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Abstract Background Recent studies report very low adherence of practitioners to ATS/IDSA recommendations for the treatment of nontuberculous mycobacteria pulmonary disease (NTM-PD), as well as a great variability of practices. Type of management could impact prognosis. Methods To evaluate management and prognosis of patients with NTM-PD cases with respect to ATS recommendations, we conducted a multicenter retrospective cohort study (18 sentinel sites distributed throughout France), over a period of six years. We collected clinical, radiological, microbiological characteristics, management and outcome of the patients (especially death or not). Results 477 patients with NTM-PD were included. Respiratory comorbidities were found in 68% of cases, tuberculosis sequelae in 31.4% of patients, and immunosuppression in 16.8% of cases. The three most common NTM species were Mycobacterium avium complex (60%), M. xenopi (20%) and M. kansasii (5.7%). Smear-positive was found in one third of NTM-PD. Nodulobronchiectatic forms were observed in 54.3% of cases, and cavitary forms in 19.1% of patients. Sixty-three percent of patients were treated, 72.4% of patients with smear-positive samples, and 57.5% of patients with smear-negative samples. Treatment was in adequacy with ATS guidelines in 73.5%. The 2-year mortality was 14.4%. In the Cox regression, treatment (HR = 0.51), age (HR = 1.02), and M. abscessus (3.19) appeared as the 3 significant independent prognostic factors. Conclusion These findings highlight the adequacy between French practices and the ATS/IDSA guidelines. Treatment was associated with a better survival.

Extant research finds that environmental identity is an important motivational factor for proenvironmental behavior. However, studies typically focus on investigating the effects of the strength of this identity. Based on insights from identity research, we theorize that the influence of individuals’ environmental identity on their proenvironmental behavior may depend on other identity dimensions as well. We argue that the frequency of activation of environmental identity in relevant life domains—environmental identity salience—may predict proenvironmental behavior beyond what environmental identity strength can explain. To test our theorizing, we propose a parsimonious measure of environmental identity salience. In four empirical studies, we establish that the new measure has sound psychometric properties in terms of internal consistency and discriminant validity with regard to measures of environmental identity strength. Importantly, our measure of environmental identity salience reliably predicts a range of self-reported and actual proenvironmental behaviors beyond the effects of environmental identity strength. In line with theoretical predictions, our data suggests that environmental identity salience and strength are related but distinct constructs. We conclude that investigating the nature and effects of environmental identity salience leads to a fruitful path to a more comprehensive understanding of proenvironmental behavior. The proposed new measure may serve as a helpful tool in this endeavor.

Mycobacterium bovis infects cattle and wildlife, and also causes a small proportion of tuberculosis cases in humans. In most European countries, M. bovis infections in cattle have been drastically reduced, but not eradicated. Here, to determine the M. bovis circulation within and between the human, cattle, and wildlife compartments, we characterized by spoligotyping and mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) typing the genetic diversity of M. bovis isolates collected from humans, cattle, and wildlife in France from 2000 to 2010. We also assessed their genetic structure within and among the different host groups, and across time and space. The M. bovis genetic structure and its spatiotemporal variations showed different dynamics in the human and animal compartments. Most genotypes detected in human isolates were absent in cattle and wildlife isolates, possibly because in patients, M. bovis infection was contracted abroad or was the reactivation of an old lesion. Therefore, they did not match the genetic pool present in France during the study period. However, some human-cattle exchanges occurred because some genotypes were common to both compartments. This study provides new elements for understanding M. bovis epidemiology in France, and calls for increased efforts to control this pathogen worldwide.

Abstract Objectives Wearing a mask is an important method for reducing severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) transmission in health care and public safety settings. We assess the evidence regarding masking in the workplace during the initial months of the COVID‐19 pandemic (PROSPERO CRD4202432097). Methods We performed a systematic review of published literature from 4 databases and evaluated the quality of evidence with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. We searched for observational and experimental research involving public safety and health care workers. We included articles evaluating the use of masks, versus no mask, on the outcome of SARS‐CoV‐2 infection. Results Our search yielded 15,013 records, of which 9 studies were included. Most studies (n = 8; 88.9%) involved infections or outbreaks among health care workers. The majority (88.9%) used in‐depth interviews of cases and non‐cases to obtain self‐reported use of masks during periods of exposure. One of 9 studies quantitatively assessed differences in SARS‐CoV‐2 infection based on use of masks in non‐patient care settings. Use of observational study designs, small sample sizes, inadequate control for confounding, and inadequate measurement of exposure and non‐exposure periods with infected coworkers contributed to the quality of evidence being judged as very low. Conclusions The available evidence from the initial months of the pandemic suggests that the use of masks in congregate, non‐patient care settings, such as breakrooms, helps to reduce risk of SARS‐CoV‐2 virus transmission. However, this evidence is limited and is of very low quality. Prospective studies incorporating active observation measures are warranted.

Abstract Background There is an emerging body of evidence that links exposure to shift work to cardiovascular disease (CVD). The risk of coronary events, such as myocardial infarction, is greater among night shift workers compared to day workers. There is reason to believe that repeated exposure to shift work, especially night shift work, creates alterations in normal circadian patterns of blood pressure (BP) and heart rate variability (HRV) and that these alterations contribute to increased risk of CVD. Recent data suggest that allowing shift workers to nap during night shifts may help to normalize BP and HRV patterns and, over time, reduce the risk of CVD. The risk of CVD related to shift work is elevated for emergency medical services (EMS) shift workers due in part to long-duration shifts, frequent use of night shifts, and a high prevalence of multiple jobs. Methods We will use a randomized crossover trial study design with three study conditions. The targeted population is comprised of EMS clinician shift workers, and our goal enrollment is 35 total participants with an estimated 10 of the 35 enrolled not completing the study protocol or classified as lost to attrition. All three conditions will involve continuous monitoring over 72 h and will begin with a 36-h at-home period, followed by 24 total hours in the lab (including a 12-h simulated night shift), ending with 12 h at home. The key difference between the three conditions is the intra-shift nap. Condition 1 will involve a simulated 12-h night shift with total sleep deprivation. Condition 2 will involve a simulated 12-h night shift and a 30-min nap opportunity. Condition 3 will involve a simulated 12-h night shift with a 2-h nap opportunity. Our primary outcomes of interest include blunted BP dipping and reduced HRV as measured by the standard deviation of the inter-beat intervals of normal sinus beats. Non-dipping status will be defined as sleep hours BP dip of less than 10%. Discussion Our study will address two indicators of cardiovascular health and determine if shorter or longer duration naps during night shifts have a clinically meaningful impact. Trial registration ClinicalTrials.gov NCT04469803 . Registered on 9 July 2020

Diagnosing a heart attack requires excessive testing and prolonged observation, which frequently requires hospital admission. Here the authors report a machine learning-based system based exclusively on ECG data that can help clinicians identify 37% more heart attacks during initial screening.

Abstract Background The objective of the IMPROVE study was patients’ preference for either endocrine-based therapy or combined chemo- and anti-angiogenic therapy in advanced HR-positive/HER2-negative breast cancer. Methods In this randomized, cross-over phase IV study, 77 patients were recruited in 26 sites in Germany. Patients were randomized 1:1 to receive either capecitabine plus bevacizumab (Cap+Bev) as first-line therapy followed by cross-over to everolimus plus exemestane (Eve+Exe) as second-line therapy (Arm A) or the reverse sequence (Arm B). The primary endpoint was patients’ preference for either regimen, assessed by the Patient Preference Questionnaire 12 weeks after cross-over. Key secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and quality of life (QoL). Results 61.5% of patients preferred Cap+Bev (p = 0.1653), whereas 15.4% preferred Eve+Exe and 23.1% were indecisive. Physicians showed a similar tendency towards Cap+Bev (58.1%) as the preferred regimen versus Eve+Exe (32.3%). Median first-line PFS was longer for Cap+Bev than for Eve+Exe (11.1 months versus 3.5 months). Median second-line PFS was similar between Cap+Bev and Eve+Exe (3.6 months versus 3.7 months). Median OS was comparable between Arm A (28.8 months) and Arm B (24.7 months). 73.0% and 52.6% (first−/second-line, Cap+Bev) and 54.1% and 52.9% (first−/second-line, Eve+Exe) of patients experienced grade 3/4 TEAEs. No treatment-related deaths occurred. QoL and treatment satisfaction were not significantly different between arms or treatment lines. Conclusions Patients tended to favor Cap+Bev over Eve+Exe, which was in line with physicians’ preference. Cap+Bev showed superior first-line PFS, while QoL was similar in both arms. No new safety signals were reported. Trial registration EudraCT No: 2013–005329-22 . Registered on 19 August 20

Saving fuel by splitting a flight mission with an intermediate stop for refuelling is described by the concept of intermediate stop operations. This can also be beneficial to the climate impact of aviation, if the flight level and intermediate stop airport are selected accordingly. This study aims to estimate the mitigation potential of an implementation of climate-optimised intermediate stop operations for European long-haul flights and compare it to fuel-optimal operations. For this purpose, fuel consumption and emissions are simulated along four-dimensional trajectories for the selected annual flight plan, and their average temperature response is calculated. A comparison between the reference case and climate-optimised as well as fuel-optimised scenarios shows a significant climate mitigation potential and reveals a shift of trajectories to lower latitudes and altitudes. However, increased flight times and fuel consumption limit implementation from stakeholders’ perspectives.

Background Late acute cellular rejection (LACR) is associated with poorer graft outcomes and non-adherence. Non-adherence to tacrolimus can be indirectly assessed by the intra-patient variability (IPV) of tacrolimus trough levels. The threshold of IPV associated with rejection is not known. Methods We conducted a case-control study comparing 25 patients with biopsy-proven LACR against 25 stable controls matched for age group, primary diagnosis and time post-transplant. IPV was calculated using coefficient of variance (CV) and mean absolute deviation (MAD) using tacrolimus levels in the preceding 12 months. We also assessed the percentage time for tacrolimus levels < 4 [mu]g/L (Tac < 4) and the concentration/weight-adjusted dose (C/D) ratio as a proxy marker of tacrolimus metaboliser status. Results LACR patients had higher CV (median, IQR 44%, 36-61% v. 24%, 19-35%, p < 0.0001) and higher MAD (33%, 25-48% v. 19%, 15-26%, p < 0.0001). The MAD was less affected by outlying tacrolimus results. Receiver operating curve analysis of the MAD resulted in a sensitivity of 76% and specificity of 76% at a threshold of 26% (AUC 0.85, p < 0.05). LACR patients had more Tac < 4 (50% v. 26%, p < 0.05). There was no difference in C/D suggesting that good IPV can be maintained in fast metabolisers. Patients with LACR had significantly increased creatinine at 12-month follow-up despite treatment (108 v. 5 umol/L increase from baseline) and four patients lost their allograft. Conclusions Monitoring of tacrolimus IPV using the MAD may be a clinical marker for LACR. A threshold IPV of 26% can potentially be used as a therapeutic target pending further validation studies., Author(s): Karmila Abu Bakar [sup.1] [sup.2] , Nor Asiah Mohamad [sup.3] , Zsolt Hodi [sup.4] , Tom McCulloch [sup.4] , Alun Williams [sup.1] , Martin Christian [sup.1] , Tim Key [...]

Haploidentical stem cell transplantation (haplo SCT) in Stage IV neuroblastoma relapsed patients has been proven efficacious, while immunotherapy utilizing the anti-GD2 antibody dinutuximab beta has become a standard treatment for neuroblastoma. The combinatorial therapy of haplo SCT and dinutuximab may potentiate the efficacy of the immunotherapy. To gain further understanding of the synergistic effects, functional immunomonitoring was assessed during the clinical trial CH14.18 1021 Antibody and IL2 After haplo SCT in Children with Relapsed Neuroblastoma (NCT02258815). Rapid immune reconstitution of the lymphoid compartment was confirmed, with clinically relevant dinutuximab serum levels found in all patients over the course of treatment. Only one patient developed human anti-chimeric antibodies (HACAs). In-patient monitoring revealed highly functional NK cell posttransplant capable of antibody-dependent cellular cytotoxicity (ADCC). Degranulation of NK cell subsets revealed a significant response increased by dinutuximab. This was irrespective of the KIR receptor–ligand constellation within the NK subsets, defined by the major KIR receptors CD158a, CD158b, and CD158e. Moreover, complement-dependent cytotoxicity (CDC) was shown to be an extremely potent effector-cell independent mechanism of tumor cell lysis, with a clear positive correlation to GD2 expression on the cancer cells as well as to the dinutuximab concentrations. The ex vivo testing of patient-derived effector cells and the sera collected during dinutuximab therapy demonstrated both high functionality of the newly established lymphoid immune compartment and provided confidence that the antibody dosing regimen was sufficient over the duration of the dinutuximab therapy (up to nine cycles in a 9-month period). During the course of the dinutuximab therapy, proinflammatory cytokines and markers (sIL2R, TNFa, IL6, and C reactive protein) were significantly elevated indicating a strong anti-GD2 immune response. No impact of FcGR polymorphism on event-free and overall survival was found. Collectively, this study has shown that in-patient functional immunomonitoring is feasible and valuable in contributing to the understanding of anti-cancer combinatorial treatments such as haplo SCT and antibody immunotherapy.

CD19CAR T cells facilitate a transformational treatment in various relapsed and refractory aggressive B-lineage cancers. In general, encouraging response rates have been observed in B-lineage-derived non-Hodgkin’s lymphomas treated with CD19CAR T cells. The major cause of death in heavily pretreated NHL patients is lymphoma progression and lymphoma recurrence. Inefficient CAR T cell therapy is the result of the limited potency of the CAR T cell product or is due to loss of the targeted antigen. Target antigen loss has been identified as the key factor that can be addressed stringently by dual- or multitargeted CAR T cell approaches. We have developed a versatile adapter CAR T cell technology (AdCAR) that allows multitargeting. Screening of three different B-lineage lymphoma cell lines has revealed distinct immune target profiles. Cancer-specific adapter molecule combinations may be utilized to prevent antigen immune escape. In general, CD19CAR T cells become non-functional in CD19 negative lymphoma subsets; however, AdCAR T cells can be redirected to alternative target antigens beyond CD19, such as CD20, CD22, CD79B, and ROR-1. The capability to flexibly shift CAR specificity by exchanging the adapter molecule’s specificity broadens the application and significantly increases the anti-leukemic and anti-lymphoma activity. The clinical evaluation of AdCAR T cells in lymphoma as a new concept of CAR T cell immunotherapy may overcome treatment failure due to antigen immune escape in monotargeted conventional CAR T cell therapies.