In-hospital mortality following surgical lung biopsy for interstitial lung disease in the USA: 2000-2011

Rationale: Surgical lung biopsy can help to determine a specific diagnosis in interstitial lung disease, but has associated risks. Most currently available mortality data are derived from case series and may not be generalizable to broader populations. Objectives: We aimed to assess in-hospital mortality following surgical lung biopsy for interstitial lung disease in a national secondary care dataset from the United States. Methods: Data were obtained from the 2000-2011 Nationwide Inpatient Sample. Cases were identified using International Classification of Diseases (ICD-9-CM) codes for interstitial lung disease and surgical lung biopsies. Lung resections and cases of lung cancer were excluded. Weighted data were used to estimate numbers of biopsies nationwide and in-hospital mortality, and multivariable logistic regression was used to adjust for sex, age, geographic region, co-morbidity, type of operation and provisional diagnosis. Measurements and Main Results: We estimated there to be around 12,000 surgical lung biopsies performed annually for interstitial lung disease in the United States, two-thirds of which were performed electively. In-hospital mortality was 1.7% for elective procedures, but significantly higher for non-elective procedures (16.0%). Male sex, increasing age, increasing co-morbidity, open surgery and a provisional diagnosis of idiopathic pulmonary fibrosis or connective tissue disease related interstitial lung disease were risk factors for increased mortality. Conclusions: In-hospital mortality following elective surgical lung biopsy for interstitial lung disease is just under 2%, but significantly higher for non-elective procedures. Identified risk factors for death should be taken into account when counselling patients on whether to pursue a histological diagnosis

Global incidence and mortality of idiopathic pulmonary fibrosis: a systematic review

Introduction: As idiopathic pulmonary fibrosis emerges as an important public health problem, there is a need to coordinate data on incidence and mortality globally. This study aims to systematically assess all available studies to investigate the global burden of disease. Methods: Medline and Embase databases were searched systematically for all population-based studies of incidence or mortality of idiopathic pulmonary fibrosis. Clinical case series and prevalence studies were excluded. The search was supplemented using Google search engine, hand-searching of references and conference abstracts. Data were extracted independently by two authors using a pre-specified proforma, with assessment of methodological quality. Results: 34 studies were identified providing data from 21 countries from 1968-2012. 28 studies reported incidence data, and eight reported mortality data. In studies from year 2000 onwards, we estimated a conservative incidence range of 3-9 cases per 100,000 per year for Europe and North America. Incidence was lower in East Asia and South America. The majority of studies showed an increase in incidence over time. Conclusions: The incidence of idiopathic pulmonary fibrosis is increasing worldwide, and rates are coming together across countries. Current data suggest incidence is similar to that of conditions such as stomach, liver, testicular and cervical cancers

Open Collaboration: A Problem Solving Strategy That Is Redefining NASA's Innovative Spirit

In 2010, NASA?s Space Life Sciences Directorate announced the successful results from pilot experiments with open innovation methodologies. Specifically, utilization of internet based external crowd sourcing platforms to solve challenging problems in human health and performance related to the future of spaceflight. The follow-up to this success was an internal crowd sourcing pilot program entitled NASA@work, which was supported by the InnoCentive@work software platform. The objective of the NASA@work pilot was to connect the collective knowledge of individuals from all areas within the NASA organization via a private web based environment. The platform provided a venue for NASA Challenge Owners, those looking for solutions or new ideas, to pose challenges to internal solvers, those within NASA with the skill and desire to create solutions. The pilot was launched in 57 days, a record for InnoCentive and NASA, and ran for three months with a total of 20 challenges posted Agency wide. The NASA@work pilot attracted over 6000 participants throughout NASA with a total of 183 contributing solvers for the 20 challenges posted. At the time of the pilot?s closure, solvers provided viable solutions and ideas for 17 of the 20 posted challenges. The solver community provided feedback on the pilot describing it as a barrier breaking activity, conveying that there was a satisfaction associated with helping co-workers, that it was "fun" to think about problems outside normal work boundaries, and it was nice to learn what challenges others were facing across the agency. The results and the feedback from the solver community have demonstrated the power and utility of an internal collaboration tool, such as NASA@work

Surgical lung biopsy for the diagnosis of interstitial lung disease in England: 1997-2008

Introduction: International guidelines and new targeted therapies for idiopathic pulmonary fibrosis have increased the need for accurate diagnosis of interstitial lung disease, which may lead to more surgical lung biopsies. This study aims to assess the risk of this procedure in patients from the United Kingdom. Methods: We used Hospital Episodes Statistics data from 1997-2008 to assess the frequency of surgical lung biopsy for interstitial lung disease in England. We identified cardiothoracic surgical patients using ICD-10 codes for interstitial lung disease and OPCS-4 codes for surgical lung biopsy. We excluded those with lung resections or lung cancer. We estimated in-hospital, 30-day and 90-day mortality following the procedure, and linked to cause of death using data from the Office of National Statistics. Results: We identified 2,820 patients with interstitial lung disease undergoing surgical lung biopsy during the 12 year period. The number of biopsies increased over the time period studied. In-hospital, 30-day and 90-day mortality were 1.7%, 2.4% and 3.9% respectively. Male sex, increasing age, increasing co-morbidity and open surgery were risk factors for mortality. Discussion: Surgical lung biopsy for interstitial lung disease has a similar mortality to lobectomy for lung cancer, and clinicians and patients should understand the likely risks involved

Using Total Fluorescence Increase (Signal Mass) to Determine the Ca2+ Current Underlying Localized Ca2+ Events

The feasibility of determining localized Ca2+ influx using only wide-field fluorescence images was explored by imaging (using fluo-3) single channel Ca2+ fluorescence transients (SCCaFTs), due to Ca2+ entry through single openings of Ca2+-permeable ion channels, while recording unitary channel currents. Since the image obtained with wide-field optics is an integration of both in-focus and out-of-focus light, the total fluorescence increase (ΔFtotal or “signal mass”) associated with a SCCaFT can be measured directly from the image by adding together the fluorescence increase due to Ca2+ influx in all of the pixels. The assumptions necessary for obtaining the signal mass from confocal linescan images are not required. Two- and three-dimensional imaging was used to show that ΔFtotal is essentially independent of the position of the channel with respect to the focal plane of the microscope. The relationship between Ca2+ influx and ΔFtotal was obtained using SCCaFTs from plasma membrane caffeine-activated cation channels when Ca2+ was the only charge carrier of the inward current. This relationship was found to be linear, with the value of the slope (or converting factor) affected by the particular imaging system set-up, the experimental conditions, and the properties of the fluorescent indicator, including its binding capacity with respect to other cellular buffers. The converting factor was used to estimate the Ca2+ current passing through caffeine-activated channels in near physiological saline and to estimate the endogenous buffer binding capacity. In addition, it allowed a more accurate estimate of the Ca2+ current underlying Ca2+ sparks resulting from Ca2+ release from intracellular stores via ryanodine receptors in the same preparation

Increasing global mortality from idiopathic pulmonary fibrosis in the twenty-first century

Rationale: Recent evidence from the United Kingdom suggests that the number of deaths from idiopathic pulmonary fibrosis is increasing, although comparable international data are limited. Objectives: We aimed to collate death certification data from multiple countries to determine global trends in mortality from idiopathic pulmonary fibrosis. Methods: Data were obtained from the national statistics agencies of countries with relevant mortality records. Age-standardised mortality rates were calculated, and Poisson regression modelling was used to calculate rate ratios. Meta-analysis was used to calculate an overall estimate of mortality change over time. Measurements and Main Results: Ten countries provided mortality data on pulmonary fibrosis over a period from 1999 to 2012. Age-standardised mortality ranged between 4 and 10 per 100,000 population for the most recent years of data, being lowest in Sweden (4.68 per 100,000), Spain (5.38 per 100,000) and New Zealand (5.55 per 100,000), and highest in the UK (9.84 per 100,000 in England and Wales, 10.71 per 100,000 in Scotland) and Japan (10.26 per 100,000). Positive associations with male sex and increasing age were consistently observed across all countries. There was an overall 2-3% annual increase in mortality depending on codes used for classification – for broad codes, overall rate ratio 1.03 (95% confidence intervals 1.02-1.04, p<0.001), for narrow codes, overall rate ratio 1.02 (95% confidence intervals 1.01-1.03, p<0.001). Validation in a local cohort showed that idiopathic pulmonary fibrosis was recorded as the underlying cause of death in two-thirds of known cases and anywhere on the death certificate in 80% of cases. Conclusions: Mortality from idiopathic pulmonary fibrosis is increasing steadily worldwide, despite that fact that death certification will almost certainly underestimate true mortality. We estimate that there will be between 28000-65000 deaths in Europe and 13000-17000 deaths in the USA from idiopathic pulmonary fibrosis clinical syndrome in 2014. Variation between countries remains but is less than previously reported

Imaging Ca2+ Entering the Cytoplasm through a Single Opening of a Plasma Membrane Cation Channel

Discrete localized fluorescence transients due to openings of a single plasma membrane Ca2+ permeable cation channel were recorded using wide-field digital imaging microscopy with fluo-3 as the Ca2+ indicator. These transients were obtained while simultaneously recording the unitary channel currents using the whole-cell current-recording configuration of the patch-clamp technique. This cation channel in smooth muscle cells is opened by caffeine (Guerrero, A., F.S. Fay, and J.J. Singer. 1994. J. Gen. Physiol. 104:375–394). The localized fluorescence transients appeared to occur at random locations on the cell membrane, with the duration of the rising phase matching the duration of the channel opening. Moreover, these transients were only observed in the presence of sufficient extracellular Ca2+, suggesting that they are due to Ca2+ influx from the bathing solution. The fluorescence transient is characterized by an initial fast rising phase when the channel opens, followed by a slower rising phase during prolonged openings. When the channel closes there is an immediate fast falling phase followed by a slower falling phase. Computer simulations of the underlying events were used to interpret the time course of the transients. The rapid phases are mainly due to the establishment or removal of Ca2+ and Ca2+-bound fluo-3 gradients near the channel when the channel opens or closes, while the slow phases are due to the diffusion of Ca2+ and Ca2+-bound fluo-3 into the cytoplasm. Transients due to short channel openings have a “Ca2+ spark-like” appearance, suggesting that the rising and early falling components of sparks (due to openings of ryanodine receptors) reflect the fast phases of the fluorescence change. The results presented here suggest methods to determine the relationship between the fluorescence transient and the underlying Ca2+ current, to study intracellular localized Ca2+ handling as might occur from single Ca2+ channel openings, and to localize Ca2+ permeable ion channels on the plasma membrane

A Close Association of RyRs with Highly Dense Clusters of Ca2+-activated Cl− Channels Underlies the Activation of STICs by Ca2+ Sparks in Mouse Airway Smooth Muscle

Ca2+ sparks are highly localized, transient releases of Ca2+ from sarcoplasmic reticulum through ryanodine receptors (RyRs). In smooth muscle, Ca2+ sparks trigger spontaneous transient outward currents (STOCs) by opening nearby clusters of large-conductance Ca2+-activated K+ channels, and also gate Ca2+-activated Cl− (Cl(Ca)) channels to induce spontaneous transient inward currents (STICs). While the molecular mechanisms underlying the activation of STOCs by Ca2+ sparks is well understood, little information is available on how Ca2+ sparks activate STICs. In the present study, we investigated the spatial organization of RyRs and Cl(Ca) channels in spark sites in airway myocytes from mouse. Ca2+ sparks and STICs were simultaneously recorded, respectively, with high-speed, widefield digital microscopy and whole-cell patch-clamp. An image-based approach was applied to measure the Ca2+ current underlying a Ca2+ spark (ICa(spark)), with an appropriate correction for endogenous fixed Ca2+ buffer, which was characterized by flash photolysis of NPEGTA. We found that ICa(spark) rises to a peak in 9 ms and decays with a single exponential with a time constant of 12 ms, suggesting that Ca2+ sparks result from the nonsimultaneous opening and closure of multiple RyRs. The onset of the STIC lags the onset of the ICa(spark) by less than 3 ms, and its rising phase matches the duration of the ICa(spark). We further determined that Cl(Ca) channels on average are exposed to a [Ca2+] of 2.4 μM or greater during Ca2+ sparks. The area of the plasma membrane reaching this level is <600 nm in radius, as revealed by the spatiotemporal profile of [Ca2+] produced by a reaction-diffusion simulation with measured ICa(spark). Finally we estimated that the number of Cl(Ca) channels localized in Ca2+ spark sites could account for all the Cl(Ca) channels in the entire cell. Taken together these results lead us to propose a model in which RyRs and Cl(Ca) channels in Ca2+ spark sites localize near to each other, and, moreover, Cl(Ca) channels concentrate in an area with a radius of ∼600 nm, where their density reaches as high as 300 channels/μm2. This model reveals that Cl(Ca) channels are tightly controlled by Ca2+ sparks via local Ca2+ signaling

Dynamics of Signaling between Ca2+ Sparks and Ca2+- Activated K+ Channels Studied with a Novel Image-Based Method for Direct Intracellular Measurement of Ryanodine Receptor Ca2+ Current

Ca2+ sparks are highly localized cytosolic Ca2+ transients caused by a release of Ca2+ from the sarcoplasmic reticulum via ryanodine receptors (RyRs); they are the elementary events underlying global changes in Ca2+ in skeletal and cardiac muscle. In smooth muscle and some neurons, Ca2+ sparks activate large conductance Ca2+-activated K+ channels (BK channels) in the spark microdomain, causing spontaneous transient outward currents (STOCs) that regulate membrane potential and, hence, voltage-gated channels. Using the fluorescent Ca2+ indicator fluo-3 and a high speed widefield digital imaging system, it was possible to capture the total increase in fluorescence (i.e., the signal mass) during a spark in smooth muscle cells, which is the first time such a direct approach has been used in any system. The signal mass is proportional to the total quantity of Ca2+ released into the cytosol, and its rate of rise is proportional to the Ca2+ current flowing through the RyRs during a spark (ICa(spark)). Thus, Ca2+ currents through RyRs can be monitored inside the cell under physiological conditions. Since the magnitude of ICa(spark) in different sparks varies more than fivefold, Ca2+ sparks appear to be caused by the concerted opening of a number of RyRs. Sparks with the same underlying Ca2+ current cause STOCs, whose amplitudes vary more than threefold, a finding that is best explained by variability in coupling ratio (i.e., the ratio of RyRs to BK channels in the spark microdomain). The time course of STOC decay is approximated by a single exponential that is independent of the magnitude of signal mass and has a time constant close to the value of the mean open time of the BK channels, suggesting that STOC decay reflects BK channel kinetics, rather than the time course of [Ca2+] decline at the membrane. Computer simulations were carried out to determine the spatiotemporal distribution of the Ca2+ concentration resulting from the measured range of ICa(spark). At the onset of a spark, the Ca2+ concentration within 200 nm of the release site reaches a plateau or exceeds the [Ca2+]EC50 for the BK channels rapidly in comparison to the rate of rise of STOCs. These findings suggest a model in which the BK channels lie close to the release site and are exposed to a saturating [Ca2+] with the rise and fall of the STOCs determined by BK channel kinetics. The mechanism of signaling between RyRs and BK channels may provide a model for Ca2+ action on a variety of molecular targets within cellular microdomains