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PURPOSE: To compare the delivered radiation dose between a low-dose hip CT (Computed Tomography) scan protocol and traditional hip CT scan protocols (referred to as: traditional CT). METHODS: This was a retrospective comparative cohort study. A group of patients who underwent hip preservation surgery (including arthroscopy, surgical hip dislocation, or periacetabular osteotomy procedures) at our institution between 2016-2017 were identified. Patients were excluded if they had a BMI>35 kg/m(2), previous surgery, or absence of a radiation dose report. The low-dose group included patients undergoing hip CT at our institution utilizing a standardized protocol of 100 kVp, 100 mAs and limited scanning field. The traditional CT group included patients who had hip CT scans performed at outside institutions. The total effective dose (E(hip)), effective dose per millimeter-body-length-scanned (E(mm)), and the patients’ age, BMI were compared by univariate analysis. The correlation of E(hip) to BMI was assessed. RESULTS: Forty-one consecutive patients were included in the low-dose group, and 18 consecutive patients were included in the traditional CT group. Low-dose CT resulted in 90% reduction in radiation exposure compared to traditional CT (E(hip)=0.97 ± 0.28 vs. 9.68 ± 6.67mSv, p

Genome-wide association studies (GWAS) have identified multiple associations with emphysema apicobasal distribution (EABD), but the biological functions of these variants are unknown. To characterize the functions of EABD-associated variants, we integrated GWAS results with 1) expression quantitative trait loci (eQTL) from the Genotype Tissue Expression (GTEx) project and subjects in the COPDGene (Genetic Epidemiology of COPD) study and 2) cell type epigenomic marks from the Roadmap Epigenomics project. On the basis of these analyses, we selected a variant near ACVR1B (activin A receptor type 1B) for functional validation. SNPs from 168 loci with P values less than 5 × 10(−5) in the largest GWAS meta-analysis of EABD were analyzed. Eighty-four loci overlapped eQTL, with 12 of these loci showing greater than 80% likelihood of harboring a single, shared GWAS and eQTL causal variant. Seventeen cell types were enriched for overlap between EABD loci and Roadmap Epigenomics marks (permutation P

There is increasing evidence that aberrant processes occurring in the airways may precede the development of idiopathic pulmonary fibrosis (IPF); however, there has been no prior confirmatory data derived from imaging studies.To assess quantitative measures of airway wall thickness (AWT) in populations characterized for interstitial lung abnormalities (ILA) and for IPF.Computed tomographic imaging of the chest and measures of AWT were available for 6,073, 615, 1,167, and 38 participants from COPDGene (Genetic Epidemiology of COPD study), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study), and the Framingham Heart Study (FHS) and in patients with IPF from the Brigham and Women's Hospital Herlihy Registry, respectively. To evaluate these associations, we used multivariable linear regression to compare a standardized measure of AWT (the square root of AWT for airways with an internal perimeter of 10 mm [Pi10]) and characterizations of ILA and IPF by computed tomographic imaging of the chest.In COPDGene, ECLIPSE, and FHS, research participants with ILA had increased measures of Pi10 compared with those without ILA. Patients with IPF had mean measures of Pi10 that were even greater than those noted in research participants with ILA. After adjustment for important covariates (e.g., age, sex, race, body mass index, smoking behavior, and chronic obstructive pulmonary disease severity when appropriate), research participants with ILA had increased measures of Pi10 compared with those without ILA (0.03 mm in COPDGene, 95% confidence interval [CI], 0.02-0.03; P 0.001; 0.02 mm in ECLIPSE, 95% CI, 0.005-0.04; P = 0.01; 0.07 mm in FHS, 95% CI, 0.01-0.1; P = 0.01). Compared with COPDGene participants without ILA older than 60 years of age, patients with IPF were also noted to have increased measures of Pi10 (2.0 mm, 95% CI, 2.0-2.1; P 0.001). Among research participants with ILA, increases in Pi10 were correlated with reductions in lung volumes in some but not all populations.These results demonstrate that measurable increases in AWT are consistently noted in research participants with ILA and in patients with IPF. These findings suggest that abnormalities of the airways may play a role in, or be correlated with, early pathogenesis of pulmonary fibrosis.

The marbled cat Pardofelismarmorata is a Near Threatened small felid. The cat’s presence in Nepal is based on an anecdote. A camera trap-based study to access diversity and abundance of terrestrial mammals in eastern Nepal accumulated 3,014 camera trap days and resulted in 5,176 photographs of 17 medium-large sized mammal species. Amongst them, a marbled cat was captured at a single camera trap station in January 2018. The camera trap-capturing the marbled cat was located in the secondary forest at an altitude of 2,750 m a.s.l., dominated by free-ranging cattle close to a permanent human settlement (1.4 km) and a temporary cattle herding camp (0.4 km). This is the first photographic evidence of a marbled cat in Nepal. In this survey, we also recorded three other felid species: common leopard Pantherapardus, Asiatic golden-cat Catopumatemminckii and leopard cat Prionailurusbengalensis. We recommend detailed year-round camera trap surveys in the mid-hills of eastern Nepal along with research on adaptation of the small felids to human-dominated areas and assessment of immediate threats for preparing sound conservation management plans of the marbled cat and its sympatric species. Initiation of conservation programmes engaging local dokpa (herders) is necessary.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem glioma, which carries the deadliest prognosis of all childhood neoplasms. Despite recent advances in molecular profiling and characterization of pediatric high-grade gliomas, patient outcomes have not improved. One critical reason why current therapeutic approaches fail to provide a durable response is the adaptive nature of the highly understudied tumor microenvironment (TME). The most abundant non-neoplastic infiltrates in the DIPG TME are the tumor-associated macrophages (TAMs). There is limited data available on the role of TAMs in DIPG tumor growth and response to therapy, and the chemokines responsible for driving the infiltration of both innate and adaptive immune cells into these tumors remain unidentified.To accurately model DIPGs, we utilized immunocompetent genetically engineered mouse models (GEMMs) based on the RCAS/tv-a gene transfer system. At postnatal days 0-2, mice were injected with retrovirus-producing DF-1 cells directly in the brainstem. Tumorigenesis was driven by PDGFB overexpression and Tp53 silencing, together with human DIPG-specific mutations including: H3 histones with K27M substitution (H3.1K27M/H3.3K27M) and Acvr1R206H. Our data using these GEMMs show that mouse tumors are strikingly similar to their human counterparts as demonstrated by hallmark pathological observations including T2-contrast enhancement, highly infiltrating margins, and pseudopalisading necrosis. Loss of H3K27 trimethylation in histone mutant tumors is also observed in these tumors. Utilizing these GEMMs, we have identified CCL8 and CCL12 as important chemokines in H3.1K27M-DIPGs. Specifically, we observed longer survival in Ccl8/Ccl12 double knockout (DKO) tumor-bearing mice compared to wild-type (WT) mice. Interestingly, spectral flow cytometry analysis revealed no differences in myeloid cell infiltration but an increased number of NK cells, CD4+, and CD8+ T cells in tumors generated in Ccl8/Ccl12 DKO mice compared to WT. We also tested the efficacy of inhibiting two CCL8 receptors using a syngeneic mouse model of DIPG. Pharmacological inhibition of CCR1 and CCR5 rendered a reduction in macrophage presence in the tumors, and resulted in an extension of survival in tumor-bearing mice comparable to the effect of standard of care, radiation therapy. Our ongoing experiments aim to elucidate the mechanisms by which CCL8 and CCL12 modulate immune cell infiltration, and determine whether the effect of CCL8/CCL12 loss on survival seen in H3.1K27M-DIPG holds true for H3.3K27M-DIPG-bearing mice. Citation Format: Gonzalo M. Pinero, Montserrat Puigdelloses Vallcorba, James L. Ross, Zhihong Chen, Tanvi Joshi, Dolores Hambardzumyan. The role of chemokines CCL8 and CCL12 in diffuse intrinsic pontine gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1340.

Rationale: Increasing awareness of the prevalence and significance of Preserved Ratio Impaired Spirometry (PRISm), alternatively known as restrictive or Global Initiative for Chronic Obstructive Lu...

Galaxy clusters are filled with hot, diffuse X-ray emitting plasma, with a stochastically tangled magnetic field whose energy is close to equipartition with the energy of the turbulent motions \cite{zweibel1997, Vacca}. In the cluster cores, the temperatures remain anomalously high compared to what might be expected considering that the radiative cooling time is short relative to the Hubble time \cite{cowie1977,fabian1994}. While feedback from the central active galactic nuclei (AGN) \cite{fabian2012,birzan2012,churazov2000} is believed to provide most of the heating, there has been a long debate as to whether conduction of heat from the bulk to the core can help the core to reach the observed temperatures \cite{narayan2001,ruszkowski2002,kunz2011}, given the presence of tangled magnetic fields. Interestingly, evidence of very sharp temperature gradients in structures like cold fronts implies a high degree of suppression of thermal conduction \cite{markevitch2007}. To address the problem of thermal conduction in a magnetized and turbulent plasma, we have created a replica of such a system in a laser laboratory experiment. Our data show a reduction of local heat transport by two orders of magnitude or more, leading to strong temperature variations on small spatial scales, as is seen in cluster plasmas \cite{markevitch2003}.

Background and Aim: Congenital diaphragmatic hernia (CDH) is a rare defect often associated with pulmonary hypoplasia and abnormal pulmonary vascular development. Even after successful hernia repair, pulmonary disease may persist into adulthood. Impaired diaphragmatic motility may lead to compromised respiratory function long after index repair. This study investigates whether a novel ultrasound measurement, the diaphragmatic excursion ratio, can be a simple and non-invasive method to evaluate routine diaphragmatic motion after CDH repair, and whether it correlates with adverse surgical and respiratory outcomes.Materials and Methods: A cross-sectional study was conducted in consecutive patients who presented at medium-term follow-up visit between December 2017 and December 2018 after CDH repair at single pediatric hospital. Transthoracic ultrasound was performed with craniocaudal diaphragmatic excursion measured bilaterally during routine breathing. Diaphragmatic excursion ratios (diaphragmatic excursion of repaired vs. unrepaired side) were calculated and retrospectively compared with clinical data including demographics, length of stay, respiratory adjuncts, oral feeding, and need for gastrostomy.Results: Thirty-eight patients (median age at ultrasound, 24 months, interquartile range 11–60) were evaluated. Nine patients underwent primary repair, 29 had non-primary repair (internal oblique muscle flap or mesh patch). Patients with a diaphragmatic excursion ratio below the median (0.54) had longer hospital stays (median 77 vs. 28 days, p = 0.0007) more ventilator days (median 16 vs. 9 days, p =0.004), and were more likely to have been discharged on oxygen (68 vs. 16%, p = 0.001). They were also less likely to be exclusively taking oral feeds at 1-year post-surgery (37 vs. 74%, p = 0.02) and more likely to require a gastrostomy tube in the first year of life (74 vs. 21%, p = 0.003).Conclusions: Transthoracic ultrasound after CDH repair is practical method to assess diaphragm motion, and decreased diaphragm excursion ratio is associated with worse respiratory outcomes, a longer length of stay, and dependence on gastrostomy tube feeding within 1 year. Further prospective studies may help validate this novel ultrasound measurement and offer prognostic value.

The coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for the coronavirus disease 2019 pandemic, and the closely related SARS-CoV coronavirus enter cells by binding at the human angiotensin converting enzyme 2 (hACE2). The stronger hACE2 affinity of SARS-CoV-2 has been connected with its higher infectivity. In this work, we study hACE2 complexes with the receptor-binding domains (RBDs) of the human SARS-CoV-2 and human SARS-CoV viruses, using all-atom molecular dynamics simulations and computational protein design with a physics-based energy function. The molecular dynamics simulations identify charge-modifying substitutions between the CoV-2 and CoV RBDs, which either increase or decrease the hACE2 affinity of the SARS-CoV-2 RBD. The combined effect of these mutations is small, and the relative affinity is mainly determined by substitutions at residues in contact with hACE2. Many of these findings are in line and interpret recent experiments. Our computational protein design calculations redesign positions 455, 493, 494, and 501 of the SARS-CoV-2 receptor binding motif, which contact hACE2 in the complex and are important for ACE2 recognition. Sampling is enhanced by an adaptive importance sampling Monte Carlo method. Sequences with increased affinity replace CoV-2 glutamine by a negative residue at position 493; serine by a nonpolar or aromatic residue or an asparagine at position 494; and asparagine by valine or threonine at position 501. Substitutions at positions 455 and 501 have a smaller effect on affinity. Substitutions suggested by our design are seen in viral sequences encountered in other species, including bat and pangolin. Our results might be used to identify potential virus strains with higher human infectivity and assist in the design of peptide-based or peptidomimetic compounds with the potential to inhibit SARS-CoV-2 binding at hACE2.

BACKGROUND: Protective factors against the risk of bronchiectasis are unknown. A high level of cardiorespiratory fitness is associated with a lower risk of chronic obstructive pulmonary disease. But whether fitness relates to bronchiectasis remains, to the knowledge of the authors, unknown. PURPOSE: To examine the association between cardiorespiratory fitness and bronchiectasis. MATERIALS AND METHODS: This was a secondary analysis of a prospective observational study: the Coronary Artery Risk Development in Young Adults cohort (from 1985–1986 [year 0] to 2015–2016 [year 30]). During a 30-year period, healthy participants (age at enrollment 18–30 years) underwent treadmill exercise testing at year 0 and year 20 visits. Cardiorespiratory fitness was determined according to the treadmill exercise duration. The 20-year difference in cardiorespiratory fitness was used as the fitness measurement. At year 25, chest CT was performed to assess bronchiectasis and was used as the primary outcome. Multivariable logistic models were performed to determine the association between cardiorespiratory fitness changes and bronchiectasis. RESULTS: Of 2177 selected participants (at year 0: mean age, 25 years ± 4 [standard deviation]; 1224 women), 209 (9.6%) had bronchiectasis at year 25. After adjusting for age, race-sex group, study site, body mass index, pack-years smoked, history of tuberculosis, pneumonia, asthma and myocardial infarction, peak lung function, and cardiorespiratory fitness at baseline, preservation of cardiorespiratory fitness was associated with lower odds of bronchiectasis at CT at year 25 (per 1-minute–longer treadmill duration from year 0 to year 20: odds ratio [OR], 0.88; 95% CI: 0.80, 0.98; P = .02). A consistent strong association was found when cough and phlegm were included in bronchiectasis (OR, 0.72; 95% CI: 0.59, 0.87; P < .001). CONCLUSION: In a long-term follow-up, the preservation of cardiorespiratory fitness was associated with lower odds of bronchiectasis at CT. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Stojanovska in this issue.

Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection(1). Here we examine the underlying basis for this synergy. We show that PD-1 + IL-2 combination therapy, unlike PD-1 monotherapy, dramatically changes the differentiation program of the PD-1(+)TCF-1(+) stem-like CD8(+) T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8(+) T cells that resemble highly functional effector CD8(+) T cells seen after an acute viral infection. The generation of these qualitatively superior CD8(+) T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1(+)TCF-1(+) stem-like CD8(+) T cells, also referred to as precursors of exhausted CD8(+) T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8(+) T cells emerging from the stem-like CD8(+) T cells after combination therapy expressed increased levels of the high affinity IL-2 trimeric (CD25, CD122, CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 plays an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind CD25 but still binds CD122/CD132 almost completely abrogated the synergistic effects seen after PD-1 + IL-2 combination therapy. There is currently considerable interest in PD-1 + IL-2 combination therapy for patients with cancer(2,3) and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.

The design and assembly of peptide-based materials has advanced considerably, leading to a variety of fibrous, sheet, and nanoparticle structures. A remaining challenge is to account for and control different possible supramolecular outcomes accessible to the same or similar peptide building blocks. Here a de novo peptide system is presented that forms nanoparticles or sheets depending on the strategic placement of a "disulfide pin" between two elements of secondary structure that drive self-assembly. Specifically, homodimerizing and homotrimerizing de novo coiled-coil α-helices are joined with a flexible linker to generate a series of linear peptides. The helices are pinned back-to-back, constraining them as hairpins by a disulfide bond placed either proximal or distal to the linker. Computational modeling indicates, and advanced microscopy shows, that the proximally pinned hairpins self-assemble into nanoparticles, whereas the distally pinned constructs form sheets. These peptides can be made synthetically or recombinantly to allow both chemical modifications and the introduction of whole protein cargoes as required.

Background Tube thoracostomy is the definitive treatment for most significant chest trauma, including injuries resulting in pneumothorax, hemothorax, and hemopneumothorax. However, traditional chest tubes fail to sufficiently remove blood up to 20% of the time (i.e., retained hemothorax), which can lead to empyema and fibrothorax, as well as significant morbidity and mortality. Here we describe the use of a novel chest tube system in a swine model of hemothorax. Methods This was an intra-animal-paired, randomized-controlled study of hemothorax evacuation using the PleuraPath™ Thoracostomy System (PPTS) compared to a traditional chest tube in large Yorkshire-Landrace swine (75-85 kg). One liter of autologous whole blood was infused into each pleural cavity simultaneously with subsequent drainage from each device individually monitored for a total of 120 minutes, before the end of the experiment and necroscopy. Results Six animals completed the full protocol. On average, the PPTS removed 17% more blood (P=0.049) and left 19.1% less residual hemothorax (P=0.023) as compared to the standard of care during the first two hours of use. No complications or iatrogenic injury were identified in any animal for either device. Conclusions The novel PPTS device was superior to the traditional chest tube drainage system in this acute, large-animal model of retained hemothorax. While this study supports clinical translation, further research will be required to assess efficacy and optimize device use in humans.

The surgical treatment of femoroacetabular impingement has been shown to have successful early and mid-term clinical outcomes. Despite these favorable clinical outcomes that have been published in the literature, there is a subgroup of patients that present with continued or recurrent symptoms after surgical treatment. Not only has there been an increase in the number of hip arthroscopy procedures, but also there has been a corresponding increase in the number of revision hip arthroscopy and hip preservation surgeries. Previous studies have reported residual deformity to be the most common reason for revision hip arthroscopy. However, chondral, labral, and capsular considerations also are important when addressing patients not only in the primary but also, the revision setting. In this review, we outline the evaluation and treatment of the patient that presents with continued hip and groin pain after undergoing a hip.

Background Attenuation of transforming growth factor β by blocking angiotensin II has been shown to reduce emphysema in a murine model. General population studies have demonstrated that the use of angiotensin converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) is associated with reduction of emphysema progression in former smokers and that the use of ACEis is associated with reduction of FEV1 progression in current smokers. Research Question Is use of ACEi and ARB associated with less progression of emphysema and FEV1 decline among individuals with COPD or baseline emphysema? Methods Former and current smokers from the Genetic Epidemiology of COPD Study who attended baseline and 5-year follow-up visits, did not change smoking status, and underwent chest CT imaging were included. Adjusted linear mixed models were used to evaluate progression of adjusted lung density (ALD), percent emphysema (%total lung volume Results Over 5 years of follow-up, compared with nonusers, ACEi and ARB users with COPD showed slower ALD progression (adjusted mean difference [aMD], 1.6; 95% CI, 0.34-2.9). Slowed lung function decline was not observed based on phase 1 medication (aMD of FEV1 % predicted, 0.83; 95% CI, –0.62 to 2.3), but was when analysis was limited to consistent ACEi and ARB users (aMD of FEV1 % predicted, 1.9; 95% CI, 0.14-3.6). No effect modification by smoking status was found for radiographic outcomes, and the lung function effect was more pronounced in former smokers. Results were similar among participants with baseline emphysema. Interpretation Among participants with spirometry-confirmed COPD or baseline emphysema, ACEi and ARB use was associated with slower progression of emphysema and lung function decline. Trial Registry ClinicalTrials.gov ; No.: NCT00608764; URL: www.clinicaltrials.gov

Introduction: PAH is characterized by a loss of pulmonary vascular complexity. In this study, total, arterial, and venous vasculatures of patients with PAH and with ePAH were analyzed using fractal analysis and compared against controls Methods: Data from 1514 consecutive right heart catheterizations from 4/27/2011 to 10/2/2018 representing subjects referred to our dyspnea center were searched for availability of imaging. 388 CT angiography (CTA) scans were identified (used given retrospective availability of thin slice reconstructions). Three initial cohorts (no overlap) were identified from individuals in this set. Control patients had normal resting and exercise hemodynamics and no history of cardiopulmonary disease. The second group met the current definition of PAH (resting mean pulmonary arterial pressure >20mmHg, pulmonary vascular resistance >3 Wood Units, pulmonary capillary wedge pressure Results: Venous fractal dimensions of controls (2.10±0.07) were higher than those of PAH (2.03±0.08; p=3e-6) and of ePAH (2.04±0.13; p=0.008). Total fractal dimension also yielded higher values for controls (2.30±0.05) compared against PAH (2.28±0.07; p=0.009) and ePAH (2.26±0.10; p=0.04). No significant differences were found between arterial fractal dimensions of controls (2.17±0.04) against those of PAH (2.16±0.07; p=0.15) and of ePAH (2.15±0.10; p=0.14). Conclusions: Fractal dimension allows for non-invasive characterization of pulmonary vascular complexity. Using this method, patients with PAH or ePAH were found to have lower total and venous vascular complexities than controls without PAH or ePAH.

Introduction: Increased vascular tortuosity has been proposed as a marker of pulmonary arterial hypertension (PAH). In this analysis, we compared arterial and venous vascular tortuosity between controls and subjects with resting PAH. Furthermore, we examined if abnormalities could be detected in exercise PAH (EPAH), thought to be an early form of PAH. Methods: From an institutional registry, 388 patients with both right heart catheterization and computed tomography angiography (CTA) data were selected. Within this cohort, three distinct groups were identified: 1) controls, who had no cardiopulmonary disease and normal resting and exercise hemodynamics; 2) EPAH, with normal resting hemodynamics but age-adjusted pre-capillary pulmonary hypertension on exertion, and 3) PAH, defined as resting mPAP >20mmHg, pulmonary vascular resistance >3 Wood Units, and pulmonary capillary wedge pressure 10% was defined as the number of arterial segments with tortuosity >10% divided by the same venous measure. Analysis was performed with Wilcoxon rank sum tests in R 3.5. Results: There were 99 patients in the final cohort, including 47 (47.4%) with PAH, 12 (12.1%) with EPAH, and 40 (40.4%) without disease. Compared to controls, median arterial tortuosity was increased in PAH (3.3 ± 0.1% vs. 3.4 ± 0.1%, p=0.0009; Figure 1) but not in EPAH (3.3 ± 0.1%, p=0.82). Median venous tortuosity did not differ between groups. AV>10% was increased in EPAH (vs. controls, 1.86 ± 0.38 vs. 1.56 ± 0.44, p=0.03) and resting PAH (2.0 ± 1.2 p=2e-6). Conclusions: Increased arterial tortuosity on CTA is a biomarker of resting PAH. When corrected for venous tortuosity, arterial tortuosity also appears to be abnormal in EPAH. Figure 1 . Arterial vessels in PAH, EPAH, and control subjects. Red segments have tortuosity > 10%.

Background: Protective factors for bronchiectasis (BE) are unknown. High cardiorespiratory fitness (CRF) is associated with a lower risk of chronic obstructive pulmonary disease, which shares clinical characteristics with BE. We aimed to examine the association between CRF and BE. Method: Healthy participants (age at enrollment 18-30 years in 1985) in the Coronary Artery Risk Development in Young Adults Study had treadmill exercise testing performed at baseline (year 0) and year 20 visits. CRF was determined as a treadmill exercise duration. The 20-yr difference in CRF was used as exposure. At year 25, BE ascertainment was performed on chest computed tomography scans and used as the main outcome. Logistic multivariable models were performed to test the association between CRF changes and BE. Method: Out of 2,177 selected participants, 209 (9.6%) had BE at year 25. After adjusting for age, sex-race group, center, BMI, pack-years smoked, history of tuberculosis, pneumonia, and asthma and myocardial infarction, peak lung function, and CRF at baseline, an increase in CRF was associated with lower odds of BE at year 25 (per 1-minute increase in treadmill duration from year 0 to year 20, OR 0.88, [95% CI 0.80 - 0.98] P=0.018). A consistent result was found when BE was defined with imaging plus cough or phlegm (OR 0.72 [0.59 – 0.87] P=0.0007). Method: An increasee in CRF is associated with lower odds of BE at middle age.

Perioperative Management; International audience; Purpose: Hospital-acquired infections have been associated with significant morbidity and mortality in critically ill surgical patients. However, little is known about mortality due to hospital-acquired infections in cardiac surgery.Methods: We conducted a retrospective analysis of prospectively collected data from the cardiac surgery unit of a university hospital. All patients who underwent cardiac surgery over a 7-year period were included. Patients with hospital-acquired infections were matched 1:1 with patients with nonhospital-acquired infections based on risk factors for hospital-acquired infections and death after cardiac surgery using propensity score matching. We performed a competitive risk analysis to study the mortality fraction due to hospital-acquired infections.Results: Of 8853 patients who underwent cardiac surgery, 370 (4.2%) developed 500 postoperative infections (incidence density rate 4.2 hospital-acquired infections per 1000 patient-days). Crude hospital mortality was significantly higher in patients with hospital-acquired infections than in matched patients who did not develop hospital-acquired infections, 15.4% and 5.7%, respectively (P < .001). The in-hospital mortality fraction due to hospital-acquired infections in our cohort was 17.1% (12.3%-22.8%). Pseudomonas aeruginosa infection (hazard ratio, 2.09; 95% confidence interval, 1.23-3.49; P = .005), bloodstream infection (hazard ratio, 2.08; 95% confidence interval, 1.19-3.63; P = .010), and pneumonia (hazard ratio, 1.68; 95% confidence interval, 1.02-2.77; P = .04) were each independently associated with increased hospital mortality.Conclusions: Although hospital-acquired infections are relatively uncommon after cardiac surgery (4.2%), these infections have a major impact on postoperative mortality (attributable mortality fraction, 17.1%).

The design and assembly of peptide based materials has advanced considerably, leading to a variety of fibrous, sheet and nanoparticle structures. A remaining challenge is to account for and control different possible supramolecular outcomes accessible to the same or similar peptide building blocks. Here we present a de novo peptide system that forms nanoparticles or sheets depending on the strategic placement of a ‘disulfide pin’ between two elements of secondary structure that drive self-assembly. Specifically, we join homodimerizing and homotrimerizing de novo coiled-coil α-helices with a flexible linker to generate a series of linear peptides. The helices are pinned back-to-back, constraining them as hairpins by a disulfide bond placed either proximal or distal to the linker. Computational modeling and advanced microscopy show that the proximally pinned hairpins self-assemble into nanoparticles, whereas the distally pinned constructs form sheets. These peptides can be made synthetically or recombinantly to allow both chemical modifications and the introduction of whole protein cargoes as required.

Background: The ex vivo human perfused lung model has enabled optimizing donor lungs for transplantation and delineating mechanisms of lung injury. Perfusate and airspace biomarkers are a proxy of the lung response to experimental conditions. However, there is a lack of studies evaluating biomarker kinetics during perfusion and after exposure to stimuli. In this study we analyzed the ex vivo perfused lung response to three key perturbations: exposure to the perfusion circuit, exogenous fresh whole blood, and bacteria.Results: 99 lungs rejected for transplantation underwent ex vivo perfusion. One hour after reaching experimental conditions, fresh whole blood was added to the perfusate (n=55). Two hours after reaching target temperature, Streptococcus pneumoniae was added to the perfusate (n=42) or to the airspaces (n=17). Perfusate and airspace samples were collected at baseline (once lungs were equilibrated for 1 hour, but before blood or bacteria were added) and 4 hours later. Interleukin (IL)-6, IL-8, Angiopoietin (Ang)-2, and soluble tumor necrosis factor receptor (sTNFR)-1 were quantified. Baseline perfusate and airspace biomarker levels varied significantly, and this was not related to pre-procurement PaO2:FiO2 ratio, cold ischemia time, and baseline alveolar fluid clearance (AFC). After 4 hours of ex vivo perfusion, the lung demonstrated a sustained production of proinflammatory mediators. The change in biomarker levels was not influenced by baseline donor lung characteristics (cold ischemia time, baseline AFC) nor was it associated with measures of experimental epithelial (final AFC) or endothelial (percent weight gain) injury. In the presence of exogenous blood, the rise in biomarkers was attenuated. Lungs exposed to intravenous (IV) bacteria relative to control lungs demonstrated a significantly higher rise in perfusate IL-6.Conclusions: The ex vivo perfused lung has a marked endogenous capacity to produce inflammatory mediators over the course of short-term perfusion that is not significantly influenced by donor lung characteristics or the presence of exogenous blood, and only minimally affected by the introduction of systemic bacteremia. The lack of association between biomarker change and donor lung cold ischemia time, final alveolar fluid clearance, and experimental percent weight gain suggest that the maintained ability of the human lung to produce biomarkers is not merely a marker of lung epithelial or endothelial injury, but may support the function of the lung as an immune cell reservoir.

Nest count surveys provide an important means for tracking trends in marine turtle populations. In 2015 the IUCN Red List global status review changed the loggerhead turtle (Carretta caretta) from Endangered to Vulnerable status, and, with a revised regional management unit (RMU) assessment system in place, concluded that the Northwest Indian Ocean loggerhead turtle RMU was Critically Endangered (CR). We analyzed annual time series nest count survey data between 1978 and 2016 to evaluate population trend and characterize the existing spatial and temporal attributes of a globally significant rookery on Masirah Island, Oman. A two-point trend assessment using a subset of historical data (1985-1996) combined with recent data (2008-2016) on a representative, 9-km section of index beaches revealed a change from 584 tracks-1 km-1 season-1 (SD = 109.5) to 122.43 tracks-1 km-1 season-1 (SD = 37.3), representing a statistically significant 79% decline. Comparative data were tested for spatial and temporal conformity, and the influence of other parameters on the trend result were considered, such as nesting success ratios and spatial shifts in density. Our analyses confirm that the decline occurred within a single loggerhead generation. Mean multiyear nest counts from recent surveys provides an estimate of 55,202 nests year-1 (SD=16,814, CI 0.95 53,326- 57,078) across 83 km of nesting beach. Considering recent clutch frequency estimates the mean number of nesting loggerheads per year is estimated between 10,223 (CI 0.95 9,875- 10,570) and 11,500 (CI 0.95 11,109- 11,891). The Northwest Indian Ocean RMU is thought to represent 35% of the global nesting population. Recognizing a pressing need to address the decline in this population we identify potential threats on nesting beaches and at sea which point towards priority actions for conservation of this CR RMU.

International audience; Few patients with bacteremia from a nonpulmonary source develop acute respiratory distress syndrome (ARDS). However, the mechanisms that protect the lung from injury in bacteremia have not been identified. We simulated bacteremia by adding Streptococcus pneumoniae to the perfusate of the ex vivo perfused human lung model. In contrast to a pneumonia model in which bacteria were instilled into the distal air spaces of one lobe, injection of high doses of S. pneumoniae into the perfusate was not associated with alveolar epithelial injury as demonstrated by low protein permeability of the alveolar epithelium, intact alveolar fluid clearance, and the absence of alveolar edema. Unexpectedly, the ex vivo human lung rapidly cleared large quantities of S. pneumoniae even though the perfusate had very few intravascular phagocytes and lacked immunoglobulins or complement. The bacteria were cleared in part by the small number of neutrophils in the perfusate, alveolar macrophages in the airspaces, and probably by interstitial pathways. Together, these findings identify one mechanism by which the lung and the alveolar epithelium are protected from injury in bacteremia.

Mobile genetic elements have significantly shaped our genomic landscape. LINE-1 retroelements are the only autonomously active elements left in the human genome. Since new insertions can have detrimental consequences, cells need to efficiently control LINE-1 retrotransposition. Here, we demonstrate that the intrinsic immune factor TRIM5α senses and restricts LINE-1 retroelements. Previously, rhesus TRIM5α has been shown to efficiently block HIV-1 replication, while human TRIM5α was found to be less active. Surprisingly, we found that both human and rhesus TRIM5α efficiently repress human LINE-1 retrotransposition. TRIM5α interacts with LINE-1 ribonucleoprotein complexes in the cytoplasm, which is essential for restriction. In line with its postulated role as pattern recognition receptor, we show that TRIM5α also induces innate immune signaling upon interaction with LINE-1 ribonucleoprotein complexes. The signaling events activate the transcription factors AP-1 and NF-κB, leading to the down-regulation of LINE-1 promoter activity. Together, our findings identify LINE-1 as important target of human TRIM5α, which restricts and senses LINE-1 via two distinct mechanisms. Our results corroborate TRIM5α as pattern recognition receptor and shed light on its previously undescribed activity against mobile genetic elements, such as LINE-1, to protect the integrity of our genome.

Global efforts to combat the Covid-19 pandemic caused by the beta coronavirus SARS-CoV-2 are currently based on RT-qPCR-based diagnostic tests. However, their high cost, moderate throughput and reliance on sophisticated equipment limit widespread implementation. Loop-mediated isothermal amplification after reverse transcription (RT-LAMP) is an alternative detection method that has the potential to overcome these limitations. Here we present a rapid, robust, highly sensitive and versatile RT-LAMP based SARS-CoV-2 detection assay. Our forty-minute procedure bypasses a dedicated RNA isolation step, is insensitive to carry-over contamination, and uses a hydroxynaphthol blue (HNB)-based colorimetric readout, which allows robust SARS-CoV-2 detection from various sample types. Based on this assay, we have substantially increased sensitivity and scalability by a simple nucleic acid enrichment step (bead-LAMP), established a pipette-free version for home testing (HomeDip-LAMP), and developed a version with open source enzymes that can be produced in any molecular biology setting. Our advanced, universally applicable RT-LAMP assay is a major step towards population-scale SARS-CoV-2 testing.

Few patients with bacteremia from a nonpulmonary source develop acute respiratory distress syndrome (ARDS). However, the mechanisms that protect the lung from injury in bacteremia have not been identified. We simulated bacteremia by adding Streptococcus pneumoniae to the perfusate of the ex vivo perfused human lung model. In contrast to a pneumonia model in which bacteria were instilled into the distal air spaces of one lobe, injection of high doses of S. pneumoniae into the perfusate was not associated with alveolar epithelial injury as demonstrated by low protein permeability of the alveolar epithelium, intact alveolar fluid clearance, and the absence of alveolar edema. Unexpectedly, the ex vivo human lung rapidly cleared large quantities of S. pneumoniae even though the perfusate had very few intravascular phagocytes and lacked immunoglobulins or complement. The bacteria were cleared in part by the small number of neutrophils in the perfusate, alveolar macrophages in the airspaces, and probably by interstitial pathways. Together, these findings identify one mechanism by which the lung and the alveolar epithelium are protected from injury in bacteremia.

Prostate cancer accounts for around 15% of male deaths in Western Europe and is the second leading cause of cancer death in men after lung cancer. Mounting evidence suggests that prostate cancer deposits exist within a hypoxic environment and this contributes to radio-resistance thus hampering one of the major therapies for this cancer. Recent reports have shown that nitric oxide (NO) donating non-steroidal anti-inflammatory drugs (NSAIDs) reduced tumour hypoxia as well as maintaining a radio-sensitising/therapeutic effect on prostate cancer cells. The aim of this study was to evaluate the impact of hypoxia on the proteome of the prostate and to establish whether NO-NSAID treatment reverted the protein profiles back to their normoxic status. To this end an established hormone insensitive prostate cancer cell line, PC-3, was cultured under hypoxic and normoxic conditions before and following exposure to NO-NSAID in combination with selected other common prostate cancer treatment types. The extracted proteins were analysed by ion mobility-assisted data independent acquisition mass spectrometry (MS), combined with multivariate statistical analyses, to measure hypoxia-induced alterations in the proteome of these cells. The analyses demonstrated that under hypoxic conditions there were well-defined, significantly regulated/differentially expressed proteins primarily involved with structural and binding processes including, for example, TUBB4A, CIRP and PLOD1. Additionally, the exposure of hypoxic cells to NSAID and NO-NSAID agents, resulted in some of these proteins being differentially expressed; for example, both PCNA and HNRNPA1L were down-regulated, corresponding with disruption in the nucleocytoplasmic shuttling process.

Background Smokers with chronic obstructive pulmonary disease (COPD) have smaller left ventricles (LVs) due to reduced preload. Skeletal muscle wasting is also common in COPD, but less is known about its contribution to LV size. Purpose To explore the relationships between CT metrics of emphysema, venous vascular volume, and sarcopenia with the LV epicardial volume (LVEV) (myocardium and chamber) estimated from chest CT images in participants with COPD and then to determine the clinical relevance of the LVEV in multivariable models, including sex and anthropomorphic metrics. Materials and Methods The COPDGene study (ClinicalTrials.gov identifier: NCT00608764) is an ongoing prospective longitudinal observational investigation that began in 2006. LVEV, distal pulmonary venous blood volume for vessels smaller than 5 mm2 in cross section (BV5), CT emphysema, and pectoralis muscle area were retrospectively extracted from 3318 nongated, unenhanced COPDGene CT scans. Multivariable linear and Cox regression models were used to explore the association between emphysema, venous BV5, pectoralis muscle area, and LVEV as well as the association of LVEV with health status using the St George's Respiratory Questionnaire, 6-minute walk distance, and all-cause mortality. Results The median age of the cohort was 64 years (interquartile range, 57-70 years). Of the 2423 participants, 1806 were men and 617 were African American. The median LVEV between Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 and GOLD 4 COPD was reduced by 13.9% in women and 17.7% in men (P < .001 for both). In fully adjusted models, higher emphysema percentage (β = -4.2; 95% confidence interval [CI]: -5.0, -3.4; P < .001), venous BV5 (β = 7.0; 95% CI: 5.7, 8.2; P < .001), and pectoralis muscle area (β = 2.7; 95% CI: 1.2, 4.1; P < .001) were independently associated with reduced LVEV. Reductions in LVEV were associated with improved health status (β = 0.3; 95% CI: 0.1, 0.4) and 6-minute walk distance (β = -12.2; 95% CI: -15.2, -9.3). These effects were greater in women than in men. The effect of reduced LVEV on mortality (hazard ratio: 1.07; 95% CI: 1.05, 1.09) did not vary by sex. Conclusion In women more than men with chronic obstructive pulmonary disease, a reduction in the estimated left ventricle epicardial volume correlated with a loss of pulmonary venous vasculature, greater pectoralis muscle sarcopenia, and lower all-cause mortality. © RSNA, 2020 Online supplemental material is available for this article.

Isotonic 0.9% sodium chloride (normal saline; NS) solution use is common, but its high chloride content has been shown to contribute to acid-base disturbances and acute kidney injury (AKI). As kidney transplant recipients are at high risk of postoperative AKI and renal replacement therapy, we aimed to evaluate the impact of perioperative NS administration on graft function after kidney transplantation. All adult patients undergoing deceased-donor kidney transplantation between January 2010 and December 2014 at the Rennes University Hospital were included. Logistic regression models were constructed to evaluate the association of hyperchloremia and hyperchloremic acidosis on delayed graft function (DGF), defined as the need for renal replacement therapy within the first week after transplantation. Three hundred and fifty-nine patients were included, 20% developed DGF. The mean (standard deviation) volume of NS infused in the operating room and in the standard postoperative intensive care unit stay was 4,832 (2,242) mL. In the first 24 postoperative hours, 11% of patients developed hyperchloremia and 11% developed hyperchloremic acidosis. These outcomes were not associated with significantly higher total volumes of NS administration or with DGF. In contrast, multivariable analysis showed that cold ischemia time, donor terminal creatinine, and perioperative NS volume were all independent predictors of DGF. Perioperative NS infusion volume was associated with DGF in deceased-donor kidney transplant recipients. Conversely, postoperative hyperchloremia and hyperchloremic acidosis were not associated with an increased risk of DGF, suggesting other mechanisms than a chloride effect.

The common brushtail possum (Trichosurus vulpecula), introduced from Australia in the mid-nineteenth century, is an invasive species in New Zealand where it is widespread and forms the largest self-sustained reservoir of bovine tuberculosis (Mycobacterium bovis) among wild populations. Conservation and agricultural authorities regularly apply a series of population control measures to suppress brushtail possum populations. The evolutionary consequence of more than half a century of intensive population control operations on the species’ genomic diversity and population structure is hindered by a paucity of available genomic resources. This study is the first to characterise the functional content and diversity of brushtail possum liver and brain cerebral cortex transcriptomes. Raw sequences from hepatic cells and cerebral cortex were assembled into 58,001 and 64,735 transcripts respectively. Functional annotation and polymorphism assignment of the assembled transcripts demonstrated a considerable level of variation in the core metabolic pathways that represent potential targets for selection pressure exerted by chemical toxicants. This study suggests that the brushtail possum population in New Zealand harbours considerable variation in metabolic pathways that could potentially promote the development of tolerance against chemical toxicants.

This study demonstrates the use of a multiyear country-scale automatic identification system (AIS) data set to partition a nationwide portfolio of navigation structures managed by the US Ar...

Accurately and precisely characterizing the morphology of small pulmonary structures from Computed Tomography (CT) images, such as airways and vessels, is becoming of great importance for diagnosis of pulmonary diseases. The smaller conducting airways are the major site of increased airflow resistance in chronic obstructive pulmonary disease (COPD), while accurately sizing vessels can help identify arterial and venous changes in lung regions that may determine future disorders. However, traditional methods are often limited due to image resolution and artifacts. We propose a Convolutional Neural Regressor (CNR) that provides cross-sectional measurement of airway lumen, airway wall thickness, and vessel radius. CNR is trained with data created by a generative model of synthetic structures which is used in combination with Simulated and Unsupervised Generative Adversarial Network (SimGAN) to create simulated and refined airways and vessels with known ground-truth. For validation, we first use synthetically generated airways and vessels produced by the proposed generative model to compute the relative error and directly evaluate the accuracy of CNR in comparison with traditional methods. Then, in-vivo validation is performed by analyzing the association between the percentage of the predicted forced expiratory volume in one second (FEV1\%) and the value of the Pi10 parameter, two well-known measures of lung function and airway disease, for airways. For vessels, we assess the correlation between our estimate of the small-vessel blood volume and the lungs' diffusing capacity for carbon monoxide (DLCO). The results demonstrate that Convolutional Neural Networks (CNNs) provide a promising direction for accurately measuring vessels and airways on chest CT images with physiological correlates., 19 pages, 13 figures

Introduction: Bladder augmentation is a surgery that can increase bladder capacity and compliance. The objective of this study was to provide a longitudinal review of pediatric bladder augmentation at a tertiary Canadian center. Methods: A retrospective review was performed on patients who underwent bladder augmentation at a tertiary pediatric hospital between 1986 and 2014. The primary objective was short- and long-term complications of augmentation. Secondary objectives were to review number of augmentation procedures performed over time and the utility of routine postoperative cystograms. Results: A total of 56 procedures were performed on 54 patients (28 males, 26 females) of mean age 10 years (standard deviation [SD] 5) and mean followup eight years (SD 5). The most common bowel segment used was ileum (87.5%). Twenty-eight patients (50%) received catheterizable channels. Overall complication rate was 15%, and the most common complications were urinary tract infections (68.5%), worsening hydronephrosis (14.8%), bladder stone formation (14%), and hematuria (13%). In total, 19 of 54 (35.2%) patients returned to the operating room. The incidence of bladder perforation was 3.6%. Complications with the catheterizable channel occurred in 13 of 28 (46.4%), of which 10 were related to stomal stenosis. Forty patients had postoperative cystograms and extravasation was seen in three (7.5%). There was no malignancy during the followup. Only four augmentations were performed from 2008–2014. Conclusions: Bladder augmentation likely represents a safe surgical treatment option. Extravasation on postoperative cystogram was uncommon and thus it may not be indicated routinely. The number of augmentation procedures performed has declined in recent years.

Contains fulltext : 220761.pdf (Publisher’s version ) (Open Access) Rationale: The decades-long progression of chronic obstructive pulmonary disease (COPD) renders identifying different trajectories of disease progression challenging.Objectives: To identify subtypes of patients with COPD with distinct longitudinal progression patterns using a novel machine-learning tool called "Subtype and Stage Inference" (SuStaIn) and to evaluate the utility of SuStaIn for patient stratification in COPD.Methods: We applied SuStaIn to cross-sectional computed tomography imaging markers in 3,698 Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1-4 patients and 3,479 controls from the COPDGene (COPD Genetic Epidemiology) study to identify subtypes of patients with COPD. We confirmed the identified subtypes and progression patterns using ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) data. We assessed the utility of SuStaIn for patient stratification by comparing SuStaIn subtypes and stages at baseline with longitudinal follow-up data.Measurements and Main Results: We identified two trajectories of disease progression in COPD: a "Tissue-->Airway" subtype (n = 2,354, 70.4%), in which small airway dysfunction and emphysema precede large airway wall abnormalities, and an "Airway-->Tissue" subtype (n = 988, 29.6%), in which large airway wall abnormalities precede emphysema and small airway dysfunction. Subtypes were reproducible in ECLIPSE. Baseline stage in both subtypes correlated with future FEV1/FVC decline (r = -0.16 [P < 0.001] in the Tissue-->Airway group; r = -0.14 [P = 0.011] in the Airway-->Tissue group). SuStaIn placed 30% of smokers with normal lung function at elevated stages, suggesting imaging changes consistent with early COPD. Individuals with early changes were 2.5 times more likely to meet COPD diagnostic criteria at follow-up.Conclusions: We demonstrate two distinct patterns of disease progression in COPD using SuStaIn, likely representing different endotypes. One third of healthy smokers have detectable imaging changes, suggesting a new biomarker of "early COPD."

This study develops multi-item scales of the financial wellbeing of customers of a major Australian bank using self-reported survey data that are matched with the customers' financial records. Using Item Response Theory (IRT) models, the study develops: First a Reported Financial Wellbeing Scale that is formed from responses to 10 questions about people's experiences and perceptions of financial outcomes, and second an Observed Financial Wellbeing Scale that is formed from five financial-record measures of customers' account balances, net spending, and payment problems. The IRT models show that each scale reliably differentiates between a wide range of outcomes and that the components within each scale have similar power to discriminate. We validate the scales by estimating Least Absolute Shrinkage and Selection Operator machine-learning models of how they correlate with other measurable characteristics. Savings habits, spending habits, credit card behavior, household income, education, difficulties with housing payments, and the use of and access to social or government support are each associated with both types of financial wellbeing.

Rationale Chronic obstructive pulmonary disease (COPD) comprises distinct phenotypes, all characterised by airflow limitation. Objectives We hypothesised that somatotype changes – as a surrogate of adiposity – from early adulthood follow different trajectories to reach distinct phenotypes. Methods Using the validated Stunkard's Pictogram, 356 COPD patients chose the somatotype that best reflects their current body build and those at ages 18, 30, 40 and 50 years. An unbiased group-based trajectory modelling was used to determine somatotype trajectories. We then compared the current COPD-related clinical and phenotypic characteristics of subjects belonging to each trajectory. Measurements and main results At 18 years of age, 88% of the participants described having a lean or medium somatotype (estimated body mass index (BMI) between 19 and 23 kg·m−2) while the other 12% a heavier somatotype (estimated BMI between 25 and 27 kg·m−2). From age 18 onwards, five distinct trajectories were observed. Four of them demonstrating a continuous increase in adiposity throughout adulthood with the exception of one, where the initial increase was followed by loss of adiposity after age 40. Patients with this trajectory were primarily females with low BMI and DLCO (diffusing capacity of the lung for carbon monoxide). A persistently lean trajectory was seen in 14% of the cohort. This group had significantly lower forced expiratory volume in 1 s (FEV1), DLCO, more emphysema and a worse BODE (BMI, airflow obstruction, dyspnoea and exercise capacity) score thus resembling the multiple organ loss of tissue (MOLT) phenotype. Conclusions COPD patients have distinct somatotype trajectories throughout adulthood. Those with the MOLT phenotype maintain a lean trajectory throughout life. Smoking subjects with this lean phenotype in early adulthood deserve particular attention as they seem to develop more severe COPD., In smoking-related COPD, somatotype trajectories are associated with the final COPD phenotype. Specifically, the “pink puffer” or multiorgan loss of tissue (MOLT) phenotype occurs where the patient remains lean. https://bit.ly/2YNhwfu

Carabidae (Coleoptera) are commonly used as indicators of ecosystem health due to their high diversity, conservation value and relative ease of identification. Carabids were monitored at Ah...

Control or eradication of feral cats (Felis cattus) is necessary for a number of reasons, including controlling zoonotic diseases and protecting native species in New Zealand. Estimating feral cat ...

Purpose: Transthyretin (ATTR) amyloidosis is a rare but serious infiltrative disease associated with a wide spectrum of morphologic and functional cardiac involvement. 99mTc-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD), initially developed as a bone-seeking radiotracer, is remarkably sensitive for imaging cardiac ATTR amyloid deposits. Our aim was to investigate the feasibility and utility of estimating 99mTc-DPD uptake in myocardial tissue; this has the potential to yield reliable quantitative information on cardiac amyloid burden, which is urgently required to monitor disease progression and response to novel treatments. Methods: Three methods of quantitation were developed and tested on 74 patients with proven cardiac ATTR amyloidosis who had recently undergone 99mTc-DPD planar whole-body imaging and SPECT-CT. Quantitative results were compared to measurements of extracellular volume fraction (ECV) by cardiac magnetic resonance imaging, a validated technique for measuring amyloid burden. Results: An experienced clinician graded uptake using a widely-used visual scoring system as 1 (n = 15), 2 (n = 39) or 3 (n = 20). Linear correlations between the SPECT and ECV data (p 99mTc-DPD uptake in the heart was significantly greater in patients with grade-3 uptake than in those with grade-2 uptake. Conclusions: Quantitation of 99mTc-DPD uptake in cardiac transthyretin amyloid deposits is complex and is hindered by competition for radiotracer with amyloid in skeletal muscle. The latter underlies differences in uptake between grade-2 and grade-3 patients, not cardiac uptake.

Ōtamahua/Quail Island is an 85 ha Recreation Reserve in Lyttelton Harbour, New Zealand. It is being ecologically restored and cats, hedgehogs, rabbits, mustelids and rats have been eradicated. However, the house mouse (Mus musculus) survived two eradication attempts, a bait station operation in 2002 and an aerial operation in 2009. Data on aerial bait deposition, bait degradation, mouse resurgence and non-target mortalities were collected. Brodifacoum bait deposition in many areas was considerably lower than the prescribed rate of 8 kg/ha. Mouse sign was simultaneously detected at seven sites around the island 6 months after the aerial operation. Tails were collected from trapped mice on Quail Island, the adjacent mainland and on the stepping-stone island (King Billy) to undertake DNA analysis. Little genetic discrimination was observed between samples obtained after the 2009 aerial bait operation, and samples from before or outside of the bait drop. By contrast, samples taken from a location 15 k...

Stoats (Mustela erminea) were introduced to New Zealand to control rabbits in the 1880s and their impact on native birds has been devastating. Stoat control needs to be ongoing if some iconic speci...

Chronic obstructive pulmonary disease (COPD) is a syndrome caused by damage to the lungs that results in decreased pulmonary function and reduced structural integrity. Pulmonary function testing (PFT) is used to diagnose and stratify COPD into severity groups, and computed tomography (CT) imaging of the chest is often used to assess structural changes in the lungs. We hypothesized that the combination of PFT and CT phenotypes would provide a more powerful tool for assessing underlying morphologic differences associated with pulmonary function in COPD than does PFT alone. We used factor analysis of 26 variables to classify 8,157 participants recruited into the COPDGene cohort between January 2008 and June 2011 from 21 clinical centers across the United States. These factors were used as predictors of all-cause mortality using Cox proportional hazards modeling. Five factors explained 80% of the covariance and represented the following domains: factor 1, increased emphysema and decreased pulmonary function; factor 2, airway disease and decreased pulmonary function; factor 3, gas trapping; factor 4, CT variability; and factor 5, hyperinflation. After more than 46,079 person-years of follow-up, factors 1 through 4 were associated with mortality and there was a significant synergistic interaction between factors 1 and 2 on death. Considering CT measures along with PFT in the assessment of COPD can identify patients at particularly high risk for death.

Groundwater models developed for specific sites generally become obsolete within a few years due to changes in: (1) modeling technology; (2) site/project personnel; (3) project funding; and (4) modeling objectives. Consequently, new models are sometimes developed for the same sites using the latest technology and data, but without potential knowledge gained from the prior models. When it occurs, this practice is particularly problematic because, although technology, data, and observed conditions change, development of the new numerical model may not consider the conceptual model's underpinnings. As a contrary situation, we present the unique case of a numerical flow and trichloroethylene (TCE) transport model that was first developed in 1993 and since revised and updated annually by the same personnel. The updates are prompted by an increase in the amount of data, exposure to a wider range of hydrologic conditions over increasingly longer timeframes, technological advances, evolving modeling objectives, and revised modeling methodologies. The history of updates shows smooth, incremental changes in the conceptual model and modeled aquifer parameters that result from both increase and decrease in complexity. Myriad modeling objectives have included demonstrating the ineffectiveness of a groundwater extraction/injection system, evaluating potential TCE degradation, locating new monitoring points, and predicting likelihood of exceedance of groundwater standards. The application emphasizes an original tenet of successful groundwater modeling: iterative adjustment of the conceptual model based on observations of actual vs. model response.

The Kalman filter is an efficient data assimilation tool to refine an estimate of a state variable using measured data and the variable's correlations in space and/or time. The ensemble Kalman filter (EnKF) (Evensen 2004, 2009) is a Kalman filter variant that employs Monte Carlo analysis to define the correlations that help to refine the updated state. While use of EnKF in hydrology is somewhat limited, it has been successfully applied in other fields of engineering (e.g., oil reservoir modeling, weather forecasting). Here, EnKF is used to refine a simulated groundwater tetrachloroethylene (TCE) plume that underlies the Tooele Army Depot-North (TEAD-N) in Utah, based on observations of TCE in the aquifer. The resulting EnKF-based assimilated plume is simulated forward in time to predict future plume migration. The correlations that underpin EnKF updating implicitly contain information about how the plume developed over time under the influence of complex site hydrology and variable source history, as they are predicated on multiple realizations of a well-calibrated numerical groundwater flow and transport model. The EnKF methodology is compared to an ordinary kriging-based assimilation method with respect to the accurate representation of plume concentrations in order to determine the relative efficacy of EnKF for water quality data assimilation.

Recent in vitro cardiac safety studies demonstrate the ability of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to detect electrophysiologic effects of drugs. However, variability contributed by unique approaches, procedures, cell lines, and reagents across laboratories makes comparisons of results difficult, leading to uncertainty about the role of hiPSC-CMs in defining proarrhythmic risk in drug discovery and regulatory submissions. A blinded pilot study was conducted to evaluate the electrophysiologic effects of 8 well-characterized drugs on 4 cardiomyocyte lines using a standardized protocol across 3 microelectrode array platforms (18 individual studies). Drugs were selected to define assay sensitivity of prominent repolarizing currents (E-4031 for IKr, JNJ303 for IKs) and depolarizing currents (nifedipine for ICaL, mexiletine for INa) as well as drugs affecting multichannel block (flecainide, moxifloxacin, quinidine, and ranolazine). Inclusion criteria for final analysis was based on demonstrated sensitivity to IKr block (20% prolongation with E-4031) and L-type calcium current block (20% shortening with nifedipine). Despite differences in baseline characteristics across cardiomyocyte lines, multiple sites, and instrument platforms, 10 of 18 studies demonstrated adequate sensitivity to IKr block with E-4031 and ICaL block with nifedipine for inclusion in the final analysis. Concentration-dependent effects on repolarization were observed with this qualified data set consistent with known ionic mechanisms of single and multichannel blocking drugs. hiPSC-CMs can detect repolarization effects elicited by single and multichannel blocking drugs after defining pharmacologic sensitivity to IKr and ICaL block, supporting further validation efforts using hiPSC-CMs for cardiac safety studies.

Background Low muscle mass is associated with increased mortality in the general population but its prognostic value in at-risk smokers, those without expiratory airflow obstruction, is unknown. We aimed to test the hypothesis that reduced muscle mass is associated with increased mortality in at-risk smokers. Methods Measures of both pectoralis and paravertebral erector spinae muscle cross-sectional area (PMA and PVMA, respectively) as well as emphysema on chest computed tomography (CT) scans were performed in 3705 current and former at-risk smokers (≥10 pack-years) aged 45–80 years enrolled into the COPDGene Study between 2008 and 2013. Vital status was ascertained through death certificate. The association between low muscle mass and mortality was assessed using Cox regression analysis. Results During a median of 6.5 years of follow-up, 212 (5.7%) at-risk smokers died. At-risk smokers in the lowest (vs. highest) sex-specific quartile of PMA but not PVMA had 84% higher risk of death in adjusted models for demographics, smoking, dyspnea, comorbidities, exercise capacity, lung function, emphysema on CT, and coronary artery calcium content (hazard ratio [HR] 1.85 95% Confidence interval [1.14–3.00] P = 0.01). Results were consistent when the PMA index (PMA/height2) was used instead of quartiles. The association between PMA and death was modified by smoking status (P = 0.04). Current smokers had a significantly increased risk of death (lowest vs. highest PMA quartile, HR 2.25 [1.25–4.03] P = 0.007) while former smokers did not. Conclusions Low muscle mass as measured on chest CT scans is associated with increased mortality in current smokers without airflow obstruction. Trial registration NCT00608764 Electronic supplementary material The online version of this article (10.1186/s12931-018-0771-6) contains supplementary material, which is available to authorized users.