The role of fractional exhaled nitric oxide in the assessment of athletes reporting exertional dyspnoea

Background: Exercise-induced bronchoconstriction (EIB) is a common cause of breathing difficulty in athletes. Fractional exhaled nitric oxide (FeNO) is an indirect marker of airway inflammation, recommended for the assessment and management of asthma; however, the role of FeNO in detecting and monitoring EIB has yet to be fully established. The aim of this study was therefore to evaluate the predictive value of FeNO to confirm or refute EIB in athletes presenting with exertional dyspnoea. Method: Seventy athletes (male: n = 45) (age: 35 ± 11 years) reporting respiratory symptoms (i.e. wheeze, cough and dyspnoea) during exercise attended the laboratory on a single occasion. All athletes performed resting FeNO and spirometry pre-and-post a eucapnic voluntary hyperpnoea challenge (EVH) in accordance with international guidelines. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for established FeNO thresholds: (intermediate [≥25ppb] and high [>50ppb]) and evaluated against objective evidence of EIB: (EVH diagnostic cut-off [-10% ΔFEV1 at two consecutive time-points] and [-15% ΔFEV1 at one time-point]). The diagnostic accuracy of FeNO was calculated using receiver operating characteristics area under the curve (ROC-AUC). Results: All had normal resting lung function (>80% FEV1 pred). The prevalence of EIB was 33% (-10% ΔFEV1) and 23% (-15% ΔFEV1) (median (IQR) ΔFEV1 = -7% (10.02)). FeNO values ≥25ppb and >50ppb were observed in 49% and 23% of the cohort, respectively. ROC-AUC for FeNO was 75% (-10% ΔFEV1) and 86% (-15% ΔFEV1). Sensitivity, specificity, PPV and NPV are presented in Table 1. Conclusion: Our findings indicate that FeNO >50ppb provides good specificity for a positive EVH test; however, should not replace indirect bronchoprovocation for diagnostic purposes. The high proportion of athletes reporting breathing difficulty in the absence of EIB highlights the requirement to consider alternative causes of exertional dyspnoea during clinical work-up

Ethical challenges in preclinical Alzheimer's disease observational studies and trials:Results of the Barcelona summit

AbstractAlzheimer's disease (AD) is among the most significant health care burdens. Disappointing results from clinical trials in late-stage AD persons combined with hopeful results from trials in persons with early-stage suggest that research in the preclinical stage of AD is necessary to define an optimal therapeutic success window. We review the justification for conducting trials in the preclinical stage and highlight novel ethical challenges that arise and are related to determining appropriate risk-benefit ratios and disclosing individuals' biomarker status. We propose that to conduct clinical trials with these participants, we need to improve public understanding of AD using unified vocabulary, resolve the acceptable risk-benefit ratio in asymptomatic participants, and disclose or not biomarker status with attention to study type (observational studies vs clinical trials). Overcoming these challenges will justify clinical trials in preclinical AD at the societal level and aid to the development of societal and legal support for trial participants

Prevalencia y factores de riesgo asociados a las enfermedades de transmisión sexual en bovinos de la provincia de La Pampa, Argentina

La tricomonosis bovina (TB) y campylobacteriosis genital bovina (CGB) son enfermedades de transmisión sexual (ETS) que causan muerte embrionaria temprana, infertilidad transitoria y abortos, impactando en el rendimiento reproductivo de los rodeos. El objetivo del presente estudio fue estimar la prevalencia general y por zonas fitogeográficas (Z1: Este pampeana, Z2: Monte central Z3: Monte occidental), así como los factores de riesgo asociados a ambas enfermedades en la provincia de La Pampa, Argentina. Se realizó un estudio transversal entre enero y diciembre del 2006 que abarcó a 4018 propietarios de rodeos con un stock de 684116 vacas y 33969 toros (54% y 51,5% del stock provincial, respectivamente). Se detectaron 622 (15,5%) rodeos con al menos 1 toro positivo a TB y/o CGB. Las prevalencias halladas fueron de 2,15% (Z1:1,62%; Z2:1,90%; Z3:4,61%) y 2,36% (Z1:2,08%; Z2: 2,28%; Z3: 3,51%) para TB y CGB, respectivamente. Los factores de riesgo asociados a la presencia de ETS fueron: traspaso de animales vecinos al establecimiento (Odds Ratio – OR = 1,8; Intervalo de Confianza-IC: 1,5-2,2) realización de servicio continuo (OR=1,3; IC: 1,1-1,6), productores que no realizan el tacto rectal (OR=1,2; IC: 1,0-1,5) y alta relación vaca/toro (χ2 =35,1, p=<0,0001). Asimismo, las ETS se relacionaron con presencia de abortos (OR=1,3; IC: 1,0-1,7) y bajo porcentaje de preñez (OR=1,8; IC: 1,3-2,6). Este estudio provee información de interés para ser utilizada en los planes de control y erradicación en áreas en donde las ETS son de carácter endémico.Bovine Tricomonosis (BT) and Bovine Genital Campylobacteriosis (BGC) are sexual transmission diseases (STD) that produce early embryonic death, transitory infertility and abortion, impacting on livestock reproductive performance. The objective of the study was to estimate the global and specific prevalence by phytogeography area (Z1: East Pampeana, Z2: Central Forest, Z3. West Forest) as well as the risk factor associated to both diseases in La Pampa province, Argentina. A cross sectional study was carried out between January and December 2006 which included 4018 farmers having a stock of 684116 cows and 33969 bulls (54% and 51.5% of the provincial stock, respectively). Six hundred and twenty two (15.5%) cattle herds were detected with at least one bull positive for TB and / or CGB. Prevalence was 2.15% (Z1: 1.62%, Z2: 1.90%, Z3: 4.61%) and 2.36% (Z1: 2.08%; Z2: 2.28%; Z3: 3.51%) for BT and BGC, respectively. Risk factors associated with the presence of STD were: Passage of bulls from in-contact herds (Odds ratio OR=1,8; Confidence Intervals-IC: 1,5-2,2), no defined breeding season (OR=1,3; IC: 1,1-1,6), farmers who do not detect pregnancy by rectal examination (OR=1,2; IC: 1,0-1,5) and high cows/bulls ratio (χ2 =35,1, p=<0,0001). Moreover, STD were related to abortion (OR=1.3; IC: 1.0-1.7) and low pregnancy rate (OR=1.8; IC: 1.3-2.6). This study provided information to use by control programs and erradication in a region where these diseases are considered to be endemic.EEA AnguilFil: Miranda, Ariel Omar. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Anguil; ArgentinaFil: Fort, Marcelo Cristian. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Anguil; ArgentinaFil: Fuchs, Lumila Ivana. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Anguil; ArgentinaFil: Baldone, Valeria. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Anguil; ArgentinaFil: Gimenez, Hugo Daniel. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Anguil; ArgentinaFil: Carné, L. Servicio Nacional de Sanidad y Calidad Agroalimentaria. Centro Regional La Pampa-San Luis; ArgentinaFil: Sago, Adrián Miguel. Servicio Nacional de Sanidad y Calidad Agroalimentaria. Centro Regional La Pampa-San Luis; ArgentinaFil: Otermin, H. Colegio Veterinario de la provincia de La Pampa; ArgentinaFil: Dubié, D. Colegio Veterinario de la provincia de La Pampa; ArgentinaFil: Goyeneche, P. Provincia de La Pampa. Subsecretaría Agricultura; ArgentinaFil: Campero, Carlos Manuel. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Balcarce; Argentina

Evolution of form in metal-organic frameworks

Self-assembly has proven to be a widely successful synthetic strategy for functional materials, especially for metal-organic materials (MOMs), an emerging class of porous materials consisting of metal-organic frameworks (MOFs) and metal-organic polyhedra (MOPs). However, there are areas in MOM synthesis in which such self-assembly has not been fully utilized, such as controlling the interior of MOM crystals. Here we demonstrate sequential self-assembly strategy for synthesizing various forms of MOM crystals, including double-shell hollow MOMs, based on single-crystal to single-crystal transformation from MOP to MOF. Moreover, this synthetic strategy also yields other forms, such as solid, core-shell, double and triple matryoshka, and single-shell hollow MOMs, thereby exhibiting form evolution in MOMs. We anticipate that this synthetic approach might open up a new direction for the development of diverse forms in MOMs, with highly advanced areas such as sequential drug delivery/release and heterogeneous cascade catalysis targeted in the foreseeable future.ope

Rogue Logics: Organization in the Grey Zone

This paper explores the concept of the ‘rogue’ through an examination of how the figure appears in business ethics and as the rogue trader. Reading the rogue trader through institutional logics and Jacques Derrida’s book Rogues, we suggest that the rogue is not on the dark side of organization so much as in an indeterminate grey zone, where the boundary between acceptable behaviour and misconduct is unclear. We further argue that this boundary is necessarily unclear as it is in the nature of organization, at least within capitalist trading systems, to push the boundaries of what is possible and acceptable. The rogue thus helps produce the boundaries of ethically acceptable organizational behaviour in the very act of transgressing them. The location-bound specificity of the rogue, as well as the symbolic process of naming an individual or a state a rogue finds a relevant correlate in the villain, as Derrida suggests. But what we call ‘rogue organization’ may be constitutive of organization per se. As such, there is a potential roguishness in organization that should be addressed when considering the dark side of ethics in organization studies

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy respons

The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance

In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.</p