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While other works use segments of nonlinear crystal to compensate for walk-off, this work utilizes a quantum dot (QD) nanostructure for such compensation. Such nanocrystal structures allow two benefits: the high nonlinear susceptibility in these nanocrystals and the high surface density of QDs in the structure. Good results are obtained for pre-chirping and modulation parameters. The results are computed at 10 and 100 kV/cm applied electric fields. Compared to ordinary nonlinear crystals, the pulse width, intensity, and efficiency of the second harmonic (SH) pulse are all higher in QD nanocrystals, even with a low electric field applied. Higher applied fields give higher results.

Background Mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) occur in a subset of cancers and have been shown to confer sensitivity to immune checkpoint inhibition (ICI); however, there is a lack of prospective data in urothelial carcinoma (UC).Methods and analysis We performed a systematic review to estimate the prevalence of dMMR and MSI-H in UC, including survival and clinical outcomes. We searched for studies published up to 26 October 2022 in major scientific databases. We screened 1745 studies and included 110. Meta-analyses were performed if the extracted data were suitable.Results The pooled weighted prevalences of dMMR in bladder cancer (BC) and upper tract UC (UTUC) were 2.30% (95% CI 1.12% to 4.65%) and 8.95% (95% CI 6.81% to 11.67%), respectively. The pooled weighted prevalences of MSI-H in BC and UTUC were 2.11% (95% CI 0.82% to 5.31%) and 8.36% (95% CI 5.50% to 12.53%), respectively. Comparing localised versus metastatic disease, the pooled weighted prevalences for MSI-H in BC were 5.26% (95% CI 0.86% to 26.12%) and 0.86% (95% CI 0.59% to 1.25%), respectively; and in UTUC, they were 18.04% (95% CI 13.36% to 23.91%) and 4.96% (95% CI 2.72% to 8.86%), respectively. Cumulatively, the response rate in dMMR/MSI-H metastatic UC treated with an ICI was 22/34 (64.7%) compared with 1/9 (11.1%) with chemotherapy.Conclusion Both dMMR and MSI-H occur more frequently in UTUC than in BC. In UC, MSI-H occurs more frequently in localised disease than in metastatic disease. These biomarkers may predict sensitivity to ICI in metastatic UC and resistance to cisplatin-based chemotherapy.

The main purpose of this work is studying the linear Susceptibility in the hybrid nanostructure that composed of a dual quantum dot (DQD) and metal nanoparticle (MNP) hybrid system under a standing-wave field. In our model, we used density matrix equations by taking into our account the interaction between excitons and surface plasmons. The proposed DQD is composed of two QDs. Each QD contains an InAs QD with a disk shape. The interaction between the QD and the wetting layer (WL) is taken into consideration. The application of the standing wave field on DQD-MNP hybrid system was modeled and examined. The susceptibility of thehybridDQD-MNPsystem reduced by the pump field under a standing-wave field. The high susceptibility obtained with a wide MNP radius. An interesting result was shown in the inversion of the grating period with the tunneling component in the conduction band. The smaller size of DQD gave us high susceptibility due to the quantization effect.

Summary: Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and a heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are the limited understanding of its gene regulatory programs and the low diagnostic yield of tumor biopsies due to spatial heterogeneity. Herein, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries from tissue and plasma samples from 50 patients with RCC and healthy volunteers. By profiling histone modifications and DNA methylation, we identified highly recurrent epigenomic reprogramming enriched in sRCC. Furthermore, CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs, and FOSL1 expression was associated with the response to ICIs in RCC in two randomized clinical trials. Finally, we established a blood-based diagnostic approach using detectable sRCC epigenomic signatures in patient plasma, providing a framework for discovering epigenomic correlates of tumor histology via liquid biopsy.

The use of steel beams with variable sections along their length is getting more attention in recent years. These variable sections can vary gradually along the beam or change abruptly as a drop or a step. The current study investigates the lateral torsional buckling (LTB) of stepped steel beams with flanged I section subjected to uniformly distributed pressure on the top flange. The studied parameters are the step height, the step length, and the boundary conditions of the beam. The finite element method is used to carry out a linear buckling analysis of the beams’ models. The results show significant degradation in beams LTB strength due to the jump of the beam's section. Reducing the simply supported beam depth by 25 % reduces LTB strength by about 40–50 %, while reducing the fixed beam depth by 25 % reduces LTB strength by about 30–40 %. Further reduction in depth showed no significant additional reduction in simply supported beams strength, while the fixed beams showed another 30–40 % reduction in strength with another 25 % reduction in beam total depth. The step made the compressive stress transfer between the two flange parts through the web.

Background Patients with paraneoplastic syndromes (PNS) are excluded from clinical trials involving immune checkpoint inhibitors (ICIs) due to safety concerns. Moreover, real-world data on efficacy and safety is scarce.Methods In this retrospective study, data were collected on patients with PNS and solid tumors receiving ICI between 2015 and 2022 at nine institutions. Patients were classified into: Cohort 1 (pre-existing PNS before ICI initiation), cohort 2 (PNS during ICI treatment), and cohort 3 (PNS after ICI discontinuation). Patients with metastatic non-small cell lung cancer (NSCLC) (mNSCLC) from cohort 1 were matched to patients who were PNS-free at each institution up to a 1:3 ratio for age, sex, type of ICI, use of concurrent chemotherapy, and number of lines of systemic therapy prior to ICI initiation. Kaplan-Meier method was used to assess overall survival (OS) and time-to-next treatment (TTNT).Results Among 109 patients with PNS treated with ICIs, median age at ICI initiation was 67 years (IQR: 58–74). The most represented cancer type was NSCLC (n=39, 36%). In cohort 1 (n=55), PNS exacerbations occurred in 16 (29%) patients with median time to exacerbation after ICI of 1.1 months (IQR: 0.7–3.3). Exacerbation or de novo PNS prompted temporary/permanent interruption of ICIs in 14 (13%) patients. For cohort 2 (n=16), median time between ICI initiation and de novo PNS was 1.2 months (IQR: 0.4–3.5). Treatment-related adverse events (trAEs) occurred in 43 (39%) patients. Grade ≥3 trAEs occurred in 18 (17%) patients. PNS-directed immunosuppressive therapy was required in 55 (50%) patients. We matched 18 patients with mNSCLC and PNS (cohort 1) to 40 without PNS, treated with ICIs. There was no significant difference in OS or TTNT between patients with mNSCLC with and without PNS, although a trend was seen towards worse outcomes in patients with PNS. TrAEs occurred in 6/18 (33%) and 14/40 (35%), respectively. Grade ≥3 trAEs occurred in 4 (22%) patients with PNS and 7 (18%) patients without PNS.Conclusions Exacerbations of pre-existing PNS occurred in 29% of patients treated with ICIs and both exacerbations and de novo PNS occur early in the ICI course. TrAE from ICIs were similar between patients with and without PNS. Our data suggest that pre-existing PNS should not preclude consideration of ICI therapy although patients may not derive the same clinical benefit compared with patients without PNS.

Multi-objective design optimization problems offer a set of solution alternatives within a Pareto-front. In structural design, the design variables are typically the section properties. The outcomes of these design variables are usually used in selecting standard sections. However, the properties of the selected standard sections normally have different values from the determined design variables. Accordingly, the values of the objective functions for these solutions will change after selecting standard sections. This change may be different among these solutions. Thus far, only Pareto-optimal solutions have been standardized in the literature. The effects of the inclusion of non-Pareto solutions in the standardization process have never been examined. In this paper, the differences between including the near-optimal solutions and not including them in the final structural design optimization set are explored. The paper investigates the impact of selecting standard sections on both Pareto-front solutions and near-optimal solutions, and it studies the importance of keeping track of the near-optimal solutions. A modified version of a multiple-objective particle swarm optimization method, enhanced with a proposed computationally efficient section standardization algorithm, is used to solve multi-objective system-reliability design optimization problems. The concepts of the paper are applied to examples of bridge structures. The results demonstrate the efficiency of the proposed technique in capturing final design solutions that would have been otherwise missed due to standardization.

The energy consumption levels of buildings in the United Arab Emirates (UAE) are among the highest in the world. One of the main reasons for this energy consumption is the need to cool buildings due to the hot climate of the UAE. As a large part of the heat accumulated inside buildings comes from windows, in this study, the effects of window size and direction in a typical building in the UAE on energy consumption and thermal performance are investigated through numerical modeling. The modeling process includes thermal conductivity, thermal convection, and solar radiation simulation. The energy performance of any building at any location can be obtained based on local weather data and the computational thermal characteristics of the building elements, such as its walls, roofs, windows, and doors. The study covered all different seasons of the year and different orientations for the windows, allowing the daily and yearly energy consumption associated with the windows to be obtained. Furthermore, the energy consumption was obtained for solar radiation and heat gain separately for both single- and double-glazed windows. It was found that north-facing windows consume significantly less annual energy (36% less), when compared with windows facing in the other three directions. Furthermore, the east- and west-facing windows consumed about 41% and 35% more daily cooling energy in August, when compared to north- and south-facing windows, respectively. The use of a window with a height equal to that of the wall can cause a clear greenhouse effect; hence, it is recommended to limit the window’s height to two-thirds of the wall height, which can save about one-third of the associated yearly cooling energy. This study should be considered as a general guideline, as the thermal performance of any specific building will be affected by its own thermal characteristics.

Abstract Gain spectra of CdxZn1−xTe/AlGaN undoped and doped quantum dot (QD) structures are studied under the inhomogeneous broadening assumption at four Cd mole fractions (x=0.25,0.5,0.75,0.95). For the Cd0.25Zn0.75Te QD structure, two peaks appear due to the excited state (ES) and ground state (GS) transitions. The gain for the doped structures doubles the undoped ones. The gain increases while the wavelength is reduced with increasing Cd content due to the broader band discontinuity between the QD states. The discontinuity of the bands for each structure (mole fraction) is calculated, which is one of the merits of this work. While the structure Cd0.25Zn0.75Te offers the peak wavelengths 470 and 630 nm, other mole fractions offer the wavelengths between them. These visible bands are essential in different applications. The effect of QD size effect is also examined. The wavelength is extended by 20 nm for each 1 nm QD height increment.

The epigenomic landscape of renal cell carcinoma (RCC) remains to be explored. Here, integrative epigenomic analysis of primary human RCC samples and RCC GWAS risk SNPs identifies transcription-factor specific subtypes and enrichment of risk variants in allelically-imbalanced peaks.

Abstract This work proposes the double quantum dot (DQD)-metal nanoparticle (MNP) hybrid system for a high energy absorption rate. The structure is modeled using density matrix equations that consider the interaction between excitons and surface plasmons. The wetting layer (WL)-DQD transitions are considered, and the orthogonalized plane wave (OPW) between these transitions is considered. The DQD energy states and momentum calculations with OPW are the figure of merit recognizing this DQD-MNP work. The results show that at the high pump and probe application, the total absorption rate $$({Q}_{tot})$$ ( Q tot ) of the DQD-MNP hybrid system is increased by reducing the distance between DQD-MNP. The high $${Q}_{tot}$$ Q tot obtained may relate to two reasons: first, the WL washes out modes other than the condensated main mode. Second, the high flexibility of manipulating DQD states compared to QD states results in more optical properties for DQD. The $${Q}_{DQD}$$ Q DQD is increased at a small MNP radius on the contrary to the $${Q}_{MNP}$$ Q MNP which is increased at a wider MNP radius. Under high tunneling, a broader blue shift in the $${Q}_{tot}$$ Q tot due to the destructive interference between fields is seen and the synchronization between $${Q}_{MNP}$$ Q MNP and $${Q}_{DQD}$$ Q DQD is destroyed. $${Q}_{tot}$$ Q tot for the DQD-MNP is increased by six orders while $${Q}_{DQD}$$ Q DQD is by eight orders compared to the single QD-MNP hybrid system. The high absorption rate of the DQD-MNP hybrid system comes from the transition possibilities and flexibility of choosing the transitions in the DQD system, which strengthens the transitions and increases the linear and nonlinear optical properties. This will make the DQD-MNP hybrid systems preferable to QD-MNP systems.

LSD1 inhibition blocks the neuroendocrine phenotype of some small cell lung cancers (SCLCs). Here, a genome-wide CRISPR/Cas9 LSD1 inhibitor resistance screen identifies the mRNA-binding protein ZFP36L1 as a gene repressed by LSD1 that when restored inhibits SCLC neuroendocrine differentiation.

Abstract Background Genomic alterations in 8 genes are now the targets of FDA-approved therapeutics in non-small cell lung cancer (NSCLC), but their distribution according to genetic ancestry, sex, histology, and smoking is not well established. Methods Using multi-institutional genetic testing data from GENIE, we characterize the distribution of targetable genomic alterations in 8 genes among 8675 patients with NSCLC (discovery cohort: DFCI, N = 3115; validation cohort: Duke, Memorial Sloan Kettering Cancer Center, Vanderbilt, N = 5560). For the discovery cohort, we impute genetic ancestry from tumor-only sequencing and identify differences in the frequency of targetable alterations across ancestral groups, smoking pack-years, and histologic subtypes. Results We identified variation in the prevalence of KRAS G12C , sensitizing EGFR mutations, MET alterations, ALK, and ROS1 fusions according to the number of smoking pack-years. A novel method for computing continental (African, Asian, European) and Ashkenazi Jewish ancestries from panel sequencing enables quantitative analysis of the correlation between ancestry and mutation rates. This analysis identifies a correlation between Asian ancestry and EGFR mutations and an anti-correlation between Asian ancestry and KRAS G12C mutation. It uncovers 2.7-fold enrichment for MET exon 14 skipping mutations and amplifications in patients of Ashkenazi Jewish ancestry. Among never/light smokers, targetable alterations in LUAD are significantly enriched in those with Asian (80%) versus African (49%) and European (55%) ancestry. Finally, we show that 5% of patients with squamous cell carcinoma (LUSC) and 17% of patients with large cell carcinoma (LCLC) harbor targetable alterations. Conclusions Among patients with NSCLC, there was significant variability in the prevalence of targetable genomic alterations according to genetic ancestry, histology, and smoking. Patients with LUSC and LCLC have 5% rates of targetable alterations supporting consideration for sequencing in those subtypes.

This work studies the thallium halogenide TlBr/BrCl quantum dot (QD) semiconductor structure and specifies its optical properties. This QD structure is poorly studied. High gain is obtained, with two peaks at 800 and 3000 nm. Doping is shown to increase the gain by one order. Then, TlBr QD semiconductor optical amplifier (SOA) characteristics are studied. High dB gain is shown mainly at the doped structure, which can be used in various inline applications.

Sarcomatoid and rhabdoid tumours are highly aggressive forms of renal cell carcinoma that are also responsive to immunotherapy. In this study, the authors perform a comprehensive molecular characterization of these tumours discovering an enrichment of specific alterations and an inflamed phenotype.

The polarized electromagnetic waves have significant impact on the performance of adaptive antenna arrays. In this paper we investigate the effect of polarized desired and undesired signals on the performance of electronically steered beam adaptive antenna arrays. To achieve this goal, we built an analytical signal model for the adaptive array, in order to analyze, and compare the effect of polarized signals on the output SINRs (signal to interference plus noise ratios) of single-dipole, and cross-dipole adaptive antenna arrays. Based on a proof-of-concept experiment, and on MATLAB simulation results, it will be shown that cross-dipole adaptive antenna arrays exhibit better performance in comparison with single-dipole adaptive antenna arrays in presence of randomly polarized signals. However, single-dipole arrays show better performance under certain operating conditions.

Sahin Lacin,1 Suayib Yalcin,2 Yusuf Karakas,2 Manal M Hassan,3 Hesham Amin,4 Yehia Ibrahim Mohamed,5 Asif Rashid,6 Jeffrey S Morris,7 Lianchun Xiao,8 Aliya Qayyum,9 Ahmed O Kaseb5 1Yeditepe University, Faculty of Medicine, Department of Medical Oncology, İstanbul, Turkey; 2Hacettepe University, Hacettepe Cancer Institute, Department of Medical Oncology, Ankara, Turkey; 3University of Texas, MD Anderson Cancer Center, Department of Epidemiology, Division of Cancer Prevention and Population Sciences, Houston, Texas, USA; 4University of Texas, MD Anderson Cancer Center, Department of Hematopathology, Division of Pathology and Laboratory Medicine, Houston, Texas, USA; 5University of Texas, MD Anderson Cancer Center, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, Houston, Texas, USA; 6University of Texas, MD Anderson Cancer Center, Department of Pathology, Division of Pathology and Laboratory Medicine, Houston, Texas, USA; 7Department of Biostatistics, Epidemiology and Informatics Center for Clinical Epidemiology and Biostatistics University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA; 8University of Texas, MD Anderson Cancer Center, Department of Biostatistics, Division of Basic Sciences, Houston, Texas, USA; 9University of Texas, MD Anderson Cancer Center, Department of Diagnostic Radiology, Division of Diagnostic Imaging, Houston, Texas, USACorrespondence: Suayib YalcinHacettepe University Cancer Institute, Sihhiye 06100, Ankara, TurkeyTel +90 312 309 29 04Fax +90 312 309 29 05Email suayibyalcin@gmail.comBackground: The Child–Turcotte–Pugh score (CTP) is the most commonly used tool to assess hepatic reserve and predict survival in hepatocellular cancer (HCC). The CTP stratification accuracy has been questioned and attempts have been made to improve the objectivity of the system. Serum insulin-like growth factor-1 (IGF-1)-CTP has been proposed to improve CTP prognostic accuracy. We aimed to validate the IGF-CTP score in our patient population.Patients and Methods: A total of 84 diagnosed HCC patients were enrolled prospectively. IGF-CTP scores in addition to CTP scores were calculated. C-index was used to compare the prognostic significance of the two scoring systems and overall survival (OS).Results: Cirrhosis was present in 48 (57.1%) patients, 35 (41.7%) patients were non-cirrhotic, 36 (42.8%) patients were hepatitis B (HBV) positive, and 8 (9.5%) patients were hepatitis C (HCV) positive. Serum IGF-1 levels were significantly lower in cirrhotic compared with non-cirrhotic patients (p=0.04). There was a significant difference in OS rates of patients with serum IGF-1 level < 50 ng/mL and patients with serum IGF-1 levels ≥ 50 ng/mL (p=0.02); the OS rates were 6.5 and 14.8 months, respectively (p=0.02). The median OS of all patients was 7.38 months (95% CI: 5.89– 13.79). The estimated C-index for CTP and IGF-CTP scores was 0.605 (95% CI: 0.538, 0.672) and 0.599 (95% CI: 0.543, 0.655), respectively. The U statistics indicated that the C-indices between two scoring systems are not statistically different (P= 0.91).Conclusion: This study evaluated IGF-1 levels and the IGF-CTP classification in a predominantly HBV (+) cohort of HCC patients with 41.7% non-cirrhotic. Although the prognostic value was similar, among patients with CTP-A, class those reclassified as IGF-CTP B had shorter OS than those with IGF-CTP score A. Thus, further validations of IGF-CTP score in similar populations may add additional value as a stratification tool to predict HCC outcome.Keywords: Child–Turcotte–Pugh, cirrhosis, hepatocellular carcinoma, insulin-like growth factor-1

Multiple myeloma (MM) is treated with induction chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. Here, the authors show that the presence of clonal haematopoiesis of indeterminate potential (CHIP) at time of ASCT is associated with adverse outcomes in MM patients.

Summary: Prior studies of the renal cell carcinoma (RCC) germline landscape investigated predominantly patients of European ancestry. We examine the frequency of germline pathogenic and likely pathogenic (P/LP) variants in 1,829 patients with RCC from various ancestries. Overall, P/LP variants are found in 17% of patients, among whom 10.3% harbor one or more clinically actionable variants with potential preventive or therapeutic utility. Patients of African ancestry with RCC harbor significantly more P/LP variants in FH compared to patients of non-African ancestry with RCC and African controls from the Genome Aggregation Database (gnomAD). Patients of non-African ancestry have significantly more P/LP variants in CHEK2 compared to patients of African ancestry with RCC and non-Finnish Europeans controls. Non-Africans with RCC have more actionable variants compared to Africans with RCC. This work helps understand the underlying biological differences in RCC between Africans and non-Africans and paves the way to more comprehensive genomic characterization of underrepresented populations.

Background: The recent COVID-19 pandemic sweeping the globe has caused great concern worldwide. Due to the limited evidence available on the dynamics of the virus and effective treatment options available, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a huge impact in terms of morbidity and mortality. The economic impact is still to be assessed.Aims: The purpose of this article is to review the evidence for the multiple treatment options available, to consider the future of this global pandemic, and to identify some potential options that could revolutionize the treatment of COVID-19. Moreover, this article underscores the sheer importance of repurposing some of the available antiviral and antimicrobial agents that have long been in use so as to have an effective and expeditious response to this widespread pandemic and the need to conduct a multicenter global randomized controlled trial to find an effective single antiviral agent or a cocktail of available antimicrobial agents.Method: We thoroughly searched and reviewed various case reports, retrospective analyses, and in vitro studies published in PubMed, EMBASE, and Google Scholar regarding the treatment options used for SARS-CoV, MERS-CoV, and SARS-CoV-2 since its outbreak in an attempt to highlight treatments with the most promising results.Conclusion: We are currently facing one of the worst pandemics in history. Although SARS-CoV-2 is associated with a lower mortality rate than are SARS-CoV and MERS-CoV, its higher infectivity is making it a far more serious threat. Unfortunately, no vaccine against SARS-CoV-2 or effective drug regimen for COVID-19 currently exists. Drug repurposing of available antiviral agents may provide a respite; moreover, a cocktail of antiviral agents may be helpful in treating this disease. Here, we have highlighted a few available antimicrobial agents that could be very effective in treating COVID-19; indeed, a number of trials are underway to detect and confirm the efficacy of these agents.

BackgroundImmune checkpoint inhibitors (ICI) induce a range of immune-related adverse events (irAEs) with various degrees of severity. While clinical experience with ICI retreatment following clinically significant irAEs is growing, the safety and efficacy are not yet well characterized.MethodsThis multicenter retrospective study identified patients with metastatic renal cell carcinoma treated with ICI who had >1 week therapy interruption for irAEs. Patients were classified into retreatment and discontinuation cohorts based on whether or not they resumed an ICI. Toxicity and clinical outcomes were assessed descriptively.ResultsOf 499 patients treated with ICIs, 80 developed irAEs warranting treatment interruption; 36 (45%) of whom were restarted on an ICI and 44 (55%) who permanently discontinued. Median time to initial irAE was similar between the retreatment and discontinuation cohorts (2.8 vs 2.7 months, p=0.59). The type and grade of irAEs were balanced across the cohorts; however, fewer retreatment patients required corticosteroids (55.6% vs 84.1%, p=0.007) and hospitalizations (33.3% vs 65.9%, p=0.007) for irAE management compared with discontinuation patients. Median treatment holiday before reinitiation was 0.9 months (0.2–31.6). After retreatment, 50% (n=18/36) experienced subsequent irAEs (12 new, 6 recurrent) with 7 (19%) grade 3 events and 13 drug interruptions. Median time to irAE recurrence after retreatment was 2.8 months (range: 0.3–13.8). Retreatment resulted in 6 (23.1%) additional responses in 26 patients whose disease had not previously responded. From first ICI initiation, median time to next therapy was 14.2 months (95% CI 8.2 to 18.9) and 9.0 months (5.3 to 25.8), and 2-year overall survival was 76% (95%CI 55% to 88%) and 66% (48% to 79%) in the retreatment and discontinuation groups, respectively.ConclusionsDespite a considerable rate of irAE recurrence with retreatment after a prior clinically significant irAE, most irAEs were low grade and controllable. Prospective studies are warranted to confirm that retreatment enhances survival outcomes that justify the safety risks.

BackgroundThere is limited experience regarding the safety and efficacy of checkpoint inhibitors (CPI) in patients with autoimmune disorders (AD) and advanced urological cancers as they are generally excluded from clinical trials due to risk of exacerbations.MethodsThis multicenter retrospective cohort analysis of patients with advanced renal cell cancer (RCC) and urothelial cancer (UC) with pre-existing AD treated with CPI catalogued the incidence of AD exacerbations, new immune-related adverse events (irAEs) and clinical outcomes. Competing risk models estimated cumulative incidences of exacerbations and new irAEs at 3 and 6 months.ResultsOf 106 patients with AD (58 RCC, 48 UC) from 10 centers, 35 (33%) had grade 1/2 clinically active AD of whom 10 (9%) required corticosteroids or immunomodulators at baseline. Exacerbations of pre-existing AD occurred in 38 (36%) patients with 17 (45%) requiring corticosteroids and 6 (16%) discontinuing CPI. New onset irAEs occurred in 40 (38%) patients with 22 (55%) requiring corticosteroids and 8 (20%) discontinuing CPI. Grade 3/4 events occurred in 6 (16%) of exacerbations and 13 (33%) of new irAEs. No treatment-related deaths occurred. Median follow-up was 15 months. For RCC, objective response rate (ORR) was 31% (95% CI 20% to 45%), median time to treatment failure (TTF) was 7 months (95% CI 4 to 10) and 12-month overall survival (OS) was 78% (95% CI 63% to 87%). For UC, ORR was 40% (95% CI 26% to 55%), median TTF was 5.0 months (95% CI 2.3 to 9.0) and 12-month OS was 63% (95% CI 47% to 76%).ConclusionsPatients with RCC and UC with well-controlled AD can benefit from CPI with manageable toxicities that are consistent with what is expected of a non-AD population. Prospective study is warranted to comprehensively evaluate the benefits and safety of CPI in patients with AD.

BackgroundImmune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs). Although the incidence and prevalence of irAEs have been well characterized in the literature, less is known about the cumulative incidence rate of irAEs. We studied the cumulative incidence of irAEs, defined as the probability of irAE occurrence over time and the risk factors for irAE development in metastatic urothelial carcinoma (mUC) and renal cell carcinoma (mRCC) patients treated with ICIs.MethodsWe identified a cohort of patients who received ICIs for mUC and mRCC. irAEs were classified using Common Terminology Criteria for Adverse Event (CTCAE) V.5.0 guidelines. The monthly incidence of irAEs over time was reported after landmark duration of therapy. Cumulative incidence of irAEs was calculated to evaluate the time to the first occurrence of an irAE accounting for the competing risk of death. Prognostic factors for irAE were assessed using the Fine and Gray method.ResultsA total of 470 patients were treated with ICIs between July 2013 and October 2018 (mUC: 199 (42.3%); mRCC: 271 (57.7%)). 341 (72.6%) patients received monotherapy, 86 (18.3%) received ICIs in combination with targeted therapies, and 43 (9.2%) received dual ICI therapy. Overall, 186 patients (39.5%) experienced an irAE at any time point. Common irAEs included hypothyroidism (n=42, 22.6%), rush and pruritus (n=36, 19.4%), diarrhea/colitis (n=35, 18.8%), transaminitis (n=32, 17.2%), and pneumonitis (n=14, 7.5%). Monthly incidence rates decreased over time; however, 17 of 109 (15.6%, 95% CI: 9.4% to 23.8%) experienced their first irAE at least 1 year after treatment initiation. No differences in cumulative incidence were observed based on cancer type, agent, or irAE grade. On multivariable analysis, combined ICI therapy with another ICI or with targeted therapy (p

Background: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with many neurological symptoms but there is a little evidence-based published material on the neurological manifestations of COVID-19. The purpose of this article is to review the spectrum of the various neurological manifestations and underlying associated pathophysiology in COVID-19 patients.Method: We conducted a review of the various case reports and retrospective clinical studies published on the neurological manifestations, associated literature, and related pathophysiology of COVID-19 using PUBMED and subsequent proceedings. A total of 118 articles were thoroughly reviewed in order to highlight the plausible spectrum of neurological manifestations of COVID 19. Every article was either based on descriptive analysis, clinical scenarios, correspondence, and editorials emphasizing the neurological manifestations either directly or indirectly. We then tried to highlight the significant plausible manifestations and complications that could be related to the pandemic. With little known about the dynamics and the presentation spectrum of the virus apart from the respiratory symptoms, this area needs further consideration.Conclusion: The neurological manifestations associated with COVID-19 such as Encephalitis, Meningitis, acute cerebrovascular disease, and Guillain Barré Syndrome (GBS) are of great concern. But in the presence of life-threatening abnormal vitals in severely ill COVID-19 patients, these are not usually underscored. There is a need to diagnose these manifestations at the earliest to limit long term sequelae. Much research is needed to explore the role of SARS-CoV-2 in causing these neurological manifestations by isolating it either from cerebrospinal fluid or brain tissues of the deceased on autopsy. We also recommend exploring the risk factors that lead to the development of these neurological manifestations.

Urothelial carcinoma (UC) of the bladder and upper tract (ureter, renal pelvis) is one of the most frequently occurring malignancies. While the majority of UC are chemically induced by smoking, accumulating evidence from genetic studies have demonstrated a small, but consistent impact of heritable gene variants and family history of UC on the development of the disease. Beyond the established association between upper tract UC and germline mismatch DNA repair defects as a defining feature of Lynch syndrome, newer investigations focusing on moderate- and high-risk cancer-related gene variants in DNA damage repair and other signaling pathways are expanding our knowledge on the heritable genetic basis of UC, opening new avenues in the breadth of genetic testing and in clinical counseling of these patients. Overcoming existing challenges in the interpretation of uncertain findings and family cascade testing may help expand our testing approach and guidelines. Following the paradigm of other tumor types, such as breast and ovarian cancers, germline genetic testing, particularly when combined with somatic testing, has the potential to directly benefit affected UC patients and their families in the future through therapeutic targeting (i.e. with poly(ADP-ribose)) polymerase inhibitors, immune checkpoint inhibitors) and genetically informed screening/surveillance, respectively.

A theoretical model was presented for linear susceptibility using density matrix theory for Y-configuration of double quantum dots (QDs) system including spontaneously generated coherence (SGC). Two SGC components are included for this system: V, and Λ subsystems. It is shown that at high V-component, the system have a giga gain. At low Λ-system component; it is possible to controls the light speed between superluminal and subluminal using one parameter by increasing SGC component of the V-system. This have applications in quantum information storage and spatially-varying temporal clock. Keywords: Quantum dot, Spontaneously generated coherence, Linear susceptibility

Carrier heating (CH) theory in a four-wave mixing quantum dot structure has been investigated. The impact of wetting layer (WL) carrier density, CH time constant, effective intraband relaxation time have been examined. The derived heat capacity for QD structure have (T-1) dependence. It is shown here that both WL carrier density and QD excited state (ES) occupation controls the overall nonlinear contributions. Then inclusion of WL and ES in the CH induces a new equilibrium reached at a faster recovery time. The proposed model yields results in a line with experiments at high carrier density reflecting the efficiency of our model. Keywords: Quantum dot, Carrier heating, Four-wave mixing, Excited state

A model of the dynamical equations of the density matrix describes double tunnelling between double quantum dot (QD) system states, this is to study Kerr nonlinearity in QD structure. Inhomogeneity in the QD system is included which is not included in earlier studies of Kerr nonlinearity in QDs. Possibilities of subluminal and superluminal light propagation and switching between them are examined. Double tunnelling is shown to obtain giant Kerr dispersion compared with single tunnelling. High conduction- and low valence-band tunnelling components are required to obtain high Kerr dispersion. Working with one tunnel component reduced Kerr dispersion and switching between subluminal and superluminal can be obtained and the EIT window can be removed. Keywords: Quantum dot, Tunnelling, Kerr dispersion

In this paper, we investigate the topologically weak concepts of topological groupoids by giving the concepts of α-topological groupoid and α-topological subgroupoid. Furthermore, we show the role of the density condition to allow α-topological subgroupoid inherited properties from α-topological groupoid and the irresoluteness property for the structure maps in α-topological groupoid is studied. We also give some results about the fibers of α-topological groupoids.

The construction of bridges represents a big challenge, since they require enormous economic effort and specialized technical skills. Bridges were historically important as they help connecting people and thus diffusing cultures, sharing ideas, and providing the backbone of transportation networks. This study focuses on the inspection and structural analysis of a 20th-century Ottoman railway stone arched bridge located on the Hejaz railway network in Jordan. The bridge has a very important cultural heritage value which stems from its history. The bridge stone material was cut and tested to determine its strength, in order to be used in the analysis. The structural analysis was carried out to assess the structural condition of the bridge and its suitability for reuse. The study includes static analysis under gravity loads and seismic analysis under earthquake loads. Despite the existence of deterioration in the bridge body construction materials due to a combination of human and natural factors, the analysis results proved enough structural capability to sustain the imposed gravity loads, but not a strong earthquake.