The timing of immune-related adverse events (irAE) associated with immune checkpoint inhibitors (ICI) is highly variable. Although the development of irAE has been associated with ICI clinical benefit, how irAE timing influences this association is unknown. We analyzed two independent cohorts including 154 patients with non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 inhibitors at a single institution (UTSW cohort) and a multi-center cohort of 433 patients with NSCLC who received second-line anti-PD-1/PD-L1 therapy (Global cohort) to assess the association between ICI outcomes and irAE timing. In both cohorts, late-onset irAE occurring more than 3 months after ICI initiation compared to irAE occurring earlier were associated with greater rates of radiographic response (UTSW cohort, 41% versus 28%, P = .26; Global cohort, 60% versus 35%, P = .02), longer progression-free (UTSW cohort, 13.7 versus 5.6 months, P < .01; Global cohort, not reached versus 6.0 months, P < .01) and overall survival (UTSW cohort, 30.9 versus 14.6 months, P < .01; Global cohort, not reached versus 10.6 months, P < .01). Modified landmark analysis at 6 months confirmed an overall survival difference between early- and late-onset irAE. Late-onset irAE was similarly associated with greater response rates and prolonged survival in a cohort of 130 patients with non-NSCLC malignancies, suggesting a conserved association across tumor types. The favorable association between irAE and ICI clinical outcomes may be attributed to later-onset events, which is not wholly explained by survivor bias. These results allude to a distinct biology between early- and late-onset irAE and may guide clinician expectations and thresholds for continuing or modifying immunotherapy.
An amendment to this paper has been published and can be accessed via the original article.
Background Monoclonal antibodies acting on the calcitonin gene-related peptide (CGRP) or its receptor have changed migraine preventive treatment. Those treatments have led to reconsidering the outcomes of migraine prevention. Available data mostly considered benefits in terms of relative efficacy (percent or absolute decrease in monthly migraine days [MMDs] or headache days compared with baseline). However, not enough attention has been paid to residual MMDs and/or migraine-related disability in treated patients. In the present study, we aimed at comparing the relative and absolute efficacy of erenumab. Methods ESTEEMen was a collaborative project among 16 European headache centers which already performed real-life data collections on patients treated with erenumab for at least 12 weeks. For the present study, we performed a subgroup analysis on patients with complete data on MMDs at baseline and at weeks 9-12 of treatment. Starting from efficacy thresholds proposed by previous literature, we classified patients into 0-29%, 30-49%, 50-74%, and ≥75% responders according to MMD decrease from baseline to weeks 9-12 of treatment. For each response category, we reported the median MMDs and Headache Impact test-6 (HIT-6) scores at baseline and at weeks 9-12. We categorized the number of residual MMDs at weeks 9-12 as follows: 0-3, 4-7, 8-14, ≥15. We classified HIT-6 score into four categories: ≤49, 50-55, 56-59, and ≥60. To keep in line with the original scope of the ESTEEMen study, calculations were performed in men and women. Results Out of 1215 patients, at weeks 9-12, 381 (31.4%) had a 0-29% response, 186 (15.3%) a 30-49% response, 396 (32.6%) a 50-74% response, and 252 (20.7%) a ≥75% response; 246 patients (20.2%) had 0-3 residual MMDs, 443 (36.5%) had 4-7 MMDs, 299 (24.6%) had 8-14 MMDs, and 227 (18.7%) had ≥15 MMDs. Among patients with 50-74% response, 246 (62.1%) had 4-7 and 94 (23.7%) 8-14 residual MMDs, while among patients with ≥75% response 187 (74.2%) had 0-3 and 65 (25.8%) had 4-7 residual MMDs. Conclusions The present study shows that even patients with good relative response to erenumab may have a clinically non-negligible residual migraine burden. Relative measures of efficacy cannot be enough to thoroughly consider the efficacy of migraine prevention.
Background Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are used to reduce the risk of developing Coronavirus Disease 2019 (COVID-19). Despite the significant benefits in terms of reduced risk of hospitalization and death, different adverse events may present after vaccination: among them, headache is one of the most common, but nowadays there is no summary presentation of its incidence and no description of its main features. Methods We searched PubMed and EMBASE covering the period between January 1 st 2020 and August 6 th , 2021, looking for record in English and with an abstract and using three main search terms (with specific variations): COVID-19/SARS-CoV-2; Vaccination; headache/adverse events. We selected manuscript including information on subjects developing headache after injection, and such information had to be derived from a structured form (i.e. no free reporting). Pooled estimates and 95% confidence intervals were calculated. Analyses were carried out by vaccine vs. placebo, by first vs. second dose, and by mRNA-based vs. “traditional” vaccines; finally, we addressed the impact of age and gender on post-vaccine headache onset. Results Out of 9338 records, 84 papers were included in the review, accounting for 1.57 million participants, 94% of whom received BNT162b2 or ChAdOx1. Headache was generally the third most common AE: it was detected in 22% (95% CI 18–27%) of subjects after the first dose of vaccine and in 29% (95% CI 23–35%) after the second, with an extreme heterogeneity. Those receiving placebo reported headache in 10–12% of cases. No differences were detected across different vaccines or by mRNA-based vs. “traditional” ones. None of the studies reported information on headache features. A lower prevalence of headache after the first injection of BNT162b2 among older participants was shown. Conclusions Our results show that vaccines are associated to a two-fold risk of developing headache within 7 days from injection, and the lack of difference between vaccine types enable to hypothesize that headache is secondary to systemic immunological reaction than to a vaccine-type specific reaction. Some descriptions report onset within the first 24 h and that in around one-third of the cases, headache has migraine-like features with pulsating quality, phono and photophobia; in 40–60% of the cases aggravation with activity is observed. The majority of patients used some medication to treat headache, the one perceived as the most effective being acetylsalicylic acid.
Background Obsessive–compulsive disorder (OCD) is a prevalent and severe clinical condition. Robust evidence suggests a gene-environment interplay in its etiopathogenesis, yet the underlying molecular clues remain only partially understood. In order to further deepen our understanding of OCD, it is essential to ascertain how genes interact with environmental risk factors, a cross-talk that is thought to be mediated by epigenetic mechanisms. The human microbiota may be a key player, because bacterial metabolites can act as epigenetic modulators. We analyzed, in the blood and saliva of OCD subjects and healthy controls, the transcriptional regulation of the oxytocin receptor gene and, in saliva, also the different levels of major phyla. We also investigated the same molecular mechanisms in specific brain regions of socially isolated rats showing stereotyped behaviors reminiscent of OCD as well as short chain fatty acid levels in the feces of rats. Results Higher levels of oxytocin receptor gene DNA methylation, inversely correlated with gene expression, were observed in the blood as well as saliva of OCD subjects when compared to controls. Moreover, Actinobacteria also resulted higher in OCD and directly correlated with oxytocin receptor gene epigenetic alterations. The same pattern of changes was present in the prefrontal cortex of socially-isolated rats, where also altered levels of fecal butyrate were observed at the beginning of the isolation procedure. Conclusions This is the first demonstration of an interplay between microbiota modulation and epigenetic regulation of gene expression in OCD, opening new avenues for the understanding of disease trajectories and for the development of new therapeutic strategies.
Background A previous European Headache Federation (EHF) guideline addressed the use of monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway to prevent migraine. Since then, randomized controlled trials (RCTs) and real-world evidence have expanded the evidence and knowledge for those treatments. Therefore, the EHF panel decided to provide an updated guideline on the use of those treatments. Methods The guideline was developed following the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. The working group identified relevant questions, performed a systematic review and an analysis of the literature, assessed the quality of the available evidence, and wrote recommendations. Where the GRADE approach was not applicable, expert opinion was provided. Results We found moderate to high quality of evidence to recommend eptinezumab, erenumab, fremanezumab, and galcanezumab in individuals with episodic and chronic migraine. For several important clinical questions, we found not enough evidence to provide evidence-based recommendations and guidance relied on experts’ opinion. Nevertheless, we provided updated suggestions regarding the long-term management of those treatments and their place with respect to the other migraine preventatives. Conclusion Monoclonal antibodies targeting the CGRP pathway are recommended for migraine prevention as they are effective and safe also in the long-term.
Headache is among the most frequent symptoms persisting or newly developing after coronavirus disease 2019 (COVID-19) as part of the so-called long COVID syndrome. The knowledge on long COVID headache is still limited, however growing evidence is defining the features of this novel condition, in particular regarding clinical characteristics, some pathophysiological mechanisms and first treatment recommendations. Long COVID headache can present in the form of worsening of a preexisting primary headache, or, more specifically, in the form of a new (intermittent or daily) headache starting during the acute infection or after a delay. It often presents together with other long COVID symptoms, most frequently with hyposmia. It can manifest with a migrainous or, more frequently, with a tension-type-like phenotype. Persistent activation of the immune system and trigeminovascular activation are thought to play a role. As there are virtually no treatment studies, treatment currently is largely guided by the existing guidelines for primary headaches with the corresponding phenotype. The present report, a collaborative work of the international group of the Junior Editorial Board of The Journal of Headache and Pain aims to summarize the most recent evidence about long COVID headache and suggests approaches to the diagnosis and treatment of this disorder. Graphical Abstract
We study the strong ℋ2 norm of systems modeled by semi-explicit Delay Differential Algebraic Equations (DDAEs). We recall that the finiteness of the strong ℋ2 norm is linked to an algebraic decision problem that can be solved by checking a finite numbers of equalities. We first improve the verification of the finiteness condition. In particular, the complexity of our new condition removes a dependency on the number of delays. We also show that, without imposing further conditions on the system, the number of checks cannot be further reduced. The methodology relies on interpreting the verification of the finiteness conditions in terms of a Polynomial Identity Testing problem. Second we show, in a constructive way, that if the strong ℋ2 norm is finite, the system can always be transformed into a regular neutral-type system with the same ℋ2 norm, without derivatives in the input or in the output equations. This result closes a gap in the literature as such a transformation was known to exist only under additional assumptions on the system. The transformation enables the computation of the strong ℋ2 norm using delay Lyapunov matrices. Illustrative examples are provided throughout the paper.
Grazing may represent a major threat to biodiversity in arid grasslands. The increasing use of grasslands for solar parks may represent a new important threat. No study has investigated the effects of solar parks on soil insects. Tenebrionids are a major component of the arthropod fauna of grasslands of central Asia. These ecosystems are threatened by grazing and increasing land use for solar parks. Aim of this work was to investigate the effects of grazing and solar panels on tenebrionids in arid grasslands (desert steppe) in China by comparing their community structure in ungrazed, heavily grazed, and solar park sites. Beetles were sampled by pitfall traps, and sites were compared for abundance and diversity (Hill numbers). All sites were characterized by simple, strongly dominated tenebrionid communities. Species proportions varied among sites. Grazing negatively influenced overall abundance, but did not alter species proportions; by contrast, solar panels had no effect on the average abundance, but reduced the proportion of the most abundant species. Compared with the other two sites, the solar park was characterized by a higher plant biomass and lower temperatures. A major availability of resources and less harsh conditions in the solar park might have a role in reducing the dominance of the most abundant species, allowing other species to attain higher abundances. This led to a more balanced community structure, with higher values of diversity. Although neither grazing nor solar panel installation modified radically tenebrionid species-abundance distribution or diversity, grazing and solar panel installation had different effects in species abundances and their impact might amplify the effect of other disturbance factors such as the ongoing climate change.
Solar photovoltaic (PV) systems can play a key role in ecosystems by satisfying the energy needs of people and businesses, helping countries become energy independent and propelling nations towards a climate-neutral future. Within this context, collective self-consumption (CSC) represents a new challenge, anchored in a new conception of the prosumer. The present work aims at calculating the economic profitability of PV systems with respect to both household and non-household self-consumers. The methodology is based on the calculation of net present value (NPV), with break-even point (BEP) analysis applied to the percentage of self-consumed energy. As economic viability is dependent on the specific policy tool(s) available, the analysis is applied to the Italian context, considering both a tax deduction of 110% over 5 years and a CSC subsidy of 100 €/MWh. The findings demonstrate economic profitability in multiple scenarios, strongly linked to the percentage of self-consumed energy. The mix of policy tools significantly influences the results and generates BEPs in the range of 8–13% (calculated in terms of the share of self-consumed energy) and NPVs ranging from 1035 to 3178 €/kW for 30–60% self-consumption. Profit distribution scenarios among renewables self-consumers (RSCs) and policy recommendations are provided to foster RSC development, and thereby make residents responsible for their country's energy transition.
This paper presents a novel computational approach to empirical hysteresis modelling applied to timber-based structures based on a combined data model-driven strategy. While the backbone curve is simulated using the experimental cyclic response based on a step-by-step optimization problem (data-driven approach), analytical functions describe the re-loading curves (model-driven approach). Empirical hysteresis models developed so far for timber structures are model-driven. However, the backbone curves can exhibit a highly irregular non-smooth trend, difficult to mirror using analytical formulations. The challenge in mirroring the experimental backbone using closed-form formulations has led to an extended set of parameters to be calibrated in existing literature models This paper presents a novel approach to the empirical hysteresis model, where the experimental data are directly involved, as a whole, in the model formulation. This model aims to be a possible trade-off between model complexity and accuracy. A reduced number of parameters needed to describe the re-loading paths is counterbalanced using an entire subset of the experimental data. The paper delivers the developed Matlab and Python codes for further implementation as a user-defined element within a Finite Element software.
Energy generation from waste renewable sources represent an efficient way to provide green power with the highest environmental benefits, tackling problems related to the high costs for their disposal through the conversion of these wastes in biofuels. However, several challenges hinder their intensified use, as the huge variability in the amount and composition of these sources forces authors to enlarge their studies on the entire biomass-to-energy chain sustainability where the power technology can be installed with the highest profits. In present work, the technical, environmental and economic impact of the entire biomass-to-energy supply chain is assessed with reference to a real commercially available Combined Heat and Power (CHP) system, the CMD ECO20X based on biomass gasification, installed as operational demonstration in the Municipality of Laurino in the National Park of Cilento, Vallo di Diano, and Alburni (PNCVD) in Southern part of Italy. Several calculation tools previously developed by authors for the analysis of the performance of the various components of the ECO20X system are here employed to define the mass and energy fluxes that characterize its operations in a local supply chain where forest management residues (oak and beech trees) and olive pomace from oil mills in the area are exploited. The analysis aims to quantify the energy absorption necessary for the pretreatment operations of the organic residue (shredding, briquetting, drying) which are essential for gasification, and how much they affect the production deriving from the biomass cogeneration process itself. Then, measurements in terms of pollutants related to the energy production at the municipality and of the air quality in the area, help in the evaluation of the plant environmental impact from a global perspective, by virtue of data obtained from an LCA analysis conducted considering one year functioning of the CHP plant.
Introduction During the COVID-19 pandemic various degrees of lockdown were applied by countries around the world. It is considered that such measures have an adverse effect on mental health but the relationship of measure intensity with the mental health effect has not been thoroughly studied. Here we report data from the larger COMET-G study pertaining to this question. Material and Methods During the COVID-19 pandemic, data were gathered with an online questionnaire from 55,589 participants from 40 countries (64.85% females aged 35.80 ±13.61; 34.05% males aged 34.90±13.29 and 1.10% other aged 31.64±13.15). Anxiety was measured with the STAI, depression with the CES-D and suicidality with the RASS. Distress and probable depression were identified with the use of a previously developed cut-off and algorithm respectively. Statistical Analysis It included the calculation of Relative Risk (RR), Factorial ANOVA and Multiple backwards stepwise linear regression analysis Results Approximately two-thirds were currently living under significant restrictions due to lockdown. For both males and females the risk to develop clinical depression correlated significantly with each and every level of increasing lockdown degree (RR 1.72 and 1.90 respectively). The combined lockdown and psychiatric history increased RR to 6.88 The overall relationship of lockdown with severity of depression, though significant was small. Conclusions The current study is the first which reports an almost linear relationship between lockdown degree and effect in mental health. Our findings, support previous suggestions concerning the need for a proactive targeted intervention to protect mental health more specifically in vulnerable groups
The Sustainable Development Goals (SDGs) aim to achieve a more inclusive, resilient, safe and sustainable society. Policy makers, together with entrepreneurs and citizens, are called to a great challenge to optimize land use. This work, through a multi-criteria decision analysis (MCDA), aims at comparing the sustainability of 103 Italian cities through the evaluation of 45 SDGs’ indicators, ranking cities on the base of their performance. Results show strong disparities across Italy with three northern cities at the top of the ranking and many southern cities at the bottom. The analysis then creates a framework based on experts’ view composed of 21 criteria that would facilitate the development of a sustainability plan. A hybrid methodology based on the Analytic Hierarchy Process (AHP) and the 10-point scale is used to rank among the criteria. Selected experts underlined how sustainable policy and green investment are enabling factors of sustainable cities, but political stability and streamlined public spending are also essential to achieve this goal. The analysis offers insights for different categories of stakeholders and invites to measure and monitor the progress of cities towards SDGs proposing eight directions (policy, economy, operations, environment, organization, staff, society and human).
Gallium telluride (GaTe) is a van der Waals semiconductor currently adopted for photonic and optoelectronic devices. However, the rapid degradation of GaTe in air, promoted by Te vacancies, is detrimental for device applications. Here, we demonstrate that the surface oxidation of GaTe, investigated though a combination of spectroscopic and microscopic tools, could be unexpectedly exploited for expanding the breadth of applications of GaTe. As a matter of fact, we discover that the formation of a nanoscale sub-stoichiometric Ga2O3 skin, promoted by Te vacancies, is beneficial for electrocatalysis, photocatalysis, and gas sensing. Especially, the Heyrovsky step (Hads + H+ + e− → H2) of hydrogen evolution reaction in acidic medium is barrier-free for the sub-stoichiometric gallium-oxide/gallium-telluride heterostructure, which also enables a significant reduction of costs by 160 times with respect to state-of-the-art Pt/C electrodes. Moreover, the wide-band-gap oxide skin formed over narrow-band-gap GaTex upon air exposure makes the self-assembled gallium-oxide/gallium-telluride heterostructure suitable for light harvesting and sensing. Our model indicates that, in photocatalytic process, the photo-generated electrons migrate from GaTe to Ga2Ox skin, which acts as the chemically active side of the interface. Moreover, calculations demonstrate that the Ga2O3/GaTe heterostructure is a suitable platform for sensing of H2O, NH3, and NO2 at operational temperature extended up to 600 °C (useful for gas detection in combustion processes), mainly due to the increased area of charge redistribution after adsorption achieved upon oxidation of GaTe. Our work demonstrates that defects engineering and interfacing metal chalcogenides with native oxide could be beneficial for applications in (photo)electrocatalysis, photocatalysis, light harvesting, and gas sensing.
Software product line engineering emerged as an effective approach for the development of families of software‐intensive systems in several industries. Although its use has been widely discussed and researched, there are still several open challenges for its industrial adoption and application. One of these is how to efficiently develop and reuse shared software artifacts, which have dependencies on the underlying electrical and hardware systems of products in a family. In this work, we report on our experience in tackling such a challenge in the railway industry and present a model‐based approach for the automatic generation of test scripts for product variants in software product lines. The proposed approach is the result of an effort leveraging the experiences and results from the technology transfer activities with our industrial partner Alstom SA in Sweden. We applied and evaluated the proposed approach on the Aventra software product line from Alstom SA. The evaluation showed that the proposed approach mitigates the development effort, development time, and consistency drawbacks associated with the traditional, manual creation of test scripts. We performed an online survey involving 37 engineers from Alstom SA for collecting feedback on the approach. The result of the survey further confirms the aforementioned benefits. We present a model‐based approach for the automatic generation of test scripts for product variants in software product lines. The approach is the result of the technology transfer between Mälardalen University and Alstom SA. We applied and evaluated the proposed approach on the Alstom Aventra software product line. In addition, we performed an online survey involving 37 engineers from Alstom SA. The evaluation showed that the approach mitigates the drawbacks of the traditional, manual creation of test scripts.
Purpose With the aging of the population and the epidemic spread of obesity, the frequency of older individuals with obesity is steadily growing. To date, no data evaluating the use of endoscopic sleeve gastroplasty (ESG) in the elderly have been published. In this case series, we evaluate the short- and medium-term outcomes of ESG in patients with obesity aged 65 years and older. Materials and Methods A retrospective analysis was done on a prospective database; patients aged 65 years and older were included in our analysis. EWL%, TBWL%, the Bariatric Analysis and Reporting Outcome System (BAROS) questionnaire, and the presence of comorbidities were assessed. Results Eighteen patients aged 65 years and older underwent ESG between November 2017 and July 2021. The median age was 67 years and the mean baseline BMI was 41.2 kg/m². After ESG, the median TBWL% was 15.1%, 15.5%, and 15.5% at 6, 12, and 24 months, while the median %EWL was 39%, 37%, and 41% at 6, 12, and 24 months, respectively. The median BAROS score was 3.0, 3.4, and 2.5 at 6, 12, and 24 months, respectively. Six out of twelve patients with hypertension and 3/4 diabetic patients reduced or removed their medications within 12 months following ESG. Two out of six patients with OSA stopped therapy with CPAP. No adverse events were recorded. Conclusion According to our experience, ESG is a promising therapeutic option for elder individuals with obesity who fail non-invasive methods, and who refuse or are deemed not suitable for bariatric surgery because of age and comorbidities. Graphical abstract
Objectives CD248 is a glycoprotein highly expressed on pericytes and fibroblast (FBs), and it is implicated in fibrotic process. During angiogenesis, CD248 could promote vessel regression, binding the multimerin-2 (MMRN-2). Thus, we investigated the expression of MMRN-2 in systemic sclerosis (SSc)-skin and of CD248 on isolated SSc-FBs. Anti-angiogenic property of CD248+ SSc-FBs was evaluated coculturing these cells with healthy control endothelial cells (HC-ECs). CD248 apoptotic role on HC-ECs was evaluated. Finally, CD248 ability to prevent the VEGFR2 activation was assessed. Methods By immunofluorescence (IF), MMRN-2 was investigated on SSc-skin and CD248 on SSc FBs. CD248+ SSc-FBs anti-angiogenic property was evaluated by HC-ECs/SSc-FBs cocultures. Lentiviral induced CD248 short-hairpin RNAs delivery was employed for loss of function studies on SSc-FBs. HC-ECs were cultured in presence of CD248 to assess both apoptosis by IF and VEGFR2 phosphorylation by WB. Results MMRN-2 expression was increased in skin SSc-ECs whereas CD248 was increased in SSc-FBs. Functionally, CD248+-SSc-FBs suppressed angiogenesis in the organotypic model, as assessed by reduction in total tubes length of HC-ECs. This anti-angiogenetic behaviour was reverted by CD248 silencing. Furthermore, the presence of CD248 promoted the apoptosis of HC-ECs. Finally, CD248 prevented the VEGFR2 activation, by reducing its phosphorylation after VEGF stimulation. Conclusion CD248 was anti-angiogenic in vitro due to reduction the tube formation and to induction of ECs apoptosis. Increased expression of CD248 in SSc could contribute to the microvascular rarefaction observed at tissue level during SSc. Our results suggest the pathogenic role of CD248-MMRN-2 in SSc.
Institution pages aggregate content on ResearchGate related to an institution. The members listed on this page have self-identified as being affiliated with this institution. Publications listed on this page were identified by our algorithms as relating to this institution. This page was not created or approved by the institution. If you represent an institution and have questions about these pages or wish to report inaccurate content, you can contact us here.