstrates that both sample age and polymorphic form impacted the drugs kinetic stability to hydration. For two of the polymorphs, aged samples were found to hydrate more readily than fresh samples. The aging effect was attributed to the formation of monohydrate (MH) crystals over time. The MH, despite being initially undetectable, had a seeding effect, thus impacting the hydration kinetics
Current recommendations for cancer surveillance in Gorlin syndrome:a report from the SIOPE host genome working group (SIOPE HGWG)
No full textGorlin syndrome (MIM 109,400), a cancer predisposition syndrome related to a constitutional pathogenic variation (PV) of a gene in the Sonic Hedgehog pathway (PTCH1 or SUFU), is associated with a broad spectrum of benign and malignant tumors. Basal cell carcinomas (BCC), odontogenic keratocysts and medulloblastomas are the main tumor types encountered, but meningiomas, ovarian or cardiac fibromas and sarcomas have also been described. The clinical features and tumor risks are different depending on the causative gene. Due to the rarity of this condition, there is little data on phenotype-genotype correlations. This report summarizes genotype-based recommendations for screening patients with PTCH1 and SUFU-related Gorlin syndrome, discussed during a workshop of the Host Genome Working Group of the European branch of the International Society of Pediatric Oncology (SIOPE HGWG) held in January 2020. In order to allow early detection of BCC, dermatologic examination should start at age 10 in PTCH1, and at age 20 in SUFU PV carriers. Odontogenic keratocyst screening, based on odontologic examination, should begin at age 2 with annual orthopantogram beginning around age 8 for PTCH1 PV carriers only. For medulloblastomas, repeated brain MRI from birth to 5 years should be proposed for SUFU PV carriers only. Brain MRI for meningiomas and pelvic ultrasound for ovarian fibromas should be offered to both PTCH1 and SUFU PV carriers. Follow-up of patients treated with radiotherapy should be prolonged and thorough because of the risk of secondary malignancies. Prospective evaluation of evidence of the effectiveness of these surveillance recommendations is required.</p
A validation study of the kidney failure risk equation in advanced chronic kidney disease according to disease aetiology with evaluation of discrimination, calibration and clinical utility
No full textBackground The Kidney Failure Risk Equation (KFRE) predicts the 2- and 5-year risk of end-stage renal disease (ESRD) in patients with chronic kidney disease (CKD) stages 3a-5. Its predictive performance in advanced CKD and in specific disease aetiologies requires further exploration. This study validates the 4- and 8-variable KFREs in an advanced CKD population in the United Kingdom by evaluating discrimination, calibration and clinical utility. Methods Patients enrolled in the Salford Kidney Study who were referred to the Advanced Kidney Care Service (AKCS) clinic at Salford Royal Hospital NHS Foundation Trust between 2011 and 2018 were included. The 4- and 8-variable KFREs were calculated on the first AKCS visit and the observed events of ESRD (dialysis or pre-emptive transplantation) within 2- and 5-years were the primary outcome. The area under the receiver operator characteristic curve (AUC) and calibration plots were used to evaluate discrimination and calibration respectively in the whole cohort and in specific disease aetiologies: diabetic nephropathy, hypertensive nephropathy, glomerulonephritis, autosomal dominant polycystic kidney disease (ADPKD) and other diseases. Clinical utility was assessed with decision curve analyses, comparing the net benefit of using the KFREs against estimated glomerular filtration rate (eGFR) cut-offs of <20ml/min/1.73m2 and <15ml/min/1.73m2 to guide further treatment. Results A total of 743 patients comprised the 2-year analysis and 613 patients were in the 5-year analysis. Discrimination was good in the whole cohort: the 4-variable KFRE had an AUC of 0.796 (95% confidence interval [CI] 0.762-0.831) for predicting ESRD at 2-years and 0.773 (95% CI 0.736-0.810) at 5-years, and there was good-to-excellent discrimination across disease aetiologies. Calibration plots revealed underestimation of risk at 2-years and overestimation of risk at 5-years, especially in high-risk patients. There was, however, underestimation of risk in patients with ADPKD for all KFRE calculations. The predictive accuracy was similar between the 4- and 8-variable KFREs. Finally, compared to eGFR-based thresholds, the KFRE was the optimal tool to guide further care based on decision curve analyses. Conclusions The 4- and 8-variable KFREs demonstrate adequate discrimination and calibration for predicting ESRD in an advanced CKD population and, importantly, can provide better clinical utility than using an eGFR-based strategy to inform decision-making
Enrolment of older cancer patients in early phase clinical trials – an observational study on the experience in the north west of England
No full textIntroduction: Older patients represent the majority of cancer patients but are under-represented in trials, particularly early phase clinical trials (EPCTs). Material and Methods: Observational retrospective study of patients referred for EPCTs (January-December 2018) at a specialist cancer centre in the United Kingdom. The primary aim was to analyse the successful enrolment into EPCTs according to age (<65/65+). The secondary aims were to identify enrolment obstacles and the outcomes of enrolled patients. Patient data was analysed at: referral; in-clinic assessment; and after successful enrolment. Amongst patients assessed in clinic, a sample was defined by randomly matching the older cohort with the younger cohort (1:1) by tumour type. Results: 555 patients were referred for EPCTs with a median age of 60 years, of whom 471 were assessed in new patient clinics (38% were 65+). From those assessed, a randomly tumour-matched sample of 318 patients (159 per age cohort) was selected. Older patients had a significantly higher comorbidity score measured by ACE-27 (p<0.0001), lived closer to the hospital (p=0.045) and were referred at a later point in their cancer management (p=0.002). There was no difference in suitability for EPCTs according to age with overall 84% deemed suitable. For patients successfully enrolled into EPCTs there was no difference between age cohorts (20.1% vs 22.6% for younger and older, respectively; p=0.675) and no significant differences in their safety and efficacy outcomes. Discussion: Older age did not affect the enrolment into EPCTs. However, the selected minority referred for EPCTs suggests a pre-selection upstream by primary oncologists
Energy efficiency in extrusion-related polymer processing: a review of state of the art and potential efficiency improvements
No full textEnergy saving and industrial pollution have become increasingly important issues,therefore the identification and adoption of more energy efficient machines and industrial processesare now industrial priorities, and worthy topics for furtherdevelopment through academic research. Polymeric materials are amajor raw material, finding widespread application to a range ofcurrent industrial machine components as well as multiple productsand packaging found in our daily life. Polymer extrusion serves asa particular example of polymer processing techniques,representative of others in as much as there are analogousintermediate stages in the processing. Processing techniques whichrequire such intermediate stages includethe manufacture of blown film, blow moulding, thermo-forming, andinjection moulding. Hence, the study of polymer extrusion is arepresentative paradigm for a wider range of processingtechniques. Since polymer processing is an energy intensiveprocess and accounts for a huge share (maybe more than 1/3) of thematerials processing sector, any improvement to the process wouldcontribute significantly to global energy savings. This workpresents a review of studies, which focus on, or appertain to, theenergy consumption of extrusion related polymer processingapplications. Typical energy demand and losses during processingare considered, and possible approaches for improving the processenergy efficiency while maintaining the required end productquality are considered. Overall, this work provides a detaileddiscussion about how and where energy is utilized; how, where andwhy energy losses occur; and sets out approaches for optimizingthe process energy efficiency
Multipliers for nonlinearities with monotone bounds
No full textWe consider Lurye (sometimes written Lur’e) systems whose nonlinear operator is characterised by a possibly multivalued nonlinearity that is bounded above and below by monotone functions. Stability can be established using a subclass of the Zames-Falb multipliers. The result generalises similar approaches in the literature. Appropriate multipliers can be found using convex searches. Because the multipliers can be used for multivalued nonlinearities they can be applied after loop transformation. We illustrate the power of the new multipliers with two examples, one in continuous time and one in discrete time: in the first the approach is shown to outperform available stability tests in the literature; in the second we focus on the special case for asymmetric saturation with important consequences for systems with non-zero steady state exogenous signals
Image-based modeling of carbon storage in fractured organic-rich shale with deep learning acceleration
No full textIn this study, we present three methods of predicting CO2 adsorption upon displacing CH4 in dehydrated fractured shale samples. These methods include a dynamic numerical approach, a steady state numerical approach, and a machine learning (ML){based approach. We develop a coupled formulation for including the effects of gas competitive adsorption, decompression, Knudsen diffusion, slippage, advection, and Fickiandiffusion for multicomponent single-phase CO2-CH4 systems. Several stochastic micro{structures of fractured shale samples are generated and processed for pore network extraction. Extracted pore networks contain microporosities as well as mesopores and fractures. Next, we show that the dynamic numerical approach can be substituted with steady state model which is only 2.3% less accurate but 3 to 4 orders of magnitudecomputationally faster to execute. In order to enhance the computational limits even further, we train a deep learning model on 3982 simulated steady state cases with r{squared greater than 0.93. In addition, we dene a storage quality criterion for recognizing suitable shale samples for CO2 sequestration which depends both on the rate and amount of adsorption. Using this criterion and the developed ML tool, a large number of shale pore{scale images can be ranked based on their suitability in an efficient and accurate manner. The proposed workflow is useful for selection of the proper geological locations for subsurface CO2 storage by analysing the available image datasets
Improved risk-stratification for ventricular arrhythmias and sudden death in non-ischemic dilated cardiomyopathy
No full textBackground Risk-stratification for ventricular arrhythmias (VA) and sudden death (SD) in non-ischemic dilated cardiomyopathy (DCM) remains sub-optimal. Objectives To provide an improved risk-stratification algorithm for VA and SD in DCM. Methods Retrospective cohort study of consecutive patients with DCM who underwent cardiac magnetic resonance with late gadolinium enhancement (LGE) at two tertiary referral centers. The combined arrhythmic endpoint included appropriate implantable defibrillator (ICD) therapies, sustained ventricular tachycardia, resuscitated cardiac arrest and SD. Results In 1165 patients with median follow-up of 36 months, LGE was an independent and strong predictor of the arrhythmic endpoint (HR 9.9, p<0.001). This association was consistent across all strata of left ventricular ejection fraction (LVEF). Epicardial LGE, transmural LGE and combined septal and free-wall LGE were all associated with heightened risk. A simple algorithm combining LGE and three LVEF strata (≤20%, 21%-35%, >35%) was significantly superior to LVEF with the 35% cut-off (Harrell’s C 0.8 vs 0.69, AUC 0.82 vs 0.7, p<0.001) and reclassified the arrhythmic risk of 34% of DCM patients: LGE- patients with LVEF 21%-35% had low risk (annual event rate 0.7%) while those with high-risk LGE distributions and LVEF>35% had significantly higher risk (annual event rate 3%, p=0.007). Conclusions In a large cohort of patients with DCM, LGE was found to be a significant, consistent and strong predictor of VA or SD. Specific high-risk LGE distributions were identified. A new clinical algorithm integrating LGE and LVEF significantly improved the risk-stratification for VA and SD, with relevant implications for ICD allocation
Continuous magnitude production of loudness
No full textContinuous magnitude estimation and continuous cross-modality matching with line length can efficiently track the momentary loudness of time-varying sounds in behavioural experiments. These methods are known to be prone to systematic biases but may be checked for consistency using their counterpart, magnitude production. Thus, in Experiment 1, we performed such an evaluation for time-varying sounds. Twenty participants produced continuous cross-modality matches to assess the momentary loudness of fourteen songs by continuously adjusting the length of a line. In Experiment 2, the resulting temporal line length profile for each excerpt was played back like a video together with the given song and participants were asked to continuously adjust the volume to match the momentary line length. The recorded temporal line length profile, however, was manipulated for segments with durations between 7 to 12 s by eight factors between 0.5 and 2, corresponding to expected differences in adjusted level of -10, -6, -3, -1, 1, 3, 6 and 10 dB according to Stevens’s power law for loudness. The average adjustments 5 s after the onset of the change were -3.3, -2.4, - 1.0, -0.2, 0.2, 1.4, 2.4 and 4.4 dB. Smaller adjustments than predicted by the power law are in line with magnitude-production results by Stevens and co-workers due to ‘regression effects’. Continuous cross-modality matches of line length turned out to be consistent with current loudness models, and by passing the consistency check with cross-modal productions, demonstrate that the method is suited to track the momentary loudness of time-varying sounds
Reconstruction of the Spanish money supply, 1492-1810
No full textHow did the Spanish money supply evolve in the aftermath of the discovery of large amounts of precious metals in Spanish America? We synthesize the available data on the mining of precious metals and their international flow to estimate the money supply for Spain from 1492 to 1810. Our estimate suggests that the Spanish money supply increased more than ten-fold. Viewed through the equation of exchange this money supply increase can account for most of the price level rise in early modern Spain