Background The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of nintedanib in subgroups based on ILD diagnosis. Methods The INBUILD trial was a randomised, double-blind, placebo-controlled, parallel group trial done at 153 sites in 15 countries. Participants had an investigator-diagnosed fibrosing ILD other than IPF, with chest imaging features of fibrosis of more than 10% extent on high resolution CT (HRCT), forced vital capacity (FVC) of 45% or more predicted, and diffusing capacity of the lung for carbon monoxide (DLco) of at least 30% and less than 80% predicted. Participants fulfilled protocol-defined criteria for ILD progression in the 24 months before screening, despite management considered appropriate in clinical practice for the individual ILD. Participants were randomly assigned 1:1 by means of a pseudorandom number generator to receive nintedanib 150 mg twice daily or placebo for at least 52 weeks. Participants, investigators, and other personnel involved in the trial and analysis were masked to treatment assignment until after database lock. In this subgroup analysis, we assessed the rate of decline in FVC (mL/year) over 52 weeks in patients who received at least one dose of nintedanib or placebo in five prespecified subgroups based on the ILD diagnoses documented by the investigators: hypersensitivity pneumonitis, autoimmune ILDs, idiopathic non-specific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs. The trial has been completed and is registered with ClinicalTrials.gov, number NCT02999178.

Mosquitoes are vectors of many deadly and debilitating pathogens. In the current study, we used light and electron microscopies to study the immune response of Aedes aegypti hemocytes to bacterial inoculations, Plasmodium gallinaceum natural infections, and latex bead injections. After challenge, mosquitoes mounted strong phagocytic and melanization responses. Granulocytes phagocytosed bacteria singly or pooled them inside large membrane-delimited vesicles. Phagocytosis of bacteria, Plasmodium sporozoites, and latex beads was extensive; we estimated that individual granulocytes have the capacity to phagocytose hundreds of bacteria and thousands of latex particles. Oenocytoids were also seen to internalize bacteria and latex particles, although infrequently and with low capacity. Besides phagocytosis, mosquitoes cleared bacteria and sporozoites by melanization. Interestingly, the immune response toward 2 species of bacteria was different; most Escherichia coli were phagocytosed, but most Micrococcus luteus were melanized. Similar to E. coli, most Plasmodium sporozoites were phagocytosed. The immune response was rapid; phagocytosis and melanization of bacteria began as early as 5 min after inoculation. The magnitude and speed of the cellular response suggest that hemocytes, acting in concert with the humoral immune response, are the main force driving the battle against foreign invaders.

Mosquitoes are important vectors of disease. These insects respond to invading organisms with strong cellular and humoral immune responses that share many similarities with vertebrate immune systems. The strength and specificity of these responses are directly correlated to a mosquito's ability to transmit disease. In the current study, we characterized the hemocytes (blood cells) of Armigeres subalbatus by morphology (ultrastructure), lectin binding, enzyme activity, immunocytochemistry, and function. We found four hemocyte types: granulocytes, oenocytoids, adipohemocytes, and thrombocytoids. Granulocytes contained acid phosphatase activity and bound the exogenous lectins Helix pomatia agglutinin, Galanthus nivalis lectin, and wheat germ agglutinin. Following bacteria inoculation, granulocytes mounted a strong phagocytic response as early as 5 min postexposure. Bacteria also elicited a hemocyte-mediated melanization response. Phenoloxidase, the rate-limiting enzyme in the melanization pathway, was present exclusively in oenocytoids and in many of the melanotic capsules enveloping bacteria. The immune responses mounted against different bacteria were not identical; gram(-) Escherichia coli were predominantly phagocytosed and gram(+) Micrococcus luteus were melanized. These studies implicate hemocytes as the primary line of defense against bacteria.

SummaryMosquitoes vector pathogens. One aspect that has been overlooked in mosquito-pathogen relationships is the effect of host age on immune competence. Here, we show that there is age-associated mortality following immune challenge with Escherichia coli . This mortality correlates with a decrease in haemocyte numbers (blood cells) and a decreased ability to kill E. coli . Although the number of haemocytes decreases, the available haemocytes retain their phagocytic ability regardless of age, and we estimate that individual granulocytes can phagocytose approximately 1500 E. coli . Moreover, transcription profiles for cecropin, defensin and gambicin in E. coli challenged mosquitoes do not change with age, indicating that the increased susceptibility is not attributed to fewer humoral antimicrobial peptides. These results suggest that a contributing factor for the age-associated mortality is the decrease in circulating haemocytes, which reduces the overall phagocytic capacity of mosquitoes. To our knowledge, this is the first report detailing an age-associated decline in the immunological capabilities of mosquitoes following challenge with an infectious agent. These data also call for caution in the analysis and interpretation of experimental results when mosquito age has not been closely monitored. Lastly, a model for haemocyte function is presented.

The composite physiologic index(CPI) was derived to represent the extent of fibrosis on high resolution computed tomography, adjusting for emphysema in patients with idiopathic pulmonary fibrosis(IPF). We hypothesized longitudinal change in CPI would better predict mortality than forced expiratory volume in 1 second(FEV1), forced vital capacity(FVC), or diffusing capacity for carbon monoxide(DLCO) in all patients with IPF, and especially in those with combined pulmonary fibrosis and emphysema(CPFE). Cox proportional hazard models were performed on pulmonary function data from IPF patients at baseline (n=321), 6 months (n=211) and 12 months (n=144). Presence of CPFE was determined by high resolution computed tomography. A 5 point increase in CPI over 12 months predicted subsequent mortality (HR 2.1, p=0.004). At 12 months, a 10% relative decline in FVC, a 15% relative decline in DLCO or an absolute increase in CPI of 5 points all discriminated median survival by 2.1 to 2.2 years versus patients with lesser change. Half our cohort had CPFE. In patients with moderate/severe emphysema, only a 10% decline in FEV1 predicted mortality (HR 3.7, p=0.046). In IPF, a 5 point increase in CPI over 12 months predicts mortality similarly to relative declines of 10% in FVC or 15% in DLCO. For CPFE patients, change in FEV1 was the best predictor of mortality.

Activated protein C (APC) supplementation significantly reduces mortality in patients with severe sepsis, presumably by down-regulating coagulation, inflammation, and apoptosis. In vivo, endogenous APC is generated from protein C (PC) "on demand" in response to elevated thrombin levels. Thrombomodulin and endothelial cell protein C receptor are endothelial receptors required to generate APC endogenously. Since these receptors may be down-regulated in sepsis, we measured plasma markers of APC generation in 32 patients with severe sepsis to determine whether APC generation is impaired and whether markers of APC generation correlate with 28-day mortality. Relative to normals, all patients had elevated F1 ؉ 2 and thrombin-antithrombin complex (TAT) levels (markers of thrombin generation and inhibition, respectively), and 28 of 32 patients had reduced PC levels. In 20 patients, APC levels paralleled elevated F1 ؉ 2 levels, whereas 12 patients had low APC levels despite elevated F1 ؉ 2 levels, suggesting that APC generation is impaired in the latter. No significant differences exist between survivors and nonsurvivors with respect to baseline PC levels, F1 ؉ 2 levels, and APACHE II (acute physiology and chronic health evaluation) scores. Baseline APC levels were higher in survivors (P ‫؍‬ .024), and baseline F1 ؉ 2/APC ratios were lower in survivors (P ‫؍‬ .047). Larger studies are warranted to establish whether APC generation profiles aid in managing sepsis. IntroductionSepsis is a devastating disorder characterized by systemic activation of the inflammatory and coagulation cascades in response to microbial infection. 1 Sepsis is defined as systemic inflammatory response syndrome (SIRS) in the presence of documented or suspected infection. 2 When sepsis is associated with acute organ dysfunction, the sepsis is considered severe. 2 In the United States, approximately 750 000 episodes of severe sepsis occur each year, of which 215 000 result in death, 3 a value similar to the number of deaths due to acute myocardial infarction. 4 The mortality rate is approximately 30% and increases to 40% in the elderly, 3 and the incidence of severe sepsis is projected to increase by 1.5% per annum due to the growing proportion of elderly persons in society. 3 Over the past 15 years, many treatments for sepsis have shown early promise yet failed to improve survival in septic patients. These therapies were directed at treating sepsis largely through attenuation of inflammatory mediators or by neutralization of endotoxin. 5 It is now well accepted that inflammation, coagulation, and apoptosis occur concomitantly in sepsis and are intimately linked. Recently, a large phase 3 multinational placebo-controlled randomized clinical trial demonstrated the efficacy and safety of recombinant activated protein C (APC) for severe sepsis. 6 Compared with placebo, a 4-day infusion of recombinant APC resulted in a reduction in the relative risk of death of 19.4% and an absolute reduction in the risk of death of 6.1% (P ϭ .005). This was the first ra...

579ment highlighted that the disease course of an individual patient is variable, with some patients surviving for many years, others progressing more rapidly, and still others having acute exacerbations. 1 This heterogeneity complicates the ability to provide clear prognostic information to patients and complicates the design of therapeutic clinical trials. With no cure, IPF has been the focus of multiple therapeutic studies over the last decade. [2][3][4][5][6][7][8][9][10][11][12] Unfortunately, effective treatments have been elusive. While there are many considerations as to why any given trial may not show I diopathic pulmonary fi brosis (IPF) is the most common idiopathic, diffuse parenchymal lung disease. Although the median survival is often described as 2 to 3 years, the more recent IPF consensus state- Abbreviations: D lco 5 diffusion capacity of the lung for carbon monoxide; HR 5 hazard ratio; IPF 5 idiopathic pulmonary fi brosis; PFT 5 pulmonary function test

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