Non-Malignant Etiologies for Cystectomy: Trends from 2013-2020

Introduction: Simple cystectomy (SC) may be performed for a variety of non-malignant bladder conditions. However, SC can involve many complications. We seek to characterize the indications for SC including neurogenic bladder, interstitial cystitis, radiation cystitis, and fistulae. We aim to provide an updated analysis of the temporal and demographic trends from 2013-2020. Methods The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was reviewed for patients undergoing SC. The non-malignant etiologies for SC were separated into 9 subgroups: anatomical, autoimmune, benign neoplasm, bladder outlet obstruction/ lower urinary tract symptoms / reflux, fistula, infectious, neurogenic, vascular, and other. ANOVA analysis was performed to assess for significant changes in indication frequency. A two-sided Z-test comparing frequencies of SC in 2013 vs 2020 for each subgroup. Statistical significance was accepted at alpha of 0.05. Results A total of 1,516 patients met inclusion criteria. Neurogenic bladder, fistula, and vascular were the most common indications with 376 (25%), 259 (17%), and 227 (15%) of patients, respectively (Table 1). The average length of stay (LOS) for neurogenic etiologies was 11.05 days. The trends of neurogenic (p\u3c0.01), other (p=0.003), autoimmune (p=0.011), and fistula (p=0.025) etiologies had a statistically significant decrease from 2013 to 2020 (Table 1). Discussion From 2013-2020, the most common indication for SC was neurogenic bladder though there has been a statistically significant decrease in SC from 2013 to 2020. We observed that while cystectomy continues to have long LOS and with high rates of complication, there has been a decrease in frequency with which SC is performed as more conservative management is pursued. While performing cystectomy for non-malignant conditions remains relatively rare, it is important to retrospectively look at the diagnoses that warrant this procedure. This information is of interest to urologists as they consider surgical versus non-surgical management of these benign diseases. The trends identified in this study will help define the prevalence of SC in treating non-malignant disease and the need for future research in this area

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Energy Estimation of Cosmic Rays with the Engineering Radio Array of the Pierre Auger Observatory

The Auger Engineering Radio Array (AERA) is part of the Pierre Auger Observatory and is used to detect the radio emission of cosmic-ray air showers. These observations are compared to the data of the surface detector stations of the Observatory, which provide well-calibrated information on the cosmic-ray energies and arrival directions. The response of the radio stations in the 30 to 80 MHz regime has been thoroughly calibrated to enable the reconstruction of the incoming electric field. For the latter, the energy deposit per area is determined from the radio pulses at each observer position and is interpolated using a two-dimensional function that takes into account signal asymmetries due to interference between the geomagnetic and charge-excess emission components. The spatial integral over the signal distribution gives a direct measurement of the energy transferred from the primary cosmic ray into radio emission in the AERA frequency range. We measure 15.8 MeV of radiation energy for a 1 EeV air shower arriving perpendicularly to the geomagnetic field. This radiation energy -- corrected for geometrical effects -- is used as a cosmic-ray energy estimator. Performing an absolute energy calibration against the surface-detector information, we observe that this radio-energy estimator scales quadratically with the cosmic-ray energy as expected for coherent emission. We find an energy resolution of the radio reconstruction of 22% for the data set and 17% for a high-quality subset containing only events with at least five radio stations with signal.Comment: Replaced with published version. Added journal reference and DO

Measurement of the Radiation Energy in the Radio Signal of Extensive Air Showers as a Universal Estimator of Cosmic-Ray Energy

We measure the energy emitted by extensive air showers in the form of radio emission in the frequency range from 30 to 80 MHz. Exploiting the accurate energy scale of the Pierre Auger Observatory, we obtain a radiation energy of 15.8 \pm 0.7 (stat) \pm 6.7 (sys) MeV for cosmic rays with an energy of 1 EeV arriving perpendicularly to a geomagnetic field of 0.24 G, scaling quadratically with the cosmic-ray energy. A comparison with predictions from state-of-the-art first-principle calculations shows agreement with our measurement. The radiation energy provides direct access to the calorimetric energy in the electromagnetic cascade of extensive air showers. Comparison with our result thus allows the direct calibration of any cosmic-ray radio detector against the well-established energy scale of the Pierre Auger Observatory.Comment: Replaced with published version. Added journal reference and DOI. Supplemental material in the ancillary file

Toxoplasma gondii Clonal Strains All Inhibit STAT1 Transcriptional Activity but Polymorphic Effectors Differentially Modulate IFN gamma Induced Gene Expression and STAT1 Phosphorylation

Host defense against the parasite Toxoplasma gondii requires the cytokine interferon-gamma (IFNγ). However, Toxoplasma inhibits the host cell transcriptional response to IFNγ, which is thought to allow the parasite to establish a chronic infection. It is not known whether all strains of Toxoplasma block IFNγ-responsive transcription equally and whether this inhibition occurs solely through the modulation of STAT1 activity or whether other transcription factors are involved. We find that strains from three North American/European clonal lineages of Toxoplasma, types I, II, and III, can differentially modulate specific aspects of IFNγ signaling through the polymorphic effector proteins ROP16 and GRA15. STAT1 tyrosine phosphorylation is activated in the absence of IFNγ by the Toxoplasma kinase ROP16, but this ROP16-activated STAT1 is not transcriptionally active. Many genes induced by STAT1 can also be controlled by other transcription factors and therefore using these genes as specific readouts to determine Toxoplasma inhibition of STAT1 activity might be inappropriate. Indeed, GRA15 and ROP16 modulate the expression of subsets of IFNγ responsive genes through activation of the NF-κB/IRF1 and STAT3/6 transcription factors, respectively. However, using a stable STAT1-specific reporter cell line we show that strains from the type I, II, and III clonal lineages equally inhibit STAT1 transcriptional activity. Furthermore, all three of the clonal lineages significantly inhibit global IFNγ induced gene expression

Chronic Obstructive Pulmonary Diseased Human Lung Fibroblasts Secrete Increased Matrix Metalloproteases -12 and -8

INTRODUCTION: According to the American Lung Association, 16.5 million people have Chronic Obstructive Pulmonary Disease (COPD), the third leading cause of death in the United States. COPD is a condition in which the airways of the lung are inflamed, and the alveoli thicken leading to decreased oxygen exchange and the ability to breathe. The thickening of the airway is in part due to abnormal remodeling of the extracellular matrix. Dysregulation of Matrix Metalloprotease (MMP) activity leads to the breakdown of collagen type I, a necessary component of the extracellular matrix in the lung tissue. In this study, we measure MMP-8 and MMP-12 production by Human Lung Fibroblasts (HLFB) reared in serum-free media (normal (NHLFB) and COPD Diseased (DHLFB)). METHODS: Commercially available early passage HLFB established from lung tissue, obtained during a biopsy, were cultured and passaged in our laboratory through passage 4. Both normal (NHLFB) and diseased (DHLFB) cells were viable when cultured at subconfluence for 24 hours in a serum-free medium. We collected conditioned media (secreted fraction) and cell-associated matrix (incorporated fraction) from the cultures following 24 hours in serum-free medium or treatment with 5ug Extracellular Matrix Protection Factor-2 (ECPF-2). ECPF-2 is a novel inhibitor of MMP-8 and -12 activity. Utilizing commercially available ELISA kits, we measured intact collagen type I (Chondrex), degraded collagen type I (CUSABIO), MMP-8 (Quantikine, Abcam), MMP-12 (Abcam), and MMP-9 (Abcam). RESULTS: There were detectable levels of MMP-12 (ng/culture) and MMP-8 (pg/culture) in both the secreted (conditioned media) and incorporated (extracellular matrix) fractions. Overall, DHLFB produced 3-fold more secreted MMP-12 [150ng/culture versus 50ng/culture] and 14-fold less incorporated MMP-12 [20ng/culture versus 300ng/culture] than the NHLFB. In the case of MMP-8, DHLFB produced 2-fold less secreted MMP-8 [30pg/culture versus 80pg/culture], while the incorporated fractions of MMP-8 were relatively similar in both normal and diseased cultures. In line with these findings, the diseased lung fibroblasts secreted approximately 10-fold higher levels of degraded collagen type I, confirming the diseased nature of the cells. DISCUSSION: Our findings suggest that MMP-8 has a role in the increased degradation of the extracellular matrix in COPD since collagen type I is a preferred substrate for MMP-8. But the role of MMP-12 in the disease process may be more indirect and involve elastolysis that could disrupt the interactions with collagen type I and facilitate collagen degradation by allowing access to the fibril by MMP-8. Future studies will measure elastin turnover in these cultures to get a clearer picture of the dysregulation of the extracellular matrix associated with COPD

Extracellular Matrix Protection Factor-2, a metalloprotease inhibitor and potential lung fibrosis therapeutic, targets Transforming Growth Factor-β storage through the Latent Transforming Growth Factor-β Binding Protein

Introduction: Pulmonary fibrosis is a disease that presents as an accumulation of scar tissue by the fibroblasts in the lungs. The scar tissue results from the excessive remodeling of the alveolar air spaces and the breakdown of components of the extracellular matrix (ECM) via elastolysis. Latent transforming growth factor-β binding protein (LTBP-1) is a key regulator of transforming growth factor-β (TGF-β) activation by storing the TGF-β in the ECM, thus maintaining the growth factor in a latent state. In cultured lung fibroblasts, decreased LTBP-1 leads to increased expression of fibrosis-causing TGF-β target genes. Therefore, increased production of LTBP-1 should lead to increased storage of TGF-β in the ECM and reduced fibrotic activity in the disease state. Methods: In the current study, we measured LTBP-1 production in Human Lung Fibroblasts (HLFB) reared in serum-free media (normal (NHLFB) and COPD Diseased (DHLFB)). Commercially available early passage HLFB cells established from lung tissue, obtained during a biopsy, were cultured through passage 4 and transferred to serum-free media for treatment. Serum-free cultures were treated with a novel MMP-12 inhibitor, Extracellular Matrix Protection Factor-2 (ECPF-2), at 5 ug/ml and 10 ug/ml for 24 hours. Conditioned media (secreted fraction) and cell-associated matrix (incorporated fraction) were collected, and the total LTBP-1 produced was measured by enzyme-linked immunosorbent assay (ELISA). Results: Normal fibroblasts (NHLFB) produced an average of 65pg/ml (secreted) and 340pg/ml (incorporated) LTBP-1. This was significantly different from the 47pg/ml (secreted) and 237pg/ml (incorporated) LTBP-1 produced by the diseased fibroblasts (DHLFB) (one-way ANOVA p\u3c 0.01). These data are in line with published findings that demonstrate a decrease in incorporated LTBP-1 is associated with increased fibrosis in the lung. Treatment of diseased cultures with 10 ug/ml ECPF-2, an inhibitor of MMP-12 enzyme activity, resulted in an increased incorporated fraction of LTBP-1 compared to diseased serum-free control (p\u3c0.02 by student’s t-test). At the same time, no significant effect was detected in the normal fibroblast cultures. Discussion: This finding highlights the therapeutic potential of inhibition of MMP-12 that can lead to increased TGF-β storage, thereby slowing the progression of lung fibrosis. An Alumni Grant through the Division of Research at the Philadelphia College of Osteopathic Medicine supported this study

Käytännön kosteikkosuunnittelu

Maatalouden vesiensuojelua edistetään monin tavoin. Ravinteita ja eroosioainesta sisältäviä valumavesiä pyritään puhdistamaan erilaisissa kosteikoissa. Tämä opas on kirjoitettu avuksi pienimuotoisten kosteikkojen perustamiseen. Oppaassa esitetään käytännönläheisesti kosteikon toteuttamisen eri vaiheet paikan valinnasta suunnitteluun ja rakentamiseen. Vuonna 2010 julkaistun painoksen tiedot on saatettu ajantasalle. Julkaisu on toteutettu osana Tehoa maatalouden vesiensuojeluun (TEHO) -hanketta ja päivitetty TEHO Plus -hankkeen toimesta. Oppaan toivotaan lisäävän kiinnostusta kosteikkojen suunnitteluun ja edelleen niiden rakentamiseen

Number of Hajj Pilgrims Departured(1) to the Holyland of Mecca by Province, 2012–2015

The azimuthal asymmetry in the risetime of signals in Auger surface detector stations is a source of information on shower development. The azimuthal asymmetry is due to a combination of the longitudinal evolution of the shower and geometrical effects related to the angles of incidence of the particles into the detectors. The magnitude of the effect depends upon the zenith angle and state of development of the shower and thus provides a novel observable, (secθ)max, sensitive to the mass composition of cosmic rays above 3×1018 eV. By comparing measurements with predictions from shower simulations, we find for both of our adopted models of hadronic physics (QGSJETII-04 and EPOS-LHC) an indication that the mean cosmic-ray mass increases slowly with energy, as has been inferred from other studies. However, the mass estimates are dependent on the shower model and on the range of distance from the shower core selected. Thus the method has uncovered further deficiencies in our understanding of shower modeling that must be resolved before the mass composition can be inferred from (secθ)max