Explore the vast range of titles available.

Key Points CTLA-4 regulates T-cell activation upon initiation of an immune response, in the lymphoid organs, where naive T cells are primed, and potentially in the periphery via regulatory T-cell (T REG ) depletion This diverse role of CTLA-4 in initiating and mounting immune responses might explain the plethora of immune-related adverse events (irAEs) experienced by patients receiving treatment with anti-CTLA-4 antibodies PD-1 suppresses T-cell activity, mostly within the peripheral tissues and in the tumour microenvironment, which might explain the distinct spectrum and reduced incidence of adverse effects of anti-PD-1 antibodies Thyroid disorders are more frequent adverse effects of treatment with anti-PD-1 antibodies (pembrolizumab and nivolumab) whereas colitis and hypophysitis are more frequent with anti-CTLA-4 antibodies (ipilimumab) General guidelines on the management of irAEs recommend treatment of symptoms; corticosteroids are generally indicated together with dose skipping or discontinuation in patients with persistent grade ≥2 adverse events Immune checkpoint inhibition is a novel approach to cancer treatment with enormous potential to improve the outcomes of patients with a range of malignancies. However, owing to this novel approach, a range of adverse events have emerged with different aetiologies to those of more conventional cancer treatments. In this Review, the authors describe the occurrence, and optimal management of adverse events resulting from use of immune checkpoint inhibitors. Inhibition of immune checkpoints using anti-programmed cell death-1 (PD-1) or anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibodies has revolutionized the management of patients with advanced-stage melanoma and is among the most promising treatment approaches for many other cancers. Use of CTLA-4 and PD-1 inhibitors, either as single agents, or in combination, has been approved by the US FDA for the treatment of metastatic melanoma. Treatment with these novel immunotherapies results in a unique and distinct spectrum of adverse events, which are mostly related to activation of the immune system and are, therefore, an unwanted consequence of their mechanisms of action. Adverse effects of CTLA-4 and/or PD-1 inhibition are most commonly observed in the skin, gastrointestinal tract, liver and endocrine systems and include pruritus, rash, nausea, diarrhoea and thyroid disorders. In this Review, the authors describe the adverse event profile of checkpoint inhibitors targeting CTLA-4 and PD-1, used both as monotherapies and in combination and aim to provide some general guidelines, based upon the mechanisms of action of these therapies and on the management of these immune-related adverse events.

Previous studies reported an association between transportation noise and self-reported health status (SRHS). They also suggested a mediating role of noise annoyance using conventional statistical methods. These methods are subject to bias in longitudinal studies with time-dependent exposure, mediator and confounding factors. This study aims to investigate the mediating role of aircraft noise annoyance in the effect of aircraft noise on SRHS using a causal inference approach to address time-dependent variables issues. We used data from 881 participants in all three visits in the DEBATS longitudinal study conducted around three French airports. Participants over 18 years of age reported their self-perceived health status, aircraft noise annoyance, and noise sensitivity by completing a questionnaire at three visits in 2013, 2015 and 2017. Noise maps were used to estimate aircraft noise levels outside their homes. Marginal structural models with inverse probability weighting were used to estimate the total effect of aircraft noise levels on SRHS and its decomposition into direct and indirect effect through aircraft noise annoyance. This study showed a deleterious effect of aircraft noise on SRHS. The odds ratio (OR) corresponding to the total effect and comparing the highest aircraft noise category (≥60 dBA) to the reference category (<50 dBA) was significant (ORpoor/fair_SHRS = 1.25 (95%CI: 1.06 to 2.08)). It also showed no direct effect of aircraft noise levels on SRHS, but an indirect effect through annoyance. This indirect effect increased as aircraft noise levels increased, with a statistically significant OR when comparing the highest noise category (≥60 dBA) to the lowest (<50 dBA) (ORpoor/fair_SHRS = 1.16 (95%CI: 1.03 to 1.52)). Nearly 66% of aircraft noise's effect on SRHS was mediated by aircraft noise annoyance. This study supports the deleterious causal effect of aircraft noise on SRHS. The results highlight the important mediating role of aircraft noise annoyance in the causal pathway from exposure to aircraft noise to poor/fair SRHS.

Background Socioeconomic disparity in smoking prevalence is increasing in France, which may be partially related to lower rates of smoking cessation in lower socioeconomic groups. Research suggests that this socioeconomic gradient may extend to the neighbourhood level, as deprived neighbourhoods present characteristics that reduce the likelihood of quitting. However, longitudinal studies are limited; therefore, this study aims to investigate the effect of neighbourhood deprivation on smoking cessation. Methods Data from Constances, a French national population-based cohort collecting annual data from adults aged 18 to 69 at inception, were used. Participants who enrolled between 2012 and 2018 with at least one follow-up wave and with information on smoking status before 2020 were included. The hazard of quitting was estimated by the decile of the French Deprivation Index (FDEP) using a Cox model on a cohort of 21,110 smokers at baseline. Results After adjustment for relevant demographic and individual-level socioeconomic factors, individuals in the highest deprivation decile were less likely to quit smoking compared to those in the lowest, with a hazard ratio of 0.89 (95% CI 0.81, 0.98). Stratified analyses indicated that this effect was present for those with the least education. Conclusions In a large representative cohort, we found that smokers living in highly deprived neighbourhoods are less likely to quit. These smokers may be facing multiple barriers to cessation, underscoring the importance of targeting such neighbourhoods in smoking cessation interventions.

Patients with hematological malignancy and COVID-19 display a high mortality rate. In such patients, immunosuppression due to underlying disease and previous specific treatments impair humoral response, limiting viral clearance. Thus, COVID-19 convalescent plasma (CCP) therapy appears as a promising approach through the transfer of neutralizing antibodies specific to SARS-CoV-2. We report the effect of CCP in a cohort of 112 patients with hematological malignancy and COVID-19 and a propensity score analysis on subgroups of patients with B-cell lymphoid disease treated (n = 81) or not (n = 120) with CCP between May 1, 2020 and April 1, 2021. The overall survival of the whole cohort was 65% (95% CI = 56–74.9) and 77.5% (95% CI = 68.5–87.7) for patients with B-cell neoplasm. Prior anti-CD20 monoclonal antibody therapy was associated with better overall survival, whereas age, high blood pressure, and COVID-19 severity were associated with a poor outcome. After an inverse probability of treatment weighting approach, we observed in anti-CD20–exposed patients with B-cell lymphoid disease a decreased mortality of 63% (95% CI = 31–80) in the CCP-treated group compared to the CCP-untreated subgroup, confirmed in the other sensitivity analyses. Convalescent plasma may be beneficial in COVID-19 patients with B-cell neoplasm who are unable to mount a humoral immune response.

Patients treated with systemic anticancer drugs often show changes to their nails, which are usually well tolerated and disappear on cessation of treatment. However, some nail toxicities can cause pain and functional impairment and thus substantially affect a patient's quality of life, especially if they are given taxanes or EGFR inhibitors. These nail toxicities can affect both the nail plate and bed, and might present as melanonychia, leukonychia, onycholysis, onychomadesis, Beau's lines, or onychorrhexis, as frequently noted with conventional chemotherapies. Additionally, the periungual area (perionychium) of the nail might be affected by paronychia or pyogenic granuloma, especially in patients treated with drugs targeting EGFR or MEK. We review the nail changes induced by conventional chemotherapies and those associated with the use of targeted anticancer drugs and discuss preventive or curative options.

IntroductionStroke volume is a major determinant of tissue perfusion and, therefore, a key parameter to monitor in patients with haemodynamic instability and hypoperfusion. Left ventricular outflow tract (LVOT) velocity-time integral (VTI) measurement using pulsed-wave Doppler is widely used as an estimation of stroke volume and should be a competence required for every intensive care unit (ICU) physician. Artificial intelligence (AI) applied to ultrasound facilitates the acquisition of adequate images. The aim of the present study is to evaluate the interchangeability of LVOT VTI measurements obtained by minimally trained operators and expert physicians, both guided by AI.Methods and analysisThis is a prospective multicentre randomised controlled trial. ICU patients in whom fluid administration is considered necessary will be included. A minimally trained operator and an expert will independently measure LVOT VTI, guided by the UltraSight AI software to obtain the best five-chamber view, before and after a 250 mL fluid challenge. The order of acquisition between each operator will be randomised. 100 patients will be included.The primary endpoint is the relative difference in LVOT VTI between operators. Secondary outcomes include the concordance of the therapeutic decision made by the blinded physician in charge of the patient based on the measures obtained by each operator, and the agreement between absolute values of LVOT VTI obtained by minimally trained and expert operators.Ethics and disseminationThe study has been reviewed and approved by a regional ethics committee (Comité de Protection des Personnes—Ile de France II—n°24.00671.000291). An information note will be given to the participant before he or she participates in the study. The present study will be disseminated through peer-reviewed publications and academic and medical conferences.Trial registration number NCT06486467.

Background Studies over the past 10 years strongly support an association between skeletal muscle mass (SMM) depletion and outcome in metastatic colorectal cancer (mCRC). Factors influencing SMM changes over time are, however, poorly studied. We analyzed the impact of SMM on overall survival and chemotherapy toxicities in mCRC patients treated with first-line chemotherapy. Changes in weight and body composition were evaluated during follow-up. Methods Patients enrolled in the randomized phase II ACCORD trial comparing two chemotherapy regimens were screened. Body composition parameters (SMM, adipose tissue) were assessed prospectively with computed tomography (CT) imaging, and toxicities were recorded. Mixed models were used to assess weight and BC changes during 4 months of treatment follow-up. Results Among 145 patients included in ACCORD, 76 had available baseline CT scans and were included in the current study. Mean age was 60.6 ± 10.0 years, 50% were women, 82% had colon cancer, and 62% had two or more metastatic sites. At baseline, 49% had lost at least 5% of their initial weight, including 26% who had lost more than 10%; 53% had SMM depletion. In this homogenous cohort, there were no statistically significant associations between SMM depletion and overall survival, progression-free survival or chemotherapy toxicity. There were no decreases in weight or SMM during follow-up. Weight and SMM changes were not influenced by diarrhea either grade 3–4 or any grade (reported in 74% of patients). For patients with weight loss ≥10% at baseline, SMM increased significantly after 4 months of follow-up and after disease stabilization following chemotherapy ( P  = 0.008). Conclusions In a homogenous mCRC cohort, SMM depletion was not associated with survival or chemotherapy toxicity. Despite most patient experiencing diarrhea, no changes in weight or SMM were found during 4 months of follow-up. However, hypotheses deriving from our exploratory study have to be tested in further larger sample size studies. Trial registration Clinicaltrials.gov NCT00423696 (2011).

Background: Transportation noise seems to impair self-reported health status (SRHS). However, only a few studies have considered the role of noise annoyance and noise sensitivity in this deleterious effect. This study aims investigating mediator and moderator roles of noise annoyance and noise sensitivity. Methods: In 2013, the DEBATS longitudinal study included 1244 participants aged over 18 years and living around three French airports. These participants were followed up in 2015 and 2017. They self-reported their perceived health status, aircraft noise annoyance, and their noise sensitivity via a questionnaire during the three visits. Noise maps were used to estimate aircraft noise levels at the facade of participants' residence. Generalized linear mixed models with a random intercept at the participant level were used. Results: Aircraft noise levels were associated with severe annoyance. Severe annoyance tent to be associated with impaired SRHS. Aircraft noise levels were associated with impaired SRHS only in men (odds ratio [OR] = 1.47, 95% confidence interval [CI] = [1.02, 2.11], for a 10-dBA Lden increase in aircraft noise levels) with a weaker association adjusted for annoyance (OR = 1.36, 95% CI = [0.94, 1.98]). The association was stronger in men who reported high noise sensitivity (OR = 1.84, 95% CI = [0.92, 3.70], versus OR = 1.39, 95% CI = [0.90, 2.14], for men who were not highly sensitive to noise). Conclusion: From our results, the deleterious effect of aircraft noise on SRHS could be mediated by noise annoyance and moderated by noise sensitivity. Further studies using causal inference methods are needed for identifying causal effect of exposure, mediator, and moderator.

IntroductionUsing three categories of stages of HIV disease at access to care (advanced, intermediate, early HIV disease), we explored the impact of delayed access on the risk of death at up to 5 years and whether progress in antiretroviral regimens has mitigated this impact.MethodsAdults from the French Hospital Database on HIV (ANRS CO4-FHDH) cohort with HIV-1 infection and first access to care during 2002–2021 were included. To study the impact of the stage of HIV disease at first access to care on the risk of death, only participants included from 2002 to 2016 were analysed to allow for at least 5 years of follow-up until 31 December 2021. Fine and Gray competing risk models considering lost to follow-up as a competing event were used adjusting for age, gender, mode of acquisition, region of origin, time between diagnosis and access to care, period of access to care (2002–2013 vs 2014–2016).ResultsAmong the 64 400 people living with HIV included, 18 305 (28.4%) had advanced and 13 042 (20.3%) intermediate HIV disease. The 5-year cumulative incidence of death was estimated as 1.8% (95% CI 1.7% to 1.9%) overall, from 0.9% (0.8% to 1.0%) for those with early HIV disease to 6.0% (5.4% to 6.7%) for those with AIDS. People with AIDS had a much higher risk of death than those with early HIV disease, with a sub-distribution HR (sHR) of 18.4 (95% CI 12.0 to 28.4) in the first 6 months of follow-up, which remained significant at 48–60 months: sHR=2.1 (1.3 to 3.3). The risk of death was higher for the other categories of advanced HIV disease but to a smaller extent. The risk of death was not statistically different depending on the calendar period.ConclusionsDelayed access to care remains associated with an elevated risk of death, even after 48 months. There was no significant improvement in the risk of death after 2014 when immediate initiation of combined antiretroviral therapy was recommended and integrase strand transfer inhibitor-based regimens became the preferred first-line.

Background Recently, the intervention calculus when the DAG is absent (IDA) method was developed to estimate lower bounds of causal effects from observational high-dimensional data. Originally it was introduced to assess the effect of baseline biomarkers which do not vary over time. However, in many clinical settings, measurements of biomarkers are repeated at fixed time points during treatment and, therefore, this method needs to be extended. The purpose of this paper is to extend the first step of the IDA, the Peter Clarks (PC)-algorithm, to a time-dependent exposure in the context of a binary outcome. Methods We generalised the so-called “PC-algorithm” to take into account the chronological order of repeated measurements of the exposure and proposed to apply the IDA with our new version, the chronologically ordered PC-algorithm (COPC-algorithm). The extension includes Firth’s correction. A simulation study has been performed before applying the method for estimating causal effects of time-dependent immunological biomarkers on toxicity, death and progression in patients with metastatic melanoma. Results The simulation study showed that the completed partially directed acyclic graphs (CPDAGs) obtained using COPC-algorithm were structurally closer to the true CPDAG than CPDAGs obtained using PC-algorithm. Also, causal effects were more accurate when they were estimated based on CPDAGs obtained using COPC-algorithm. Moreover, CPDAGs obtained by COPC-algorithm allowed removing non-chronological arrows with a variable measured at a time t pointing to a variable measured at a time t´ where t´  <  t . Bidirected edges were less present in CPDAGs obtained with the COPC-algorithm, supporting the fact that there was less variability in causal effects estimated from these CPDAGs. In the example, a threshold of the per-comparison error rate of 0.5% led to the selection of an interpretable set of biomarkers. Conclusions The COPC-algorithm provided CPDAGs that keep the chronological structure present in the data and thus allowed to estimate lower bounds of the causal effect of time-dependent immunological biomarkers on early toxicity, premature death and progression.