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This document updates the American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guideline on idiopathic pulmonary fibrosis treatment. Systematic reviews and, when appropriate, meta-analyses were performed to summarize all available evidence pertinent to our questions. The evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and then discussed by a multidisciplinary panel. Predetermined conflict-of-interest management strategies were applied, and recommendations were formulated, written, and graded exclusively by the nonconflicted panelists. After considering the confidence in effect estimates, the importance of outcomes studied, desirable and undesirable consequences of treatment, cost, feasibility, acceptability of the intervention, and implications to health equity, recommendations were made for or against specific treatment interventions. The panel formulated and provided the rationale for recommendations in favor of or against treatment interventions for idiopathic pulmonary fibrosis.

Benzodiazepines are commonly administered to medical ICU (MICU) patients. Propylene glycol (1,2-propanediol) is the solvent used to deliver lorazepam and diazepam IV. Although propylene glycol toxicity is increasingly recognized and reported, its incidence is unknown. Herein, we describe five MICU patients who acquired severe propylene glycol toxicity due to IV lorazepam or diazepam administration. Additionally, we evaluate the incidence of propylene glycol toxicity in MICU patients receiving IV lorazepam or diazepam. Case series and prospective, observational study. Eighteen-bed MICU in a 550-bed urban academic hospital. MICU patients administered IV benzodiazepines during a 3-month period were enrolled. Patients were categorized according to the IV benzodiazepine that they received. Laboratory data and highlights of their clinical course were recorded daily. The incidence of propylene glycol toxicity was determined and the groups compared. Forty-four patients were enrolled. Twenty-one patients received a benzodiazepine delivered in propylene glycol (lorazepam or diazepam), and 23 patients received a benzodiazepine delivered in an alternative solvent (midazolam). We found that four patients (19%) who received IV lorazepam or diazepam had metabolic evidence of propylene glycol toxicity. None of the patients had clinical deterioration. Neither metabolic abnormality nor clinical deterioration suggestive of propylene glycol toxicity were identified in subjects receiving IV midazolam. Propylene glycol toxicity is a potentially life-threatening iatrogenic complication that is common and preventable. It should be considered whenever a patient has an unexplained anion gap, unexplained metabolic acidosis, hyperosmolality, and/or clinical deterioration. Close monitoring of all patients receiving IV lorazepam or diazepam for early evidence of propylene glycol toxicity is warranted.

Interstitial lung disease is a common complication of systemic sclerosis, but there is no widely accepted treatment. In this randomized, placebo-controlled trial, treatment with cyclophosphamide for one year was associated with a small but significant improvement in lung function and symptom outcomes. The long-term adverse effects of this treatment are unknown. Interstitial lung disease is a common complication of systemic sclerosis, but there is no widely accepted treatment. In this trial, treatment with cyclophosphamide for one year was associated with a small but significant improvement in lung function and symptom outcomes. Scleroderma (also called systemic sclerosis) is an autoimmune connective-tissue disorder that is characterized by microvascular injury, excessive fibrosis of the skin, and distinctive visceral changes that can involve the lungs, heart, kidneys, and gastrointestinal tract. Forty percent of patients with scleroderma have ventilatory restriction, mainly as a result of interstitial lung disease. Together with pulmonary hypertension, ventilatory restriction has emerged as the leading cause of death related to scleroderma. 1 , 2 The mortality rate among patients with severe ventilatory restriction (as reflected by a forced vital capacity [FVC] that is less than 50 percent of the predicted value) from scleroderma-related interstitial . . .

The Scleroderma Lung Study enrolled 158 patients with scleroderma-related interstitial lung disease in a placebo-controlled trial of oral cyclophosphamide (CYC). Although treatment-related benefits in pulmonary function, skin scores, and patient-centered outcomes were demonstrated after 1 year of therapy, the duration of benefit beyond 1 year was unclear. A second year of follow-up was performed to determine if these effects persisted after stopping treatment. A detailed analysis of data obtained over the two years of the study was performed. Using a longitudinal joint model, we analyzed FVC, total lung capacity, transitional dyspnea index, Rodnan skin scores, and the Health Assessment Questionnaire-Disability Index during the second year, after adjusting for baseline values, baseline fibrosis score, and nonignorable missing data. Evaluable subjects (72 CYC; 73 placebo) included 93 who completed all visits plus 52 who completed at least 6 months of therapy and returned at 24 month or had their 24-month data imputed. The beneficial effects of CYC on pulmonary function and health status continued to increase through 18 months, after which they dissipated, whereas skin improvements dissipated after 12 months. In contrast, the positive effect on dyspnea persisted through 24 months. Adverse events were uncommon. One year of CYC improved lung function, skin scores, dyspnea, and health status/disability, effects which either persisted or increased further for several months after stopping therapy. However, except for a sustained impact on dyspnea, all of these effects waned and were no longer apparent at 24 months. Treatment strategies aimed at extending the positive therapeutic effects observed with CYC should be considered. Clinical trial registered with www.clinicaltrials.gov (NCT 000004563).

Benzodiazepines are commonly administered to medical ICU (MICU) patients. Propylene glycol (1,2-propanediol) is the solvent used to deliver lorazepam and diazepam IV. Although propylene glycol toxicity is increasingly recognized and reported, its incidence is unknown. Herein, we describe five MICU patients who acquired severe propylene glycol toxicity due to IV lorazepam or diazepam administration. Additionally, we evaluate the incidence of propylene glycol toxicity in MICU patients receiving IV lorazepam or diazepam. Case series and prospective, observational study. Eighteen-bed MICU in a 550-bed urban academic hospital. MICU patients administered IV benzodiazepines during a 3-month period were enrolled. Patients were categorized according to the IV benzodiazepine that they received. Laboratory data and highlights of their clinical course were recorded daily. The incidence of propylene glycol toxicity was determined and the groups compared. Forty-four patients were enrolled. Twenty-one patients received a benzodiazepine delivered in propylene glycol (lorazepam or diazepam), and 23 patients received a benzodiazepine delivered in an alternative solvent (midazolam). We found that four patients (19%) who received IV lorazepam or diazepam had metabolic evidence of propylene glycol toxicity. None of the patients had clinical deterioration. Neither metabolic abnormality nor clinical deterioration suggestive of propylene glycol toxicity were identified in subjects receiving IV midazolam. Propylene glycol toxicity is a potentially life-threatening iatrogenic complication that is common and preventable. It should be considered whenever a patient has an unexplained anion gap, unexplained metabolic acidosis, hyperosmolality, and/or clinical deterioration. Close monitoring of all patients receiving IV lorazepam or diazepam for early evidence of propylene glycol toxicity is warranted.

The presence of inflammatory cells on bronchoalveolar lavage is often used to predict disease activity and the need for therapy in systemic sclerosis-associated interstitial lung disease. To evaluate whether lavage cellularity identifies distinct subsets of disease and/or predicts cyclophosphamide responsiveness. Patients underwent baseline lavage and/or high-resolution computed tomography as part of a randomized placebo-controlled trial of cyclophosphamide versus placebo (Scleroderma Lung Study) to determine the effect of therapy on forced vital capacity. Patients with 3% or greater polymorphonuclear and/or 2% or greater eosinophilic leukocytes on lavage and/or ground-glass opacification on computed tomography were eligible for enrollment. Lavage was performed in 201 individuals, including 141 of the 158 randomized patients. Abnormal cellularity was present in 101 of these cases (71.6%) and defined a population with a higher percentage of men (P = 0.04), more severe lung function, including a worse forced vital capacity (P = 0.003), worse total lung capacity (P = 0.005) and diffusing capacity of the lung for carbon monoxide (P = 0.004), more extensive ground-glass opacity (P = 0.005), and more extensive fibrosis in the right middle lobe (P = 0.005). Despite these relationships, the presence or absence of an abnormal cell differential was not an independent predictor of disease progression or response to cyclophosphamide at 1 year (P = not significant). The presence of an abnormal lavage in the Scleroderma Lung Study defined patients with more advanced interstitial lung disease but added no additional value to physiologic and computed tomography findings as a predictor of progression or treatment response. Clinical trial registered with www.clinicaltrials.gov (NCT 000004563).

Schizophrenia (SZ) and Bipolar Disorder (BD) are both severe psychiatric disorders that permanently alter a person’s life by afflicting their cognitive and emotional faculties. Over the course of a person’s life, the symptoms might vary in severity, but the changes in neurological determinants of their cognitive and emotional function keep a biological score. Deficits in functional connectivity unique to the two disorders have been associated with alterations in the extracellular matrix (ECM), a loose chemical substance that acts as a chemical medium for cells to communicate and build structural and functional networks, as well as performing a host of other functions. Aside from the ECM itself being a structure found throughout the brain, various tightly organized aggregates of the ECM have been studied due to their potential role in regulating neuronal activity, which then has downstream effects on cognitive and emotional function. Previous investigations from the authors’ lab have found novel ECM structures called 6-sulfated chondroitin (CS-6) glial clusters, which consist of 6-sulfated structures associated with glial cells. Findings from these investigations indicate glial clusters may be involved in synaptic regulation. Researchers from the lab have previously reported marked reductions of these clusters in the amygdalae of persons diagnosed with SZ or BD compared to healthy people. Informed by these findings, these authors theorized that glial clusters may be involved in the cognitive and emotional processing deficits suffered by people with psychotic disorders, and sought to extend findings from the amygdala to the mediodorsal thalamic nucleus (MDTN) to find quantifiable evidence to support this theory. The MDTN was chosen due to its numerous, reciprocal axonal connections with the prefrontal cortex, where imaging studies have shown marked reductions in functional activity and connectivity in persons with SZ and BD. Authors hypothesized cluster counts would be decreased in the MDTN of persons with either a psychiatric diagnosis of SZ or BD compared to controls. Quantification of CS56 immunoreactive clusters in the MDTN showed significant reductions for total number in persons with a diagnosis of SZ or BD compared to control, and for numerical density as well, with no change in volume of the nucleus between groups. During the current investigation, high resolution microscopic imaging of the clusters stained by immunoreaction to CS56 (a CS-6 specific antibody) also led investigators to find distinctions in morphology, indicating heterogeneity not previously seen. Authors detail their classification system, which revealed four novel morphological cluster types: a tendril type, a diffuse type, a densely diffuse type, and a fourth type called type-4. Discovery of morphological characteristics for clusters provides new avenues for researching neuropathological development in psychotic disorders, and findings of cluster reductions indicates a potential role for this ECM structure in the network disruptions resulting in cognitive and emotional deficits for persons with SZ and BD.

Lymphocyte chemoattractant factor (LCF) is a lymphocyte cell product that stimulates a migratory response in CD4+lymphocytes, monocytes, and eosinophils. In concert with its chemoattractant activity, LCF induces human T-lymphocyte expression of interleukin 2 receptor. Here we describe the molecular cloning of cDNA encoding human LCF. It is a novel interleukin with no significant homology to any previously described cytokine families. There is an absolute requirement for both autoaggregation of LCF monomers and for membrane-expressed CD4 molecules for LCF-induced migration in lymphocytes.