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VEGF inhibitors can enhance the efficacy of immunotherapy. However, despite high initial response rates, almost all patients eventually develop treatment resistance to EGFR tyrosine-kinase inhibitors. We aimed to evaluate the efficacy and safety of sintilimab with or without IBI305 plus pemetrexed and cisplatin, compared with pemetrexed and cisplatin alone, for the treatment of patients with locally advanced or metastatic EGFR-mutated non-small-cell lung cancer (NSCLC) who had disease progression after receiving EGFR tyrosine-kinase inhibitor therapy. This randomised, double-blind, multicentre, phase 3 trial was conducted at 52 hospitals in China. Eligible participants were adults aged 18–75 years with locally advanced or metastatic NSCLC and EGFRmut who progressed after receiving a EGFR tyrosine-kinase inhibitor, had an Eastern Cooperative Oncology Group performance status of 0 or 1 with at least one measurable lesion, and an estimated life expectancy of at least 3 months. Participants were randomly assigned (1:1:1) to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus pemetrexed (500 mg/m2) and cisplatin (75 mg/m2), sintilimab plus pemetrexed and cisplatin, or pemetrexed and cisplatin (chemotherapy alone) using block randomisation with stratification according to sex and presence or absence of brain metastases. All study drugs were administered intravenously on day 1 of each cycle, once every 3 weeks. Except for cisplatin, which was only given in the first four cycles, treatment was given for 24 months or until disease progression, intolerable toxic effects, withdrawal of consent, death, or other protocol-specified conditions, whichever occurred first. The primary endpoint was progression-free survival in the intention-to-treat population. We herein report the first planned interim analysis, with progression-free survival results for the comparison between sintilimab plus IBI305 plus chemotherapy versus chemotherapy alone. The progression-free survival results for the sintilimab plus pemetrexed and cisplatin group are immature and not reported here. This study is registered with ClinicalTrials.gov, NCT03802240 (recruiting). Between July 11, 2019, and July 31, 2021, 936 patients were screened and 444 were randomly assigned (148 to the sintilimab plus IBI305 plus chemotherapy group, 145 to the sintilimab plus chemotherapy group, and 151 to the chemotherapy alone group). Data cutoff for this interim analysis was July 31, 2021. After a median follow-up of 9·8 months (IQR 4·4–13·3), progression-free survival was significantly longer in the sintilimab plus IBI305 plus chemotherapy group versus the chemotherapy alone group (median 6·9 months [95% CI 6·0–9.3] vs 4·3 months [4·1–5·4]; hazard ratio 0·46 [0·34–0·64]; p<0·0001). The most common grade 3 or 4 treatment-related adverse events were decreased neutrophil count (30 [20%] in the sintilimab plus IBI305 plus chemotherapy group vs 26 [18%] in the sintilimab plus chemotherapy group vs 27 [18%] in the chemotherapy alone group), decreased white blood cell count (17 [11%] vs 12 [8%] vs 13 [9%]), and anaemia (18 [12%] vs ten [7%] vs 15 [10%]). Potentially treatment-related deaths occurred in six patients (intestinal obstruction, gastrointestinal haemorrhage, and myelosuppression in one patient each, and three deaths of unknown cause) in the sintilimab plus IBI305 plus chemotherapy group, and in one patient in the chemotherapy alone group (unknown cause). In this interim analysis, sintilimab plus IBI305 plus cisplatin and pemetrexed was generally efficacious and well tolerated in patients with EGFR-mutated NSCLC who progressed after receiving EGFR tyrosine-kinase inhibitor therapy. Innovent Biologics and the National Natural Science Foundation of China. For the Chinese translation of the abstract see Supplementary Materials section.

We examine the reasons for discrepancies between two alternative approaches to modeling small-amplitude tides in binary systems. The direct solution (DS) approach solves the governing differential equations and boundary conditions directly, while the modal decomposition (MD) approach relies on a normal-mode expansion. Applied to a model for the primary star in the heartbeat system KOI-54, the two approaches predict quite different behavior of the secular tidal torque. The MD approach exhibits the pseudosynchronization phenomenon, where the torque due to the equilibrium tide changes sign at a single, well-defined, and theoretically predicted stellar rotation rate. The DS approach instead shows “blurred” pseudosynchronization, where positive and negative torques intermingle over a range of rotation rates. We trace a major source of these differences to an incorrect damping coefficient in the profile functions describing the frequency dependence of the MD expansion coefficients. With this error corrected, some differences between the approaches remain; however, both are in agreement that pseudosynchronization is blurred in the KOI-54 system. Our findings generalize to any type of star for which the tidal damping depends explicitly or implicitly on the forcing frequency.

\"Memory and Agency in Ancient China offers a novel perspective on China's material culture. The volume explores the complex 'life histories' of selected objects, whose trajectories as ginle objects ('biographies') and object types ('lineages') cut across both temporal and physical space. The essays, written by a team of international scholars, analyse the objects in an effort to understand how they were shaped by the constraints of their social, political and aesthetic contexts, just as they were also guided by individual preference and capricious memory. They also demonstrate how objects were capable of effecting change\"-- Provided by publisher.

Background Older major depressive disorder (MDD) patients have more complex clinical symptoms and higher abnormal lipid metabolism (ALM) rates. This study aimed to compare clinical differences between those with and without ALM in a sample of older first-episode drug naïve (FEDN) patients. Methods We recruited 266 older MDD patients. Socio-demographic variables, clinical data, and lipid parameters were obtained. The Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA), and the positive subscale of the Positive and Negative Syndrome Scale (PANSS-P) were conducted to evaluate patients’ depression, anxiety and psychotic symptoms, respectively. Results In this study, we found that the prevalence of comorbid ALM was 86.1% in older MDD patients. Compared with the non-abnormal lipid metabolism (NALM) group, the ALM group had a higher duration of illness, higher clinical global impression of severity scale (CGI-S) and HAMD scores, higher thyroid stimulating hormone (TSH) and glucose levels. Logistic regression analysis indicated that duration of illness (OR = 1.11, P  = 0.023, 95%CI = 1.015–1.216) and CGI-S score (OR = 2.28, P  = 0.014, 95%CI = 1.18–4.39) were associated with ALM in older MDD patients. Conclusion The importance of regular lipid assessment in older MDD patients needs to be taken into account.

Summary Abaloparatide (ABL) is a US Food and Drug Administration-approved parathyroid hormone-related peptide analog for treatment of osteoporosis in postmenopausal women at high risk of fracture. However, real-world data regarding its long-term safety and tolerability in large sample population are incomplete. We evaluated abaloparatide-associated safety signals by data mining of the FDA pharmacovigilance database. Introduction We investigated 33,480(0.14%) ABL-related adverse events (AEs) through data mining of Food and Drug Administration Adverse Event Reporting System (FAERS) retrospectively. Methods Reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) were employed to quantify the signals of ABL-related AEs from 2017Quarter2 to 2022.Serious and non-serious cases were compared by Mann-Whitney U test or Chi-squared ( χ 2 ) test. Results We collected 8,470,497 reports from the FAERS database, including 11,487 reports defined ABL as the primary suspected (PS) drug. Additionally, 36.16% of the reports were submitted by healthcare professionals ( n =4154), compared to 62.26% reported by consumers ( n =7140). A total 99 signals simultaneously conforming to four algorithms were detected, among which, 35 signals were identified as unexpected signals. Such as growing pains ( n =13), waist circumference increased ( n =21), sensory disturbance ( n =103), tinnitus ( n =65), visual acuity reduced ( n =54), blood alkaline phosphatase increased ( n =61), and hair growth abnormal ( n =13). Patient age ( p < 0.001) might be associated with an increased risk of AEs severity. The most common timeframe for AE occurrence was 0–7 days. Conclusion Our study provided a deeper and broader understanding of abaloparatide’s safety profiles, which would help healthcare professionals to mitigate the risk of AEs in clinical practice, a low number of unexpected AEs supporting ongoing additional pharmacovigilance.

\"This volume examines the role of objects in the region north of early dynastic state centers, at the intersection of Ancient China and Eurasia, a large area that stretches from Xinjiang to the China Sea, from c.3000 BCE to the mid-eighth century BCE. This area was a frontier, an ambiguous space that lay at the margins of direct political control by the metropolitan states, where local and colonial ideas and practices were reconstructed transculturally. These identities were often merged and displayed in material culture. Types of objects, styles, and iconography were often hybrids or new to the region, as were the tomb assemblages in which they were deposited and found. Patrons commissioned objects that marked a symbolic vision of place and person and that could mobilize support, legitimize rule, and bind people together.\"--Back cover.

Airway epithelial cells are the first cells to be challenged upon contact with the conidia of Aspergillus . In response, they express pattern-recognition receptors that play fundamental roles as sentinels and mediators of pulmonary innate immunity. The C-type lectin Dectin-1 is expressed predominantly on the surface of myeloid lineage cells. We examined the induction, regulation, and functions of Dectin-1 in pulmonary epithelial cells by challenging human bronchial epithelial (HBE) cells with A. fumigatus . Inflammatory, antimicrobial peptide genes and reactive oxygen species (ROS) were quantified, with and without knockdown of Dectin-1. We found that A. fumigatus induced the expression of Dectin-1 mRNA and protein in HBE cells in a toll-like receptor (TLR) 2-dependent manner. In addition, A. fumigatus -mediated generation of ROS was dependent on the upregulation of Dectin-1. Moreover, A. fumigatus actively induced the expression of TNFα, GM-CSF, IL8, HBD2, and HBD9. Knockdown of Dectin-1 inhibited TNFα, IL8, HBD2, and HBD9 expression. Hence, Dectin-1 was required for the upregulation of pro-inflammatory cytokines and antimicrobial peptides. Finally, knockdown of TLR2 significantly inhibited Dectin-1 upregulation. Our results demonstrate the novel induction of Dectin-1 in human bronchial epithelial cells and its critical role in the innate immune response against A. fumigatus in non-phagocytic cells.