Inhaled corticosteroids and risk of pneumonia in newly diagnosed COPD

SummaryIntroductionThe use of inhaled corticosteroids (ICS) in COPD may be associated with an increased risk of pneumonia. Little is known of this risk in newly diagnosed COPD patients. The objective of this study was to determine if the use of ICS among newly diagnosed COPD patients is associated with an increased risk of pneumonia hospitalizations.MethodsUsing data from the Department of Veterans Affairs and Centers for Medicare and Medicaid Services, a nested case–control study was performed. We identified patients 65 years of age or older with a new diagnosis of COPD from 1998 to 2002. A total of 145,586 patients were identified. Cases were defined based on hospitalization for pneumonia and exposure was prior use of ICS. Up to 10 controls were matched for each case based on age, sex, month and year of the case. The association between ICS use and pneumonia was evaluated with conditional logistic regression controlling for age, comorbidities, medication classes associated with the risk of pneumonia, and markers of COPD severity.ResultsThere were 13,995 cases of pneumonia. The cohort was predominantly male with an average age of 75.1 (SD=5.4) years. The rate of pneumonia was 6.4 per 100 person-years. After adjustment for covariates, patients with current use of ICS were 1.38 (95% CI, 1.31–1.45) times more likely to have a hospitalization for pneumonia than those without current use of ICS.ConclusionsThe use of ICS among patients with newly diagnosed COPD is associated with an increased risk of hospitalization for pneumonia

The Association of Maximum Body Weight on the Development of Type 2 Diabetes and Microvascular Complications: MAXWEL Study

Background: Obesity precedes the development of type 2 diabetes (T2D). However, the relationship between the magnitude and rate of weight gain to T2D development and complications, especially in non-White populations, has received less attention. Methods and Findings: We determined the association of rate and magnitude of weight gain to age at T2D diagnosis (AgeT2D), HbA1c at T2D diagnosis (HbA1cT2D), microalbuminuria, and diabetic retinopathy after adjusting for sex, BMI at age 20 years, lifestyles, family history of T2D and/or blood pressure and lipids in 2164 Korean subjects aged ≥30 years and newly diagnosed with diabetes. Body weight at age 20 years (Wt20y) was obtained by recall or from participants’ medical, school, or military records. Participants recalled their maximum weight (Wtmax) prior to T2D diagnosis and age at maximum weight (Agemax_wt). The rate of weight gain (Ratemax_wt) was calculated from magnitude of weight gain (ΔWt = Wtmax–Wt20y) divided by ΔTime (Agemax_wt –20 years). The mean Agemax_wt and AgeT2D were 41.5±10.9 years and 50.1±10.5 years, respectively. The Wt20y and Wtmax were 59.9±10.5 kg and 72.9±11.4 kg, respectively. The Ratemax_wt was 0.56±0.50 kg/year. After adjusting for risk factors, greater ΔWt and higher Ratemax_wt were significantly associated with earlier AgeT2D, higher HbA1cT2D after additional adjusting for AgeT2D, and microalbuminuria after further adjusting for HbA1cT2D and lipid profiles. Greater ΔWt and higher Ratemax_wt were also significantly associated with diabetic retinopathy. Conclusions: This finding supports public health recommendations to reduce the risk of T2D and its complications by preventing weight gain from early adulthood

Ubiquitin-dependent proteasomal degradation of AMPK gamma subunit by Cereblon inhibits AMPK activity

Cereblon (CRBN), a substrate receptor for Cullin-ring E3 ubiquitin ligase (CRL), is a major target protein of immunomodulatory drugs. An earlier study demonstrated that CRBN directly interacts with the catalytic α subunit of AMP-activated protein kinase (AMPK), a master regulator of energy homeostasis, down-regulating the enzymatic activity of AMPK. However, it is not clear how CRBN modulates AMPK activity. To investigate the mechanism of CRBN-dependent AMPK inhibition, we measured protein levels of each AMPK subunit in brains, livers, lungs, hearts, spleens, skeletal muscles, testes, kidneys, and embryonic fibroblasts from wild-type and Crbn^(−/−) mice. Protein levels and stability of the regulatory AMPKγ subunit were increased in Crbn^(−/−) mice. Increased stability of AMPKγ in Crbn^(−/−) MEFs was dramatically reduced by exogenous expression of Crbn. In wild-type MEFs, the proteasomal inhibitor MG132 blocked degradation of AMPKγ. We also found that CRL4^(CRBN) directly ubiquitinated AMPKγ. Taken together, these findings suggest that CRL4^(CRBN) regulates AMPK through ubiquitin-dependent proteasomal degradation of AMPKγ

Confirmatory Spirometry for Adults Hospitalized with a Diagnosis of Asthma or Chronic Obstructive Pulmonary Disease Exacerbation

Background: Objective measurement of airflow obstruction by spirometry is an essential part of the diagnosis of asthma or COPD. During exacerbations, the feasibility and utility of spirometry to confirm the diagnosis of asthma or chronic obstructive pulmonary disease (COPD) are unclear. Addressing these gaps in knowledge may help define the need for confirmatory testing in clinical care and quality improvement efforts. This study was designed to determine the feasibility of spirometry and to determine its utility to confirm the diagnosis in patients hospitalized with a physician diagnosis of asthma or COPD exacerbation. Methods: Multi-center study of four academic healthcare institutions. Spirometry was performed in 113 adults admitted to general medicine wards with a physician diagnosis of asthma or COPD exacerbation. Two board-certified pulmonologists evaluated the spirometry tracings to determine the proportion of patients able to produce adequate quality spirometry data. Findings were interpreted to evaluate the utility of spirometry to confirm the presence of obstructive lung disease, according to the 2005 European Respiratory Society/American Thoracic Society recommendations. Results: There was an almost perfect agreement for acceptability (κ = 0.92) and reproducibility (κ =0.93) of spirometry tracings. Three-quarters (73%) of the tests were interpreted by both pulmonologists as being of adequate quality. Of these adequate quality tests, 22% did not present objective evidence of obstructive lung disease. Obese patients (BMI ≥30 kg/m2) were more likely to produce spirometry tracings with no evidence of obstructive lung disease, compared to non-obese patients (33% vs. 8%, p = 0.007). Conclusions: Adequate quality spirometry can be obtained in most hospitalized adults with a physician diagnosis of asthma or COPD exacerbation. Confirmatory spirometry could be a useful tool to help reduce overdiagnosis of obstructive lung disease, especially among obese patients

Variability of extracorporeal cardiopulmonary resuscitation utilization for refractory adult out-of-hospital cardiac arrest: an international survey study.

Objective: A growing interest in extracorporeal cardiopulmonary resuscitation (ECPR) as a rescue strategy for refractory adult out-of-hospital cardiac arrest (OHCA) currently exists. This study aims to determine current standards of care and practice variation for ECPR patients in the USA and Korea. Methods: In December 2015, we surveyed centers from the Korean Hypothermia Network (KORHN) Investigators and the US National Post-Arrest Research Consortium (NPARC) on current targeted temperature management and ECPR practices. This project analyzes the subsection of questions addressing ECPR practices. We summarized survey. Results: Overall, 9 KORHN and 4 NPARC centers reported having ECPR programs and had complete survey data available. Two KORHN centers utilized extracorporeal membrane oxygenation only for postarrest circulatory support in patients with refractory shock and were excluded from further analysis. Centers with available ECPR generally saw a high volume of OHCA patients (10/11 centers care for \u3e75 OHCA a year). Location of, and providers trained for cannulation varied across centers. All centers in both countries (KORHN 7/7, NPARC 4/4) treated comatose ECPR patients with targeted temperature management. All NPARC centers and four of seven KORHN centers reported having a standardized hospital protocol for ECPR. Upper age cutoff for eligibility ranged from 60 to 75 years. No absolute contraindications were unanimous among centers. Conclusion: A wide variability in practice patterns exist between centers performing ECPR for refractory OHCA in the US and Korea. Standardized protocols and shared research databases might inform best practices, improve outcomes, and provide a foundation for prospective studies

Orbital-Dependent Polaron Formation in the Relativistic Mott Insulator Sr\u3csub\u3e2\u3c/sub\u3eIrO\u3csub\u3e4\u3c/sub\u3e

We use optical spectroscopy to investigate the electron-phonon interaction in Sr2IrO4, a well-known 5d transition metal oxide with spin-orbit entangled states. The temperature evolution in the optical spectra is well described by the Fröhlich polaron model, indicating a large electron-phonon interaction. We further find that electrons in different orbitals selectively couple with different phonon modes. While Jeff = 3/2 holes do not seem to couple with any phonons, Jeff = 1/2 and 3z2−r2 electrons mainly couple with in-plane and out-of-plane Ir-O bending modes, respectively. The symmetries of the orbitals and phonons are consistent with our observations

Regulation of Polar Peptidoglycan Biosynthesis by Wag31 Phosphorylation in Mycobacteria

<p>Abstract</p> <p>Background</p> <p>Sensing and responding to environmental changes is a central aspect of cell division regulation. <it>Mycobacterium tuberculosis </it>contains eleven Ser/Thr kinases, two of which, PknA and PknB, are key signaling molecules that regulate cell division/morphology. One substrate of these kinases is Wag31, and we previously showed that partial depletion of Wag31 caused morphological changes indicative of cell wall defects, and that the phosphorylation state of Wag31 affected cell growth in mycobacteria. In the present study, we further characterized the role of the Wag31 phosphorylation in polar peptidoglycan biosynthesis.</p> <p>Results</p> <p>We demonstrate that the differential growth among cells expressing different <it>wag31 </it>alleles (wild-type, phosphoablative, or phosphomimetic) is caused by, at least in part, dissimilar nascent peptidoglycan biosynthesis. The phosphorylation state of Wag31 is found to be important for protein-protein interactions between the Wag31 molecules, and thus, for its polar localization. Consistent with these results, cells expressing a phosphomimetic <it>wag31 </it>allele have a higher enzymatic activity in the peptidoglycan biosynthetic pathway.</p> <p>Conclusions</p> <p>The Wag31_Mtbphosphorylation is a novel molecular mechanism by which Wag31_Mtbregulates peptidoglycan synthesis and thus, optimal growth in mycobacteria.</p

X-ray Astronomy in the Laboratory with a Miniature Compact Object Produced by Laser-Driven Implosion

Laboratory spectroscopy of non-thermal equilibrium plasmas photoionized by intense radiation is a key to understanding compact objects, such as black holes, based on astronomical observations. This paper describes an experiment to study photoionizing plasmas in laboratory under well-defined and genuine conditions. Photoionized plasma is here generated using a 0.5-keV Planckian x-ray source created by means of a laser-driven implosion. The measured x-ray spectrum from the photoionized silicon plasma resembles those observed from the binary stars Cygnus X-3 and Vela X-1 with the Chandra x-ray satellite. This demonstrates that an extreme radiation field was produced in the laboratory, however, the theoretical interpretation of the laboratory spectrum significantly contradicts the generally accepted explanations in x-ray astronomy. This model experiment offers a novel test bed for validation and verification of computational codes used in x-ray astronomy.Comment: 5 pages, 4 figures are included. This is the original submitted version of the manuscript to be published in Nature Physic

The AAA+ ATPase Thorase Regulates AMPA Receptor-Dependent Synaptic Plasticity and Behavior

SummaryThe synaptic insertion or removal of AMPA receptors (AMPAR) plays critical roles in the regulation of synaptic activity reflected in the expression of long-term potentiation (LTP) and long-term depression (LTD). The cellular events underlying this important process in learning and memory are still being revealed. Here we describe and characterize the AAA+ ATPase Thorase, which regulates the expression of surface AMPAR. In an ATPase-dependent manner Thorase mediates the internalization of AMPAR by disassembling the AMPAR-GRIP1 complex. Following genetic deletion of Thorase, the internalization of AMPAR is substantially reduced, leading to increased amplitudes of miniature excitatory postsynaptic currents, enhancement of LTP, and elimination of LTD. These molecular events are expressed as deficits in learning and memory in Thorase null mice. This study identifies an AAA+ ATPase that plays a critical role in regulating the surface expression of AMPAR and thereby regulates synaptic plasticity and learning and memory