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.

ContributionsMagdy Selim --organized the trial hypotheses, designed the trial, provided guidance about the data analysis and interpretation and presentation of the data, and drafted most of the sections of the manuscript. Lydia Foster --involved in the statistical analysis and data interpretation, and Contributed to the development and revisions to the manuscript. Claudia Moy --involved in the oversight of the trial conduct and progress Guohua Xi --organized the trial hypotheses, and provided critical revisions to the manuscript. MH, MJ, VS, and WC contributed to recruitment and randomization of trial participants, and provided critical revisions to the manuscript. LM and SG were involved in the design of the trial and provided critical revisions to the manuscript. Casey Norton --provided volumetric measurements of imaging data. Yuko Palesch --involved in the design of the study, statistical analysis and data interpretation, and provided critical revisions to the manuscript. Sharon yeatts --involved in the design of the study, statistical analysis and data interpretation, and contributed to the development and revisions to the manuscript. The idef investigators (see appendix) --contributed to the identification and, when eligible, randomization of trial participants. DECLARATION OF INTERESTSThis was an investigator-initiated study, funded by the NINDS (U01 NS074425). Deferoxamine Mesylate is a generic drug, and there was no commercial or industrial support for the trial. None of the authors has any competing interests related to the submitted work. MS reports grants from the NIH/NINDS (i-DEF) and the American Heart Association (outside the submitted work), and personal fees for serving on the advisory board of CSL Behring (outside the submitted work) during the conduct of the trial. SDY reports grant support from the NINDS, personal fees from Genentech and other fees from CR Bard Inc. (outside the submitted work) during the conduct of the study. SG, LDF, YP, and GX report grants from the NIH/NINDS. MDH reports personal fees from Merck, nonfinancial support from Hoffmann-La Roche Canada Ltd, grants from Covidien (Medtronic), grants from Boehringer-Ingleheim, grants from Stryker Inc., grants from Medtronic LLC, grants from NoNO Inc., (outside the submitted work); In addition, MDH has a patent Systems and Methods for Assisting in Decision-Making and Triaging for Acute Stroke Patients pending to US Patent office Number: 62/086,077 and owns stock in Calgary Scientific Incorporated, a company that focuses on medical imaging software, is a director of the Canadian Federation of Neurological Sciences, a not-for-profit group and has received grant support from Alberta Innovates Health Solutions, CIHR, Heart & Stroke Foundation of Canada, and NINDS. LM, VS, WC, MJ, CM, and CN have nothing to disclose.

Patients undergoing total hip or knee replacement frequently receive blood transfusion. Homologous blood transfusion carries appreciable risks and should therefore be reduced to a minimum. We have investigated the use of preoperative oral iron supplements to optimize haemoglobin concentration and iron stores prior to surgery. All patients attending a preadmission clinic 4 weeks prior to primary hip or knee replacement had a haemoglobin measurement. If the haemoglobin concentration (Hb) was less than 12 g dL-1 they were given a four week course of ferrous sulphate. If it was greater than or equal to 12 g dL-1 they were randomized to a control group or given a supplementation course of ferrous sulphate. One hundred patients were seen. Of these 18 (18%) had haemoglobin less than 12 g dL-1 and 16 were treated with iron. The mean Hb was 10.8 g dL-1 and mean cell volume (MCV) 86. These patients increased their Hb by a mean 1.1 g dL-1 prior to admission (P = 0.008). MCV was the best predictor of response (r = -0.63, P < 0.02). This group dropped their haemoglobin by a mean 1.4 g dL-1 in the first post-operative week. In the study groups there was no significant preoperative rise in Hb. However, the control group dropped their Hb by a mean 1.3 g dL-1 in the week following surgery compared with 0.4 g dL-1 in the group which had received iron supplements (P < 0.001). We conclude that at least 18% of patients attending for hip or knee replacement in this region are frankly anaemic and benefit significantly from preoperative iron supplements over 4 weeks. Iron supplementation in patients without obvious anaemia protects against a fall in Hb during the immediate post-operative period, suggesting a widespread underlying depletion of iron stores in this group despite a normal Hb. Preoperative iron supplements may reduce transfusion requirements as part of a co-ordinated strategy in this group of patients.

Intracerebral hemorrhage (ICH) is a subset of stroke resulting from bleeding within the brain parenchyma of the brain. It is potentially lethal, and survival depends on ensuring an adequate airway, reversal of coagulopathy, and proper diagnosis. ICH was chosen as an emergency neurological life support (ENLS) protocol because intervention within the first critical hour may improve outcome, and it is helpful to have a protocol to drive care quickly and efficiently.

The effect of carotid artery stenting (CAS) and carotid endarterectomy (CEA) on cognitive function is unclear. Both cognitive improvement and decline have been reported after CAS and CEA. We aimed to compare the changes in postprocedural cognitive function after CAS versus CEA. A systematic qualitative review of the literature was conducted according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement for studies evaluating the changes in cognitive function after CAS compared with CEA. Thirteen studies (403 CEAs; 368 CAS procedures) comparing the changes in cognitive function after CEA versus CAS were identified. Most studies did not show significant differences in overall cognitive function or only showed a difference in a single cognitive test between the two procedures. A definitive conclusion regarding the effect of CAS versus CEA on cognitive function was not possible owing to heterogeneity in definition, method, timing of assessment, and type of cognitive tests. For the same reasons, performing a meta-analysis was not feasible. The lack of standardization of specific cognitive tests and timing of assessment of cognitive function after CAS and CEA do not allow for definite conclusions to be drawn. Larger, adequately-powered and appropriately designed studies are required to accurately evaluate the effect of CAS versus CEA on postprocedural cognitive function.

Several literature limitations were identified including small number of subjects, lack of clinical outcome correlations, inconsistent probe location, and overall moderate quality among the included studies. These limitations preclude any firm conclusions; nevertheless we suggest that the status of cerebrovascular reactivity is not only important for cerebral perfusion pressure optimization but should also inform interpretation and interventions targeted on PbtO(2) and LPR. Assessment of reactivity can be the first step in approaching the relations among cerebral blood flow, oxygen delivery, demand, and cellular metabolism.

Intracerebral hemorrhage (ICH) is a subset of stroke due to bleeding within the parenchyma of the brain. It is potentially lethal, and survival depends on ensuring an adequate airway, reversal of coagulopathy, and proper diagnosis. ICH was chosen as an Emergency Neurological Life Support protocol because intervention within the first critical hour may improve outcome, and it is critical to have site-specific protocols to drive care quickly and efficiently.

Novel oral anticoagulants present challenges and uncertainties in the management of hemorrhagic emergencies. An 84-year-old man taking dabigatran presented with a subdural hematoma requiring neurosurgical intervention. Routine coagulation assays were prolonged at admission and following administration of Factor VIII Inhibitor Bypassing Activity (FEIBA). Thromboelastography (TEG(®)) was utilized to assess clot dynamics prior to placement of a subdural drain, which was safely inserted despite a prolonged thrombin time (TT). Exclusive reliance on the TT may delay necessary interventions. TEG(®) may be a valuable tool to investigate hemostasis in patients on dabigatran requiring emergent procedures.