A remarkably unsymmetric hexairon core embraced by two high-symmetry tripodal oligo-α-pyridylamido ligands

Oligo-α-pyridylamides offer an appealing route to polyiron complexes with short Fe-Fe separations and large room temperature magnetic moments. A derivative of tris(2‐aminoethyl)amine (H6tren) containing three oligo-α-pyridylamine branches and thirteen nitrogen donors (H6L) reacts with [Fe2(Mes)4] to yield an organic nanocage built up by two tripodal ligands with interdigitated branches (HMes = mesitylene). The nanocage has crystallographic D3 symmetry but hosts a remarkably unsymmetric hexairon-oxo core, with a central Fe5(μ5-O) square pyramid, two oxygen donors bridging basal sites, and an additional Fe center residing in one of the two tren-like pockets. Bond Valence Sum (BVS) analysis, Density Functional Theory (DFT) calculations, and electrochemical data were then used to establish the protonation state of oxygen atoms and the formal oxidation states of the metals. To this purpose, a specialized set of BVS parameters was devised for Fe2+-N3- bonds with nitrogen donors of oligo-α-pyridylamides. This allowed us to formulate the compound as [Fe6O2(OH)(H3L)L], with nominally four FeII and two FeIII ions. Mössbauer spectra indicate that the compound contains two unique FeII sites, identified as a pair of closely spaced hydroxo-bridged metal ions in the central Fe5(μ5-O) pyramid, and a substantially valence-delocalized FeII2FeIII2 unit. Broken-symmetry DFT calculations predict strong ferromagnetic coupling between the two iron(II) ions, leading to a local S = 4 state that persists to room temperature and explaining the large magnetic moment measured at 300 K. The compound behaves as a single-molecule magnet, with magnetization dynamics detectable in zero static field and dominated by an Orbach-like mechanism with Ueff/kB = 49(2) K and τ0 = 4(2)·10−10 s

Disease-associated Bias in T Helper Type 1 (Th1)/Th2 CD4+ T Cell Responses Against MAGE-6 in HLA-DRB1*0401+ Patients With Renal Cell Carcinoma or Melanoma

T helper type 1 (Th1)-type CD4+ antitumor T cell help appears critical to the induction and maintenance of antitumor cytotoxic T lymphocyte (CTL) responses in vivo. In contrast, Th2- or Th3/Tr-type CD4+ T cell responses may subvert Th1-type cell-mediated immunity, providing a microenvironment conducive to disease progression. We have recently identified helper T cell epitopes derived from the MAGE-6 gene product; a tumor-associated antigen expressed by most melanomas and renal cell carcinomas. In this study, we have assessed whether peripheral blood CD4+ T cells from human histocompatibility leukocyte antigens (HLA)-DRβ1*0401+ patients are Th1- or Th2-biased to MAGE-6 epitopes using interferon (IFN)-γ and interleukin (IL)-5 enzyme-linked immunospot assays, respectively. Strikingly, the vast majority of patients with active disease were highly-skewed toward Th2-type responses against MAGE-6–derived epitopes, regardless of their stage (stage I versus IV) of disease, but retained Th1-type responses against Epstein-Barr virus– or influenza-derived epitopes. In marked contrast, normal donors and cancer patients with no current evidence of disease tended to exhibit either mixed Th1/Th2 or strongly Th1-polarized responses to MAGE-6 peptides, respectively. CD4+ T cell secretion of IL-10 and transforming growth factor (TGF)-β1 against MAGE-6 peptides was not observed, suggesting that specific Th3/Tr-type CD4+ subsets were not common events in these patients. Our data suggest that immunotherapeutic approaches will likely have to overcome or complement systemic Th2-dominated, tumor-reactive CD4+ T cell responses to provide optimal clinical benefit

Use of benzylglycinamide by a HIV-seropositive polysubstance user: : the changing pattern of novel psychoactive substance use among youths

This document is the Accepted Manuscript of the following article: Matteo Caloro, et al, ‘Use of benzylglycinamide by a HIV-seropositive polysubstance user: The changing pattern of novel psychoactive substance use among youths’, Addictive Behaviors, Vol. 60, pp. 53-57, September 2016. The Version of Record is available online at doi: https://doi.org/10.1016/j.addbeh.2016.03.032. © 2016 Elsevier Ltd. All rights reserved.A 24-year old woman with multisubstance use since the age of 13, including opioids and cocaine, and long-standing HIV/HCV seropositivity status, presented with psychosis, agitation, and insomnia at the emergency department of a university hospital. She had been abusive and physically aggressive frequently without specific reasons and was involved in criminal legal cases. She was hospitalized twice. During her first hospital stay she experienced a brief episode of detachment from her environment, similar to episodes reportedly suffered at home. Psychosis had developed following heavy polysubstance abuse. Her mother provided sachets containing benzylglycinamide, a substance with no known psychotropic effects, which were also present in the patient's urine. She was occasionally positive for cannabinoids. She used to buy various novel psychoactive substances (NPSs) from the internet and used experimentally various substances freely made available to her by drug suppliers/dealers. She was unable to explain clearly why she was taking any of the identified NPS. She stated she was taking benzylglycinamide to calm her when smoking synthetic cannabinoids. While it appears that benzylglycinamide is not likely to constitute a novel drug of abuse, her polysubstance use exemplifies trends in NPS use patterns among the youths in the Western world and should alert mental health workers as to the possible dangers of such behavior and its reflection on social behavior and psychopathology.Peer reviewedFinal Accepted Versio

Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries

IMPORTANCE: Limited information exists about the epidemiology, recognition, management, and outcomes of patients with the acute respiratory distress syndrome (ARDS). OBJECTIVES: To evaluate intensive care unit (ICU) incidence and outcome of ARDS and to assess clinician recognition, ventilation management, and use of adjuncts-for example prone positioning-in routine clinical practice for patients fulfilling the ARDS Berlin Definition. DESIGN, SETTING, AND PARTICIPANTS:The Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) was an international, multicenter, prospective cohort study of patients undergoing invasive or noninvasive ventilation, conducted during 4 consecutive weeks in the winter of 2014 in a convenience sample of 459 ICUs from 50 countries across 5 continents. EXPOSURES:Acute respiratory distress syndrome. MAIN OUTCOMES AND MEASURES: The primary outcome was ICU incidence of ARDS. Secondary outcomes included assessment of clinician recognition of ARDS, the application of ventilatory management, the use of adjunctive interventions in routine clinical practice, and clinical outcomes from ARDS. RESULTS: Of 29,144 patients admitted to participating ICUs, 3022 (10.4%) fulfilled ARDS criteria. Of these, 2377 patients developed ARDS in the first 48 hours and whose respiratory failure was managed with invasive mechanical ventilation. The period prevalence of mild ARDS was 30.0% (95% CI, 28.2%-31.9%); of moderate ARDS, 46.6% (95% CI, 44.5%-48.6%); and of severe ARDS, 23.4% (95% CI, 21.7%-25.2%). ARDS represented 0.42 cases per ICU bed over 4 weeks and represented 10.4% (95% CI, 10.0%-10.7%) of ICU admissions and 23.4% of patients requiring mechanical ventilation. Clinical recognition of ARDS ranged from 51.3% (95% CI, 47.5%-55.0%) in mild to 78.5% (95% CI, 74.8%-81.8%) in severe ARDS. Less than two-thirds of patients with ARDS received a tidal volume 8 of mL/kg or less of predicted body weight. Plateau pressure was measured in 40.1% (95% CI, 38.2-42.1), whereas 82.6% (95% CI, 81.0%-84.1%) received a positive end-expository pressure (PEEP) of less than 12 cm H2O. Prone positioning was used in 16.3% (95% CI, 13.7%-19.2%) of patients with severe ARDS. Clinician recognition of ARDS was associated with higher PEEP, greater use of neuromuscular blockade, and prone positioning. Hospital mortality was 34.9% (95% CI, 31.4%-38.5%) for those with mild, 40.3% (95% CI, 37.4%-43.3%) for those with moderate, and 46.1% (95% CI, 41.9%-50.4%) for those with severe ARDS. CONCLUSIONS AND RELEVANCE: Among ICUs in 50 countries, the period prevalence of ARDS was 10.4% of ICU admissions. This syndrome appeared to be underrecognized and undertreated and associated with a high mortality rate. These findings indicate the potential for improvement in the management of patients with ARDS

The effect of alcohol consumption on the risk of ARDS: a systematic review and meta-analysis

BACKGROUND: To conduct a systematic review and meta-analysis evaluating the association between alcohol consumption and the risk of ARDS in adults. METHODS: Medline, EMBASE and Web of Science were searched to identify observational studies evaluating the association between prior alcohol intake and the occurrence of ARDS among adults, published between 1985 and 2015 and with no language restriction. Reference lists were also screened. Demographic baseline data were extracted independently by two reviewers and random-effects meta-analyses were used to estimate pooled effect sizes with 95% confidence intervals. Subgroup analyses were used to explore heterogeneity. RESULTS: Seventeen observational studies (177,674 people) met the inclusion criteria. Metaanalysis of 13 studies showed that any measure of high relative to low alcohol consumption was associated with a significantly increased risk of ARDS (OR, 1.89; 95% CI, 1.45-2.48; I² = 48%; 13 studies); no evidence of publication bias was seen (P = .150). Sensitivity analyses indicated that this association was attributable primarily to an effect of a history of alcohol abuse (OR, 1.90; 95% CI, 1.40-2.60; 10 studies). Also, subgroup analyses identified that heterogeneity was explained by predisposing condition (trauma, sepsis/septic shock, pneumonia; P = .003). CONCLUSIONS: Chronic high alcohol consumption significantly increases the risk of ARDS. This finding suggests that patients admitted to hospital should be screened for chronic alcohol use

Noninvasive Ventilation of Patients with Acute Respiratory Distress Syndrome: Insights from the LUNG SAFE Study

Abstract RATIONALE: Noninvasive ventilation (NIV) is increasingly used in patients with acute respiratory distress syndrome (ARDS). The evidence supporting NIV use in patients with ARDS remains relatively sparse. OBJECTIVES: To determine whether, during NIV, the categorization of ARDS severity based on the PaO2/FiO2 Berlin criteria is useful. METHODS: The LUNG SAFE (Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure) study described the management of patients with ARDS. This substudy examines the current practice of NIV use in ARDS, the utility of the PaO2/FiO2 ratio in classifying patients receiving NIV, and the impact of NIV on outcome. MEASUREMENTS AND MAIN RESULTS: Of 2,813 patients with ARDS, 436 (15.5%) were managed with NIV on Days 1 and 2 following fulfillment of diagnostic criteria. Classification of ARDS severity based on PaO2/FiO2 ratio was associated with an increase in intensity of ventilatory support, NIV failure, and intensive care unit (ICU) mortality. NIV failure occurred in 22.2% of mild, 42.3% of moderate, and 47.1% of patients with severe ARDS. Hospital mortality in patients with NIV success and failure was 16.1% and 45.4%, respectively. NIV use was independently associated with increased ICU (hazard ratio, 1.446 [95% confidence interval, 1.159-1.805]), but not hospital, mortality. In a propensity matched analysis, ICU mortality was higher in NIV than invasively ventilated patients with a PaO2/FiO2 lower than 150 mm Hg. CONCLUSIONS: NIV was used in 15% of patients with ARDS, irrespective of severity category. NIV seems to be associated with higher ICU mortality in patients with a PaO2/FiO2 lower than 150 mm Hg. Clinical trial registered with www.clinicaltrials.gov (NCT 02010073)

Optimising precision agriculture choices for arable farmers in Germany and the UK: the LINKDAPA approach

Farmer adoption of so-called Precision Agriculture (PA) or ‘smart’ technologies in the arable sector has grown in the last few decades with a focus on Global Navigation Satellite Systems (GNSS) and variable rate technologies (VRT). This has led to increased generation of large volumes of data about fields and their crop yields which could be used to increase the environmental and financial performance for farmers. However, survey results show that cost and adaptability have been issues for many farmers in the UK and Germany that have held back such adoption. The LINKDAPA (LINKing multi-source Data for Adoption of Precision Agriculture) project's approach sought to minimise both concerns by creating a customisable web platform that incorporates both GNSS and VRT into one, easy to use, affordable option for farmers. The project developed an online cloud-based decision support tool which takes into account different fertiliser strategies based on novel algorithms using soil, historic yield and satellite data. Co-created by researchers, farmers and agricultural technology firms, the LINKDAPA approach offers both economical and easy to implement solutions for farm management to mitigate resource loss-ratios such as in fertiliser use, provide financial performance analyses, and multi-year graphical imagery for soil mapping