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2022 ◽  
Vol 12 ◽  
Author(s):  
Kimberly Loo ◽  
James W. Smithy ◽  
Michael A. Postow ◽  
Allison Betof Warner

With the increasing promise of long-term survival with immune checkpoint blockade (ICB) therapies, particularly for patients with advanced melanoma, clinicians and investigators are driven to identify prognostic and predictive factors that may help to identify individuals who are likely to experience durable benefit. Several ICB combinations are being actively developed to expand the armamentarium of treatments for patients who may not achieve long-term responses to ICB single therapies alone. Thus, negative predictive markers are also of great interest. This review seeks to deepen our understanding of the mechanisms underlying the durability of ICB treatments. We will discuss the currently available long-term data from the ICB clinical trials and real-world studies describing the survivorship of ICB-treated melanoma patients. Additionally, we explore the current treatment outcomes in patients rechallenged with ICB and the patterns of ICB resistance based on sites of disease, namely, liver or CNS metastases. Lastly, we discuss the landscape in melanoma in the context of prognostic or predictive factors as markers of long-term response to ICB.


2021 ◽  
Vol 7 (1) ◽  
pp. 5
Author(s):  
Valeria Francesca Caspani ◽  
Daniel Tonelli ◽  
Francesca Poli ◽  
Daniele Zonta

Structural health monitoring is effective if it allows us to identify the condition state of a structure with an appropriate level of confidence. The estimation of the uncertainty of the condition state is relatively straightforward a posteriori, i.e., when monitoring data are available. However, monitoring observations are not available when designing a monitoring system; therefore, the expected uncertainty must be estimated beforehand. This paper proposes a framework to evaluate the effectiveness of a monitoring system accounting for temperature compensation. This method is applied to the design process of a structural health monitoring system for civil infrastructure. In particular, the focus is on the condition-state parameters representing the structural long-term response trend, e.g., due to creep and shrinkage effects, and the tension losses in prestressed concrete bridges. The result is a simple-to-use equation that estimates the expected uncertainty of a long-term response trend of temperature-compensated response measurements in the design phase. The equation shows that the condition-state uncertainty is affected by the measurement and model uncertainties, the start date and duration of the monitoring activity, and the sampling frequency. We validated our approach on a real-life case study: the Colle Isarco viaduct. We verified whether the pre-posterior estimation of expected uncertainty, performed with the experimented approach, is consistent with the real uncertainty estimated a posteriori based on the monitoring data.


Author(s):  
Anne Catrien Baakman ◽  
Carmen Gavan ◽  
Lotte Doeselaar ◽  
Marieke Kam ◽  
Karen Broekhuizen ◽  
...  

2021 ◽  
Vol 24 (2) ◽  
pp. 100-107
Author(s):  
Hitoshi Ohno ◽  
Kayo Takeoka ◽  
Chiyuki Kishimori ◽  
Fumiyo Maekawa ◽  
Miho Nakagawa ◽  
...  

2021 ◽  
Vol 12 ◽  
Author(s):  
Natalia Soledad Paulucci ◽  
Adriana Belén Cesari ◽  
María Alicia Biasutti ◽  
Marta Susana Dardanelli ◽  
María Angélica Perillo

Here, we estimate fast changes in the fluidity of Sinorhizobium meliloti membranes submitted to cyclic temperature changes (10°C–40°C–10°C) by monitoring the fluorescence polarization (P) of DPH and TMA-DPH of the whole cell (WC) as well as in its outer (OM) and inner (IM) membranes. Additionally, the long-term response to thermal changes is demonstrated through the dynamics of the phospholipid and fatty acid composition in each membrane. This allowed membrane homeoviscous adaptation by the return to optimal fluidity levels as measured by the PDPH/TMA-DPH in WC, OM, IM, and multilamellar vesicles of lipids extracted from OM and IM. Due to probe-partitioning preferences and membranes’ compositional characteristics, DPH and TMA-DPH exhibit different behaviors in IM and OM. The rapid effect of cyclic temperature changes on the P was the opposite in both membranes with the IM being the one that exhibited the thermal behavior expected for lipid bilayers. Interestingly, only after the incubation at 40°C, cells were unable to recover the membrane preheating P levels when cooled up to 10°C. Solely in this condition, the formation of threads and nodular structures in Medicago sativa infected with S. meliloti were delayed, indicating that the symbiotic interaction was partially altered but not halted.


2021 ◽  
pp. 194589242110605
Author(s):  
Giuseppe Fabio Parisi ◽  
Sara Manti ◽  
Maria Papale ◽  
Melania Amato ◽  
Amelia Licari ◽  
...  

Background Few studies have been conducted on the short-term response to sublingual immunotherapy (SLIT). Objective The purpose of our experimental trial was to evaluate if two markers such as nasal nitric oxide (nNO) and nasal cytology could be useful to identify a precocious clinical efficacy of SLIT treatment. Methods We enrolled 34 children aged 6 to 14 years old with diagnosis of allergic rhinitis (AR) and documented sensitization towards house dust mites. We started allergoid-monomeric tablets immunotherapy along with any conventional therapy for AR and we evaluated at baseline (T0), after one (T1), two (T2), three (T3), and six months (T6) the effects of the treatment through the study of: i) a visual analogue scale (VAS 1-10); ii) measurement of nNO; iii) measurement of FeNO; iv) nasal cytology; v) spirometry; and vi) evaluation of any conventional therapy. Results We observed an improvement in symptoms evaluated by global VAS (T0 vs. T6: 47.13 vs. 17.57; p < .05) and a statistically significant reduction of nNO (1035.2 ± 956.08 vs. 139.2 ± 59.01; p < .05). In this case, significance was reached when the patients completed the 6 months of treatment. Cytological evaluation revealed significant reduction in nasal eosinophils (T0 vs. T6: 87% vs. 16%; p < .01). Moreover, at T0, 56% of patients had also neutrophils that were reduced up to the 8% at T6 (p < .05). Conclusions Our data confirm the effectiveness of SLIT treatment from a clinical perspective and identifies two biomarkers, such as nNO and nasal cytology, as predictive of treatment efficacy in the short term.


2021 ◽  
Vol 10 (23) ◽  
pp. 5486
Author(s):  
Daniel Novakovic ◽  
Meet Sheth ◽  
Thomas Stewart ◽  
Katrina Sandham ◽  
Catherine Madill ◽  
...  

Laryngeal sensory dysfunction (LSD) encompasses disorders of the vagal sensory pathways. Common manifestations include chronic refractory cough (CRC) and abnormal throat sensation (ATS). This study examined clinical characteristics and treatment outcomes of LSD using a novel approach of laryngeal supraglottic Onabotulinum toxin Type A injection (BTX). This was a retrospective review of clinical data and treatment outcomes of supraglottic BTX in patients with LSD. Between November 2019 and May 2021, 14 patients underwent 25 injection cycles of supraglottic BTX for treatment of symptoms related to LSD, including ATS and CRC. Primary outcome measures included the Newcastle Laryngeal Hypersensitivity Questionnaire (LHQ), Cough Severity Index (CSI), Reflux Symptom Index (RSI), and Voice Handicap Index-10 (VHI-10) at baseline and within three months of treatment. Pre- and post-treatment data were compared using a linear mixed model. After supraglottic BTX, LHQ scores improved by 2.6. RSI and CSI improved by 8.0 and 5.0, respectively. VHI-10 did not change as a result of treatment. Short-term response to SLN block was significantly associated with longer term response to BTX treatment. These findings suggest that LSD presents clinically as ATS and CRC along with other upper airway symptoms. Supraglottic BTX injection is a safe and effective technique in the treatment of symptoms of LSD.


Author(s):  
David Barreto ◽  
Madjid Karimirad ◽  
Arturo Ortega

Abstract This paper deals with statistical and modeling uncertainty on the estimation of long-term extrapolated extreme responses in a monopile offshore wind turbine. The statistical uncertainty is addressed by studying the effect of simulation length. Modeling uncertainty is explored by evaluating the effects of considering a rigid and flexible foundation. The soil's flexibility is taking into account by considering the improved apparent fixity method. To identify the most relevant environmental conditions, the modified environmental contour method is used. The analysis focuses on the fore-aft shear force (FASF) and the fore-aft bending moment (FABM) at the mudline. The results show that using a simulation length of 10-min, does not provide sufficient accuracy. It was found that for the FASF, simulation lengths of at least 30-min are required to achieve an accuracy of about +/-5%. For the FABM, it was found that both the extrapolations made with 20-min and 30-min simulations achieved similar levels of accuracy of about 20%. Meanwhile, the results obtained from 10-min simulations reached deviations of about 40%. Finally, from the comparison made between a rigid and flexible foundation, it was found that the extrapolated responses exhibit maximum deviations up to around 5% and 10% for the FASF and the FABM, respectively. Also, for the FABM, it was observed that the consideration of a flexible foundation causes the critical wind speed to shift from 16.5 m/s (rigid) to 18 m/s (flexible).


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