The bone is one of the most commonly affected organs in sickle cell disease (SCD). Repeated ischemia, oxidative stress and inflammation within the bone is largely responsible for promoting bone pain. ...As more individuals with SCD survive into adulthood, they are likely to experience a synergistic impact of both aging and SCD on their bone health. As bone health deteriorates, bone pain will likely exacerbate. Recent mechanistic and observational studies emphasize an intricate relationship between bone remodeling and the peripheral nervous system. Under pathological conditions, abnormal bone remodeling plays a key role in the propagation of bone pain. In this review, we first summarize mechanisms and burden of select bone complications in SCD. We then discuss processes that contribute to pathological bone pain that have been described in both SCD as well as non-sickle cell animal models. We emphasize the role of bone-nervous system interactions and pitfalls when designing new therapies especially for the sickle cell population. Lastly, we also discuss future basic and translational research in addressing questions about the complex role of stress erythropoiesis and inflammation in the development of SCD bone complications, which may lead to promising therapies and reduce morbidity in this vulnerable population.
Human bocavirus 1 (HBoV1) infects well-differentiated (polarized) human airway epithelium (HAE) cultured at an air-liquid interface (ALI). In the present study, we applied next-generation RNA ...sequencing to investigate the genome-wide transcription profile of HBoV1, including viral mRNA and small RNA transcripts, in HBoV1-infected HAE cells. We identified novel transcription start and termination sites and confirmed the previously identified splicing events. Importantly, an additional proximal polyadenylation site (pA)p2 and a new distal polyadenylation site (pA)d
lying on the right-hand hairpin (REH) of the HBoV1 genome were identified in processing viral pre-mRNA. Of note, all viral nonstructural proteins-encoding mRNA transcripts use both the proximal polyadenylation sites (pA)p1 and (pA)p2 and distal polyadenylation sites (pA)d1 and (pA)d
for termination. However, capsid proteins-encoding transcripts only use the distal polyadenylation sites. While the (pA)p1 and (pA)p2 sites were utilized at roughly equal efficiency for proximal polyadenylation of HBoV1 mRNA transcripts, the (pA)d1 site was more preferred for distal polyadenylation. Additionally, small RNA-seq analysis confirmed there is only one viral noncoding RNA (BocaSR) transcribed from nt 5199⁻5340 of the HBoV1 genome. Thus, our study provides a systematic and unbiased transcription profile, including both mRNA and small RNA transcripts, of HBoV1 in HBoV1-infected HAE-ALI cultures.
Using a multi-sector trade model with heterogeneous firms, this paper examines how the high-speed railway (HSR) results in changes in market access, and affects firms’ productivity. The model shows ...that with the opening of HSR in cities and decrease in trade costs, firm productivity increases through “competition effect” (proxied by consumer market access, CMA), but decrease through “scale expansion effect” (proxied by firm market access, FMA). To distinguish between these two competing effects empirically, we manually compile data of 110 prefecture cities which are sequentially connected with HSR during 2007–2013, and match these cities with China Industrial Firms Database during same period. We find that firm productivity increase by 0.0318 percentages due to one percentage increase in CMA, and decrease by 0.0552 percentages due to one percentage increase in FMA. We find significant heterogeneity in the effect of HSR opening on firm productivity in that the effect is the largest in the central area and mostly insignificant in the west; and the effect turns out the largest for technology-intensive firms, less for capital-intensive firms and the least for labor-intensive firms. We also find the impact of HSR opening on firm revenue, output, decision of entry or exit, as well as on regional productivity. Further analyses suggest that the effect of scale expansion dominates in the period after 2009 and hinders firm productivity, which explains the puzzling divergence of rising GDP and decreasing average TFP in that period.
A new technique for design and preparation of self‐reinforced starch films is introduced. The films were based on a high‐amylose corn starch that was chemically modified in different ways. ...Hydroxypropylation was used to decrease gelatinization temperature and improve processability. The reinforcing component consisted of cross‐linked starch granules, where the crosslinking increased granule thermal stability and moisture resistance. Distribution of the cross‐linked starch was imaged by CLSM, and the matrix/particle interface was studied by SEM. Modulus and tensile properties of the starch film were increased by about 30 and 20%, respectively, after addition of rigid cross‐linked starch particles. A perfect interface between matrix and reinforce agent was obtained.
Biodegradable starch‐based self‐reinforced composites were designed and prepared using a high‐amylose corn starch. Modulus and tensile properties of the film increased by ≈30% after addition of 20 wt.‐% rigid cross‐linked starch particles with no significant loss in failure strain. CLSM demonstrates a homogeneous distribution of the particles in the matrix. There is no observable change of both particle size and brightness for the cross‐linked starch, after distribution in the suspension of hydroxypropylated starch.
To discuss the safety and effectiveness of the improved technique by comparing the effects of low temperature bone cement infusion before and after the improvement in the percutaneous vertebroplasty ...(PVP).
The clinical data of 170 patients (184 vertebrae) with osteoporotic vertebral compression fracture who met the selection criteria between January 2016 and January 2018 were retrospectively analyzed. All patients were treated with PVP by low-temperature bone cement perfusion technology. According to the technical improvement or not, the patients were divided into two groups: the group before the technical improvement (group A, 95 cases) and the group after the technical improvement (group B, 75 cases). In group A, the patients were treated by keeping the temperature of bone cement at 0℃ and parallel puncture; in group B, the patients were treated by increasing the temperature of bone cement or reducing the time of bone cement in ice salt water and cross puncture. There was no significant difference in gender
BackgroundModern machine learning (ML) models based on highly multivariate attribute sets (e.g. unbiased -omics data) can be very successful at generating clinically useful predictions, but at the ...price of less transparency in how individual attributes are used to make those predictions. In short, ML test algorithms tend to be ”black boxes”. Shapley values (SVs)1 describe the relative importance of the attributes used within a multivariate test to the generation of the test result for an individual patient.2 While typically the calculation of SVs is computationally prohibitive, our ML architecture permits the generation of SVs for large patient cohorts. In this study, we evaluate SVs for the Anti-PD-L1 Response Test (ART), that was shown in independent validation to predict outcomes for patients treated with atezolizumab,3 for the POPLAR Ph2 and OAK Ph3 studies of non-small cell lung cancer (NSCLC) patients .4 5 Abstract 831 Figure 1Radar plots illustrating the values of the 10 most important SVs for test classification generation for two samples classified as poor (A and B) and two samples classified as good (C and D). Positive SVs are shown in red and negative SVs are shown in blueAbstract 831 Figure 2Heatmaps of the SVs for samples classified as poor showing two subgroups (top and bottom, separated by horizontal line) with different patterns of SVs for (A) POPLAR and (B) OAKAbstract 831 Figure 3Heatmaps of the SVs for samples classified as good showing three subgroups, top, middle, and bottom, separated by horizontal lines) with different patterns of SVs for (A) POPLAR and (B) OAKMethodsART results, Good or Poor had been produced for 262 patients in POPLAR (NCT01903993) and 786 patients in OAK (NCT02008227). Exact SVs were generated for each pretreatment serum sample for each of the 93 attributes (proteomic features) used in the test. The distribution of SVs across the cohort was investigated to assess the relative importance of each feature to test classification. Subgroups of patients with similar patterns of SVs were identified using t-sne plots and ML methods in the POPLAR cohort and validated in the OAK cohort.ResultsThe SV distributions showed that the features influencing ART classification most were similar in both POPLAR and OAK. The relative importance of features to test classification differed between patients (figure 1), but subgroups of patients within test classification groups showed similar patterns of SVs (figures 2 and 3). Such patient subgroups, identified within POPLAR, were also found in the OAK cohort and were associated with differences in outcome and/or differences in patient characteristics.ConclusionsSVs can explain how complex ML-based tests combine molecular attributes to produce individual patient results. Exact SVs can be obtained for certain ML architectures used in molecular test development, revealing the overall relative importance of attributes used in such molecular tests. Subgrouping of patients with the same test classification by different patterns of SVs is possible. This may reveal different biologies contributing to a Good or Poor phenotype and inform translational studies.Trial RegistrationClinicalTrialsgov NCT01903993 and NCT02008227ReferencesShapley L. A value for n-person games. Contributions to the Theory of Games. 1953;2.28:307–317.Roder J, Maguire L, Georgantas R, Roder H. Explaining multivariate molecular diagnostic tests via Shapley values. BMC Med Inform Decis Mak 2021;21(1):211.Kowanetz M, Leng N, Roder J, et al. Evaluation of immune-related markers in the circulating proteomic and their association with atezolizumab efficacy in patients with 2L+ NSCLC. J Immunother Cancer 2018;6(Suppl1):114.Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 2016;387(10030):1837–1846.Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicenter randomized controlled trial. Lancet 2017;389(10066):255–265.Ethics ApprovalThe OAK study that was done in 194 academic medical centers and community oncology practices across 31 countries worldwide. The study was done in full accordance with the guidelines for Good Clinical Practice and the Declaration of Helsinki. All patients gave written informed consent.The POPLAR trial was done at 61 academic medical centers and community oncology practices across 13 countries in Europe and North America. The study was done in full accordance with the guidelines for Good Clinical Practice and the Declaration of Helsinki. Protocol (and modification) approval was obtained from anindependent ethics committee for each site. Patients gave written informed consent.
Spray deposition and distribution are affected by many factors, one of which is nozzle flow distribution. A two-dimensional automatic measurement system, which consisted of a conveying unit, a system ...control unit, an ultrasonic sensor, and a deposition collecting dish, was designed and developed. The system could precisely move an ultrasonic sensor above a pesticide deposition collecting dish to measure the nozzle flow distribution. A sensor sleeve with a PVC tube was designed for the ultrasonic sensor to limit its beam angle in order to measure the liquid level in the small troughs. System performance tests were conducted to verify the designed functions and measurement accuracy. A commercial spray nozzle was also used to measure its flow distribution. The test results showed that the relative error on volume measurement was less than 7.27% when the liquid volume was 2 mL in trough, while the error was less than 4.52% when the liquid volume was 4 mL or more. The developed system was also used to evaluate the flow distribution of a commercial nozzle. It was able to provide the shape and the spraying width of the flow distribution accurately.
Device closure of a wide-spaced multi-hole PmVSD is difficult to succeed in percutaneous approach. This study is to evaluate the feasibility, safety and efficacy of perventricular device closure of ...wide-spaced multi-hole PmVSD using a double-device implanting technique.
Sixteen patients with wide-spaced multi-hole PmVSD underwent perventricular closure with two devices through an inferior median sternotomy approach under transesophageal echocardiographic guidance. The largest hole and its adjacent small holes were occluded with an optimal-sized device. The far-away residual hole was occluded with the other device using a probe-assisted delivery system. All patients were followed up for a period of 1 to 4 years to determine the residual shunt, atrioventricular block and the adjacent valvular function.
The number of the holes of the PmVSD was 2 to 4. The maximum distance between the holes was 5.0 to 10.0 mm (median, 6.4 mm). The diameter of the largest hole was 2.5 to 7.0 mm (median, 3.6 mm). The success rate of double-device closure was 100%. Immediate residual shunts were found in 6 patients (38%), and incomplete right bundle branch block at discharge occurred in 3 cases (19%). Both complications decreased to 6% at 1-year follow-up. Neither of them had a severe device-related complication.
Perventricular closure of a wide-spaced multi-hole PmVSD using a double-device implanting technique is feasible, safe, and efficacious. In multi-hole PmVSDs with the distance between the holes of more than 5 mm, double-device implantation may achieve a complete occlusion.
BackgroundTumor samples from the phase III IMpower010 study were used to compare two programmed death-ligand 1 (PD-L1) immunohistochemistry assays (VENTANA SP263 and Dako 22C3) for identification of ...PD-L1 patient subgroups (negative, positive, low, and high expression) and their predictive value for adjuvant atezolizumab compared with best supportive care (BSC) in resectable early-stage non-small cell lung cancer (NSCLC).MethodsPD-L1 expression was assessed by the SP263 assay, which measured the percentage of tumor cells with any membranous PD-L1 staining, and the 22C3 assay, which scored the percentage of viable tumor cells showing partial or complete membranous PD-L1 staining.ResultsWhen examining the concordance at the PD-L1-positive threshold (SP263: tumor cell (TC)≥1%; 22C3: tumor proportion score (TPS)≥1%), the results were concordant between assays for 83% of the samples. Similarly, at the PD-L1–high cut-off (SP263: TC≥50%; 22C3: TPS≥50%), the results were concordant between assays for 92% of samples. The disease-free survival benefit of atezolizumab over BSC was comparable between assays for PD-L1-positive (TC≥1% by SP263: HR, 0.58 (95% CI: 0.40 to 0.85) vs TPS≥1% by 22C3: HR, 0.65 (95% CI: 0.45 to 0.95)) and PD-L1-high (TC≥50% by SP263: HR, 0.27 (95% CI: 0.14 to 0.53) vs TPS≥50% by 22C3: HR, 0.31 (95% CI: 0.16 to 0.60)) subgroups.ConclusionsThe SP263 and 22C3 assays showed high concordance and a comparable clinical predictive value of atezolizumab at validated PD-L1 thresholds, suggesting that both assays can identify patients with early-stage NSCLC most likely to experience benefit from adjuvant atezolizumab.Trial registration numberNCT02486718.
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