Publications

ISOGEOMETRIC SIMULATION FOR BUCKLING, FREE AND FORCED VIBRATION OF ORTHOTROPIC PLATES

Buckling, free and forced vibration analyses of orthotropic plates are studied numerically using Isogeometric analysis. The present formulation is based on the classical plate theory (CPT) while the NURBS basis function is employed for both the parametrization of the geometry and the approximation of plate deflection. An efficient and easy-to-implement technique is used for imposing the essential boundary conditions. Numerical examples for free and forced vibration and buckling of orthotropic plates with different boundary conditions and configurations are considered. The numerical results are compared with other existing solutions to show the efficiency and accuracy of the proposed approach for such problems.

Liquid Chromatography-Tandem Mass Spectrometry Detection of Human and Veterinary Drugs and Pesticides in Surface Water

Antibiotics and pesticides are widespread in most rivers and lakes due to the overuse of antibiotics and pesticides, but there are few methods for simultaneous analysis of antibiotics and pesticides in aquatic environments. To address this knowledge gap, a concise and sensitive analytical method is proposed in which three classes of human and veterinary drugs (sulfonamides, macrolides, and hormones) and two classes of pesticides (organophosphorus and neonicotinoids) are simultaneously extracted and determined in surface water. The solid-phase extraction column with Cleanert PEP-2 was preconditioned sequentially with 6 mL of methanol, ultrapure water, and citric acid buffer (pH 3.0) each for simultaneous extraction and further purification. The forty-seven target analytes were analysed by LC-MS/MS in positive and negative ion modes. The LC separation was performed using a Sigma-Aldrich C18 column with 0.1% formic acid in water and acetonitrile as a gradient eluting mobile phase in positive ion mode. The internal standard method was used to overcome the inevitable matrix effects in LC-MS/MS analysis. The matrix effects of most target analytes were in the range of 27-151%. The recoveries of forty analytes in the three concentrations (10, 50, and 100 ng L-1) of surface water spiked samples ranged from 41 to 127%. The method quantitative limits of the analytes were in the range of 0.40-5.49 ng L-1. Application of the method to analyze samples in the eight runoff outlets of the Pearl River Delta showed that some antibiotics and pesticides were detected, and the concentration of parathion was as high as 154 ng L-1. A powerful tool for quickly and efficiently screening for contaminants in surface water has been presented.

Evaluating the Performance of Artificial Intelligence Chatbots and Large Language Models in the FE and PE Structural Exams

Forum papers are thought-provoking opinion pieces or essays founded in fact, sometimes containing speculation, on a civil engineering topic of general interest and relevance to the readership of the journal. The views expressed in this Forum article do not necessarily reflect the views of ASCE or the Editorial Board of the journal.

811 Allelic variation in Human Leukocyte Antigen class II genes is associated with pneumonitis risk in cancer patients treated with immune checkpoint inhibitors

<h3>Background</h3> Immune-mediated adverse events (imAE) commonly occur in patients treated with immune checkpoint inhibitors (ICI), and pneumonitis is known to occur in 3 -5 % of patients treated with anti-PD-1 / PD-L1 antibodies.¹ Most cases are grade 1 or 2 events and can be treated with immunosuppression, but high-grade events occur in a minority of patients and can be fatal.² Since lung inflammatory phenotypes, including fibrotic idiopathic interstitial pneumonias and infectious pneumonias, were associated with allelic variation in Human Leukocyte Antigen (HLA) genes,^{3 4} we hypothesized that HLA variants might also be a risk factor for ICI- associated pneumonitis. <h3>Methods</h3> Out of 1761 atezolizumab (anti-PD-L1) treated patients across nine Genentech (GNE) clinical trials with available whole-genome sequencing data, 72 (4.1%) developed pneumonitis (table 1). We inferred HLA genotypes using HLA-HD⁵ and performed an association study including 87 alleles with a carrier frequency of &gt;2%. In order to confirm our results, and to test whether the association is generalizable to different classes of ICI, we genotyped two additional cohorts using an Illumina genome-wide SNP array (GSA v3), followed by HLA imputation using HIBAG⁶: (1) 20 ICI-treated cancer patients with pneumonitis and 20 matched controls without from a pilot study on the AEROSMITH trial from Parker Institute for Cancer Immunotherapy (PICI); (2) 15 ICI-treated melanoma patients with pneumonitis and 149 without from Peter MacCallum Cancer Centre (PMC) (table 1). <h3>Results</h3> Two HLA class II alleles that are part of a common haplotype showed significant associations with pneumonitis risk after multiple testing adjustment (HLA-DRB1*15:01, HLA-DQA1*01:02), with HLA-DRB1*15:01 showing the strongest association (p = 0.0002, odds ratio (OR) =2.51). No associations were identified in the control arms (N = 1192). In the PICI pilot cohort, HLA-DRB1*15:01 did not reach statistical significance in spite of a comparable OR (p = 0.26, OR = 2.75), but the allele was significantly associated with pneumonitis risk in the PMC cohort (p = 0.03, OR = 3.92). A meta-analysis across the three cohorts yielded a highly significant p-value of 1.2x10–5 (OR = 2.67, figure 1), suggesting that the association is generalizable across ICI. Importantly, the same class II haplotype was previously shown to be associated with diverse lung inflammatory, including fibrotic, phenotypes.^3,4,7,8 <h3>Conclusions</h3> In summary, our findings establish HLA class II allelic variation as a potential risk factor in ICI-associated pneumonitis, and future research is warranted to determine whether this genetic association can be refined according to specific clinical presentations. <h3>References</h3> Wang H, Guo X, Zhou J, Li Y, Duan L, Si X, et al. Clinical diagnosis and treatment of immune checkpoint inhibitor-associated pneumonitis. <i>Thorac Cancer</i> 2020;<b>11</b>:191–7. Naidoo J, Wang X, Woo KM, Iyriboz T, Halpenny D, Cunningham J, et al. Pneumonitis in patients treated with anti–programmed death-1/Programmed death ligand 1 therapy. <i>J Clin Oncol</i> 2016;<b>35</b>:709–17. Tian C, Hromatka BS, Kiefer AK, Eriksson N, Noble SM, Tung JY, et al. Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections. <i>Nat Commun</i> 2017;<b>8</b>:599. Fingerlin TE, Zhang W, Yang IV, Ainsworth HC, Russell PH, Blumhagen RZ, et al. Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia. <i>BMC Genet</i> 2016;<b>17</b>:74. Kawaguchi S, Higasa K, Shimizu M, Yamada R, Matsuda F. HLA-HD: An accurate HLA typing algorithm for next-generation sequencing data. <i>Hum Mutat</i> 2017;<b>38</b>:788–97. Zheng X, Shen J, Cox C, Wakefield JC, Ehm MG, Nelson MR, et al. HIBAG—HLA genotype imputation with attribute bagging. <i>Pharmacogenomics J</i> 2014;<b>14</b>:192–200. Voorter CEM, Drent M, Berg-Loonen EM van den. Severe pulmonary sarcoidosis is strongly associated with the haplotype HLA-DQB1*0602–DRB1*150101. <i>Hum Immunol</i> 2005;<b>66</b>:826–35. Furukawa H, Oka S, Shimada K, Sugii S, Ohashi J, Matsui T, et al. Association of human leukocyte antigen with interstitial lung disease in rheumatoid arthritis: a protective role for shared epitope. <i>Plos One</i> 2012;<b>7</b>:e33133. <h3>Ethics Approval</h3> Patients included in this study signed an optional Research Biosample Repository (RBR) Informed Consent Form (ICF) and provided whole blood samples. By signing the optional RBR ICF, patients provided informed consent for analysis of inherited and non-inherited genetic variation from whole blood samples. Ethics Committees (EC) and Institutional Review Boards (IRB) in each country and each study site for each clinical trial approved the clinical trial protocol, the main study ICF, and theRBR ICF.

Screening of 485 Pesticide Residues in Fruits and Vegetables by Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry Based on TOF Accurate Mass Database and QTOF Spectrum Library

This paper uses the LC-quadrupole-time-of-flight MS technique to evaluate the behavioral characteristics of MS of 485 pesticides under different conditions and has developed an accurate mass database and spectra library. A high-throughput screening and confirmation method has been developed for the 485 pesticides in fruits and vegetables. Through the optimization of parameters such as accurate mass number, time of retention window, ionization forms, etc., the method has improved the accuracy of pesticide screening, thus avoiding the occurrence of false-positive and false-negative results. The method features a full scan of fragments, with 80% of pesticide qualitative points over 10, which helps increase pesticide qualitative accuracy. The abundant differences of fragment categories help realize the effective separation and qualitative identification of isomer pesticides. Four different fruits and vegetables-apples, grapes, celery, and tomatoes-were chosen to evaluate the efficiency of the method at three fortification levels of 5, 10, and 20 μg/kg, and satisfactory results were obtained. With this method, a national survey of pesticide residues was conducted between 2012 and 2015 for 12 551 samples of 146 different fruits and vegetables collected from 638 sampling points in 284 counties across 31 provincial capitals/cities directly under the central government, which provided scientific data backup for ensuring pesticide residue safety of the fruits and vegetables consumed daily by the public. Meanwhile, the big data statistical analysis of the new technique also further proves it to be of high speed, high throughput, high accuracy, high reliability, and high informatization.

An experimental study of cold-formed steel connections with screwed clip angle under tension and shear loads

This paper aims to investigate the performance of typical cold-formed steel (CFS) beam-to-beam connections between floor bearers and floor joists through a series of full-scale experiments. The investigated connections consisted of a lipped channel (floor joist), an unlipped channel (floor bearer), a thin-walled clip angle (connector), and a self-drilling screw (fastener). In this study, customised T-shaped and H-shaped CFS connection specimens were tested to examine the performance under tension and shear loads, respectively. Two sizes of self-drilling screws, 10 G and 14 G, were used with the selected load bearing clip angle. The fabricated connection specimens were subjected to displacement-controlled tension and shear loads. The experiments uncovered the ultimate connection strengths, load-displacement relationships, and failure mechanisms of the designed CFS connections under the applied loads. Moreover, the experimental tensile and shear strengths of the connections were compared with the strengths predicted by the standard design equations. It was found that the screw pullout on the anchored leg of the clip angle was the main mode of failure under the tensile load. On the other hand, two different failure modes—fracturing of 10 G screws or shear buckling of the cantilevered leg of the clip angle with 14 G screws—were observed in the H-shaped specimen under the applied shear load. Among the designed connection specimens, the maximum tensile load capacity was 30.86 kN and the maximum shear load capacity 88.15 kN. The standard design calculations predicted screw pullout failure under tension, while the shear bucking failure mode of the clip angle under shear load was overlooked.

A quasi-3D hyperbolic shear deformation theory for functionally graded plates

Adjuvant Therapy of Nivolumab Combined With Ipilimumab Versus Nivolumab Alone in Patients With Resected Stage IIIB-D or Stage IV Melanoma (CheckMate 915)

Ipilimumab and nivolumab have each shown treatment benefit for high-risk resected melanoma. The phase III CheckMate 915 trial evaluated adjuvant nivolumab plus ipilimumab versus nivolumab alone in patients with resected stage IIIB-D or IV melanoma.In this randomized, double-blind, phase III trial, 1,833 patients received nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks (916 patients) or nivolumab 480 mg once every 4 weeks (917 patients) for ≤ 1 year. After random assignment, patients were stratified by tumor programmed death ligand 1 (PD-L1) expression and stage. Dual primary end points were recurrence-free survival (RFS) in randomly assigned patients and in the tumor PD-L1 expression-level < 1% subgroup.At a minimum follow-up of approximately 23.7 months, there was no significant difference between treatment groups for RFS in the all-randomly assigned patient population (hazard ratio, 0.92; 95% CI, 0.77 to 1.09; P = .269) or in patients with PD-L1 expression < 1% (hazard ratio, 0.91; 95% CI, 0.73 to 1.14). In all patients, 24-month RFS rates were 64.6% (combination) and 63.2% (nivolumab). Treatment-related grade 3 or 4 adverse events were reported in 32.6% of patients in the combination group and 12.8% in the nivolumab group. Treatment-related deaths were reported in 0.4% of patients in the combination group and in no nivolumab-treated patients.Nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks did not improve RFS versus nivolumab 480 mg once every 4 weeks in patients with stage IIIB-D or stage IV melanoma. Nivolumab showed efficacy consistent with previous adjuvant studies in a population resembling current practice using American Joint Committee on Cancer eighth edition, reaffirming nivolumab as a standard of care for melanoma adjuvant treatment.

An astrocytic basis of epilepsy

Additional file 2 of Detection of cell-free microbial DNA using a contaminant-controlled analysis framework

Additional file 2: Table S3. Decontamination criteria outcome for ASVs that passed the in silico decontamination strategy applied to the plasma samples of the initial cohort.

Expression of Rv2031c-Rv2626c fusion protein in Mycobacterium�smegmatis enhances bacillary survival and modulates innate immunity in macrophages

Dormancy-associated antigens encoded by the dormancy survival regulon (DosR) genes are required for survival of Mycobacterium tuberculosis (Mtb) in macrophages. However, mechanisms underlying survival of Mtb in macrophages remains to be elucidated. A recombinant Mycobacterium smegmatis strain (rMs) expressing a fusion protein of two dormancy‑associated antigens Rv2031c and Rv2626c from Mtb was constructed in the present study. In an in vitro culture, growth rate of rMs was lower compared with Ms. A total of 24 h following infection of murine macrophages with rMs or Ms, percentage of viable cells decreased and the number of bacteria in viable cells increased compared with Ms, demonstrating that virulence and intracellular survival of rMs were enhanced. Compared with macrophages infected with Ms, necrosis of macrophages infected with rMs was increased, while apoptosis was inhibited. Macrophages infected with rMs secreted more interferon‑γ and interleukin‑6, but fewer nitric oxide and tumor necrosis factor‑α, compared with macrophages infected with Ms. The present study demonstrated that the fusion protein composed of dormancy‑associated antigens Rv2031c and Rv2626c in Ms serves a physiological function of a dormancy‑associated antigen and modulates innate immunity of host macrophages, therefore favoring intracellular bacillary survival.

Durability assessment of surface coated bamboo strips under constant immersion conditions

Another case of PORN (bilateral progressive outer retinal necrosis) after allogeneic stem cell transplantation

SUN-127 Diagnostic Challenges Associated with the Rising Incidence of Endocrine Toxicity in the Era of Combination Immunotherapy

Abstract Background: Immune checkpoint blockade is now established as standard of care in several malignancies. Trials involving combined cytotoxic T lymphocyte associated protein 4 (CTLA4) and programmed cell death protein 1 (PD1) blockade demonstrate improved tumour responses in melanoma but at the cost of severe grade 3-4 immune related adverse events (irAEs) in 55%, and endocrine irAEs in up to 10% [1]. Immune-mediated damage to endocrine glands can be a diagnostic and management challenge. We aimed to review the incidence, biochemical evolution and imaging findings of endocrine toxicity related to combined anti CTLA-4 and anti-PD-1 therapy. Methods: We undertook a retrospective chart review of patients who received combined ipilimumab and nivolumab for metastatic melanoma at a tertiary referral centre between 2016-2019. We recorded onset and duration of abnormal biochemistry in endocrine irAEs, reviewed all available MRI images for pituitary size (mm) and appearance and 18-F FDG PET images for features of hypophysitis, thyroiditis and pancreatitis. Results: 162 patients received combination therapy. At least one irAE was recorded in 135 patients (83%), 100 (62%) required glucocorticoids, and 84 (52%) had an unplanned hospital presentation due to irAEs. Thyroiditis occurred in 50 (30.9%), with median time to onset of 30.9 days (range 1-234 days). 35 cases were identified with routine biochemistry performed every 4-6 weeks. TSH receptor antibody was measured in 13 patients and all were negative. 29 (58%) developed permanent hypothyroidism. Central cortisol deficiency was documented in 31 (19%) with a median time to diagnosis of 67.5 days (range 5-286). 4 cases were diagnosed on routine biochemistry and 14 presented with symptoms prompting investigation. 13 were diagnosed after routine neuroimaging demonstrated a pituitary abnormality, and a further 27 patients without the clinical syndrome had features of hypophysitis on neuroimaging. New onset diabetes occurred in 3 people, in which pancreatic inflammation on imaging was found in 2. A further 3/5 patients with an asymptomatic elevated lipase were found to have abnormal pancreatic imaging. In one patient with no features of endocrine or exocrine failure, there was a significant increase in FDG uptake and a subsequent loss of pancreatic volume. Conclusion: We report real world incidence of endocrine irAEs with combination immunotherapy. Routine biochemistry leads to the detection of some but not all cases. Early recognition and avoidance of unplanned presentations remains a challenge. Opportunistic assessment of endocrine gland appearance on routine imaging studies may provide useful early diagnostic information. Reference: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. (2015) 1:23-34. 10.1056/NEJMoa1504030

8-year outcomes of enzalutamide (ENZA) versus a non-steroidal anti-androgen (NSAA) for metastatic, hormone-sensitive prostate cancer (ENZAMET; ANZUP 1304).

5090 Background: We previously reported that ENZA improved overall survival (OS) after median follow-up times of 34 and 68 months, in comparison with a NSAA, when added to testosterone suppression, with or without concurrent early docetaxel, for mHSPC. We now report outcomes after median follow-up of 98 months. Methods: Participants (pts) with mHSPC were randomly assigned (1:1) from 31MAR2014-24MAR2017 to treatment with ENZA 160 mg or NSAA, in addition to testosterone suppression. Concurrent early docetaxel was used in 45%. OS was the primary endpoint and analysed with the Kaplan-Meier method, log-rank test for p-values, and Cox regression for hazard ratios (HR). Secondary outcomes included deaths due to prostate cancer (PC) versus (vs) other causes. The numbers of pts experiencing specified adverse events (AE) of grade 3-5 are expressed per 100 person-years of study treatment exposure to account for differing treatment durations. Results: After a median follow-up of 98 months, data cut-off 30JUN2024, death was reported in 285/563 (51%) pts assigned ENZA vs 337/562 (60%) assigned NSAA. OS was longer among those assigned ENZA than NSAA (medians 95 vs 70 months; OS at 96 months 50% vs 40%; HR 0.73, 95% CI 0.63 to 0.86; p=0.0001). Clinical PFS also continued to favour ENZA over NSAA (HR 0.49; 95% CI 0.42 to 0.57; p&lt;0.0001). PC accounted for 468 of all 622 deaths, and were less frequent among those assigned ENZA than NSAA (207 vs 261). Deaths due to other causes accounted for a total of 154 deaths, and were similarly frequent among those assigned ENZA vs NSAA (78 vs 76). Mean duration of study treatment was longer for ENZA than NSAA (58 vs 36 months). 185/562 (33%) remain on ENZA with 88% on full dose. G3-5 AE of interest were reported in the following numbers of pts per 100 years of study treatment with ENZA vs NSAA: cardiac disorder 2.2 vs 2.2, nervous system disorder 2.3 vs 2.0, fall 0.70 vs 0.24. Causes of death according to PSA at 7 months are tabulated below. Among those with PSA at 7 months ≤0.2, deaths were due to PC in 29%, and other causes in 13%. Among those with PSA at 7 months &gt;0.2, deaths were due to PC in 60%, and other causes in 13%. Conclusions: Treatment with enzalutamide continues to confer substantial OS benefits at 8 years. These findings highlight long-term safety, toxicities, non-PC causes of death, and survival outcomes of those with and without PSA ≤0.2 at 7 months. ClinicalTrials.gov Identifier NCT02446405. Clinical trial information: NCT02446405 . Landmark analysis by PSA at 7 months ENZA (N=555) NSAA (N=549) ALL (N=1104) Deaths due to prostate cancer, PSA ≤0.2 100/375 (27%) 87/270 (32%) 187/645 (29%) Deaths due to other causes, PSA ≤0.2 54/375 (14%) 33/270 (12%) 87/645 (13%) Deaths due to prostate cancer, PSA &gt;0.2 104/180 (58%) 170/279 (61%) 274/459 (60%) Deaths due to other causes, PSA &gt;0.2 22/180 (12%) 39/279 (14%) 61/459 (13%)

Real-world health-related quality of life outcomes for patients with resected stage III/IV melanoma treated with adjuvant anti-PD1 therapy

Improved Survival in a Cohort of Trial Participants with Metastatic Castration-resistant Prostate Cancer Demonstrates the Need for Updated Prognostic Nomograms

Machine learning-based prediction of CFST columns using gradient tree boosting algorithm