The final therapeutic effect of a drug candidate, which is directed to a specific molecular target strongly depends on its absorption, distribution, metabolism and excretion (ADME). The disruption of ...at least one element of ADME may result in serious drug resistance. In this work we described the role of one element of this resistance: phase II metabolism with UDP-glucuronosyltransferases (UGTs). UGT function is the transformation of their substrates into more polar metabolites, which are better substrates for the ABC transporters, MDR1, MRP and BCRP, than the native drug. UGT-mediated drug resistance can be associated with (i) inherent overexpression of the enzyme, named intrinsic drug resistance or (ii) induced expression of the enzyme, named acquired drug resistance observed when enzyme expression is induced by the drug or other factors, as food-derived compounds. Very often this induction occurs via ligand binding receptors including AhR (aryl hydrocarbon receptor) PXR (pregnane X receptor), or other transcription factors. The effect of UGT dependent resistance is strengthened by coordinate action and also a coordinate regulation of the expression of UGTs and ABC transporters. This coupling of UGT and multidrug resistance proteins has been intensively studied, particularly in the case of antitumor treatment, when this resistance is "improved" by differences in UGT expression between tumor and healthy tissue. Multidrug resistance coordinated with glucuronidation has also been described here for drugs used in the management of epilepsy, psychiatric diseases, HIV infections, hypertension and hypercholesterolemia. Proposals to reverse UGT-mediated drug resistance should consider the endogenous functions of UGT.
•A new route for concrete recycling within the European C2CA project is developed.•This novel recycling technology can be performed purely mechanically and in situ.•The process applies ADR to extract ...high-grade recycled aggregate.•We used ADR recycled aggregates for production of RAC.•Results show minor impact of RA on the performance of RAC.
One of the main environmental challenges in the construction industry is a strong social force to decrease the bulk transport of the building materials in urban environments. Considering this fact, applying more in-situ recycling technologies for Construction and Demolition Waste (CDW) is an urgent need. The European C2CA project develops a novel concrete recycling technology that can be performed purely mechanically and in situ. The technology consists of a combination of smart demolition, gentle grinding of the crushed concrete in an autogenous mill, and a novel dry classification technology called ADR to remove the fines. The feasibility of this recycling process was examined in demonstration projects involving in total 20,000tons of End of Life (EOL) concrete from two office towers in Groningen, The Netherlands. This paper concentrates on the second demonstration project of C2CA, where EOL concrete was recycled on an industrial site. After recycling, the properties of the produced Recycled Aggregate (RA) were investigated, and results are presented. An experimental study was carried out on mechanical and durability properties of produced Recycled Aggregate Concrete (RAC) compared to those of the Natural Aggregate Concrete (NAC). The aim was to understand the importance of RA substitution, w/c ratio and type of cement to the properties of RAC. In this regard, two series of reference concrete with strength classes of C25/30 and C45/55 were produced using natural coarse aggregates (rounded and crushed) and natural sand. The RAC series were created by replacing parts of the natural aggregate, resulting in series of concrete with 0%, 20%, 50% and 100% of RA. Results show that the concrete mix design and type of cement have a decisive effect on the properties of RAC. On the other hand, the substitution of RA even at a high percentage replacement level has minor and manageable impact on the performance of RAC. This result is a good indication towards the feasibility of using RA in structural concrete by modifying the mix design and using a proper type of cement.
Patient demographics, comorbidities, and baseline quality of life (QOL) are major contributors to postoperative outcomes. The frequency and cost of lumbar spine surgery has been increasing, with ...controversy revolving around optimal management strategies and outcome predictors. The goal of this study was to generate predictive nomograms and a clinical calculator for postoperative clinical and QOL outcomes following lumbar spine surgery for degenerative disease.
Patients undergoing lumbar spine surgery for degenerative disease at a single tertiary care institution between June 2009 and December 2012 were retrospectively reviewed. Nomograms and an online calculator were modeled based on patient demographics, comorbidities, presenting symptoms and duration of symptoms, indication for surgery, type and levels of surgery, and baseline preoperative QOL scores. Outcomes included postoperative emergency department (ED) visit or readmission within 30 days, reoperation within 90 days, and 1-year changes in the EuroQOL-5D (EQ-5D) score. Bootstrapping was used for internal validation.
A total of 2996 lumbar surgeries were identified. Thirty-day ED visits were seen in 7%, 30-day readmission in 12%, 90-day reoperation in 3%, and improvement in EQ-5D at 1 year that exceeded the minimum clinically important difference in 56%. Concordance indices for the models predicting ED visits, readmission, reoperation, and dichotomous 1-year improvement in EQ-5D were 0.63, 0.66, 0.73, and 0.84, respectively. Important predictors of clinical outcomes included age, body mass index, Charlson Comorbidity Index, indication for surgery, preoperative duration of symptoms, and the type (and number of levels) of surgery. A web-based calculator was created, which can be accessed here: https://riskcalc.org/PatientsEligibleForLumbarSpineSurgery/.
The prediction tools derived from this study constitute important adjuncts to clinical decision-making that can offer patients undergoing lumbar spine surgery realistic and personalized expectations of postoperative outcome. They may also aid physicians in surgical planning, referrals, and counseling to ultimately lead to improved patient experience and outcomes.
Relative value units (RVUs) are a compensation model based on the effort required to provide a procedure or service to a patient. Thus, procedures that are more complex and require greater technical ...skill and aftercare, such as multilevel spine surgery, should provide greater physician compensation. However, there are limited data comparing RVUs with operative time. Therefore, this study aims to compare mean (1) operative times; (2) RVUs; and (3) RVU/min between posterior segmental instrumentation of 3–6, 7–12, and ≥13 vertebral segments, and to perform annual cost difference analysis.
A total of 437 patients who underwent instrumentation of 3–6 segments (Cohort 1, current procedural terminology CPT code: 22842), 67 patients who had instrumentation of 7–12 segments (Cohort 2, CPT code: 22843), and 16 patients who had instrumentation of ≥13 segments (Cohort 3, CPT code: 22844) were identified from the National Surgical Quality Improvement Program (NSQIP) database. Mean operative times, RVUs, and RVU/min, as well as an annualized cost difference analysis, were calculated and compared using Student t test. This study received no funding from any party or entity.
Cohort 1 had shorter mean operative times than Cohorts 2 and 3 (217 minutes vs. 325 minutes vs. 426 minutes, p<.05). Cohort 1 had a lower mean RVU than Cohorts 2 and 3 (12.6 vs. 13.4 vs. 16.4). Cohort 1 had a greater RVU/min than Cohorts 2 and 3 (0.08 vs. 0.05, p<.05; vs. 0.08 vs. 0.05, p>.05). A $112,432.12 annualized cost difference between Cohorts 1 and 2, a $176,744.76 difference between Cohorts 1 and 3, and a $64,312.55 difference between Cohorts 2 and 3 were calculated.
The RVU/min takes into account not just the value provided but also the operative times required for highly complex cases. The RVU/min for fewer vertebral level instrumentation being greater (0.08 vs. 0.05), as well as the $177,000 annualized cost difference, indicates that compensation is not proportional to the added time, effort, and skill for more complex cases.
Photodynamic therapy (PDT) can lead to development of antigen-specific immune response and PDT-mediated immunity can be potentiated by T regulatory cell (Treg) depletion. We investigated whether the ...combination of PDT with cyclophosphamide (CY) could foster immunity against wild-type tumours expressing self-antigen (gp70).
Mice with CT26 tumours were treated with PDT alone or in combination with low-dose CY. T regulatory cell numbers and transforming growth factor-β (TGF-β) levels were measured at several time points after treatment. Mice cured by PDT+CY were rechallenged with CT26 and monitored for long-term survival.
Photodynamic therapy+CY led to complete tumour regression and long-term survival in 90% of treated mice while the absolute numbers of Treg decreased after PDT+CY and the TGF-β levels were reduced to a level comparable to naïve mice. Sixty-five percent of the mice treated with PDT+CY that survived over 90 days tumour free rejected the rechallenge with the same tumour when a second dose of CY was administered before rechallenge but not without.
Administration of CY before PDT led to depletion of Treg and potentiated PDT-mediated immunity, leading to long-term survival and development of memory immunity that was only uncovered by second Treg depletion.
Summary
In this paper a new type of cooling ceiling panel with corrugated surface has been studied experimentally. A heat flux and a heat transfer coefficient for the new type panel were compared ...with the reference values obtained for a panel of a flat surface. It was shown that increase of the new panel cooling performance results both from increase of its area and from enhancement of natural convection heat transfer. For typical operation conditions, the increase of the new type panel cooling capacity varies from 26 to 55%, in comparison with the reference panel. In addition, the new type panel is more resistant to the risk of dew point and enables the achievement of higher EER values by the heat pump cooperating with it.
A new type cooling ceiling panel with corrugated surface and monolithic structure was presented and investigated experimentally. A considerable improvement in cooling capacity of the new panel was achieved by increasing both its working surface area and the convective heat transfer coefficient. The new panel has great development potential.
Background:
Repetitive lumbar hyperextension and rotation during athletic activity affect the structural integrity of the lumbar spine. While many sports have been associated with an increased risk ...of developing a pars defect, few previous studies have systematically investigated spondylolysis and spondylolisthesis in professional baseball players.
Purpose:
To characterize the epidemiology and treatment of symptomatic lumbar spondylolysis and isthmic spondylolisthesis in American professional baseball players. We also sought to report the return-to-play (RTP) and performance-based outcomes associated with the diagnosis of a pars defect in this elite athlete population.
Study Design:
Descriptive epidemiology study.
Methods:
A retrospective cohort study was conducted among all Major and Minor League Baseball (MLB and MiLB, respectively) players who had low back pain and underwent lumbar spine imaging between 2011 and 2016. Players with radiological evidence of a pars defect (with or without listhesis) were included. Analyses were conducted to assess the association between player-specific characteristics and RTP time. Baseball performance metrics were also compared before and after the injury episode to determine whether there was an association between the diagnosis of a pars defect and diminished player performance.
Results:
During the study period of 6 MLB seasons, 272 professional baseball players had low back pain and underwent lumbar spine imaging. Overall, 75 of these athletes (27.6%) received a diagnosis of pars defect. All affected athletes except one (98.7%) successfully returned to professional baseball, with a median RTP time of 51 days. Players with spondylolisthesis returned to play faster than those with spondylolysis, MLB athletes returned faster than MiLB athletes, and position players returned faster than pitchers. Athletes with a diagnosed pars defect did not show a significant decline in performance after returning to competition after their injury episode.
Conclusion:
Lumbar pars defects were a common cause of low back pain in American professional baseball players. The vast majority of affected athletes were able to return to competition without demonstrating a significant decline in baseball performance.
We present here a nearly complete census of classical Cepheids in the Magellanic System. The sample extends the set of Cepheids published in the past by the Optical Gravitational Lensing Experiment ...(OGLE) to the outer regions of the Large (LMC) and Small Magellanic Cloud (SMC). The entire collection consists of 9535 Cepheids of which 4620 belong to the LMC and 4915 are members of the SMC. We provide the I- and V-band time-series photometry of the published Cepheids, their finding charts, and basic observational parameters. Based on this unique OGLE sample of Cepheids we present updated period-luminosity relations for fundamental, first, and second mode of pulsations in the I- and V-bands and for the W sub(I) extinction-free Wesenheit index. We also show the distribution of classical Cepheids in the Magellanic System. The OGLE collection contains several classical Cepheids in the Magellanic Bridge - the region of interaction between the Magellanic Clouds. The discovery of classical Cepheids and their estimated ages confirm the presence of young stellar population between these galaxies.
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