bluuebunny/crossref_metadata_2025_split huggingface dataset:
How much green does it take to be orange? Determining the cost associated with trauma center readiness
Authors: Ashley Dennis W. , Mullins Robert F. , Dente Christopher J. , Johns Tracy J. , Garlow Laura E. , Medeiros Regina S. , Atkins Elizabeth V. , Solomon Gina , Abston Dena , Ferdinand Colville H. 
Published: February 2019

BACKGROUND
Readiness costs are real expenses incurred by trauma centers to maintain essential infrastructure to provide emergent services on a 24/7 basis. Although the components for readiness are well described in the American College of Surgeons' Resources for Optimal Care of the Injured Patient, the cost associated with each component is not well defined. We hypothesized that meeting the requirements of the 2014 Resources for Optimal Care of the Injured Patient would result in significant costs for trauma centers.

METHODS
The state trauma commission in conjunction with trauma medical directors, program managers, and financial officers of each trauma center standardized definitions for each component of trauma center readiness cost and developed a survey tool for reporting. Readiness costs were grouped into four categories: administrative/program support staff, clinical medical staff, in-house operating room, and education/outreach. To verify consistent cost reporting, a financial auditor analyzed all data. Trauma center outliers were further evaluated to validate variances. All level I/level II trauma centers (n = 16) completed the survey on 2016 data.

RESULTS
Average annual readiness cost is US $10,078,506 for a level I trauma center and US $4,925,103 for level IIs. Clinical medical staff was the costliest component representing 55% of costs for level Is and 64% for level IIs. Although education/outreach is mandated, levels I and II trauma centers only spend approximately US $100,000 annually on this category (1%–2%), demonstrating a lack of resources.

CONCLUSION
This study defines the cost associated with each component of readiness as defined in the Resources for Optimal Care of the Injured Patient manual. Average readiness cost for a level I trauma center is US $10,078,506 and US $4,925,103 for a level II. The significant cost of trauma center readiness highlights the need for additional trauma center funding to meet the requirements set forth by the American College of Surgeons.

LEVEL OF EVIDENCE
Economic and value-based evaluations, level III.
Impact of Aortoiliac Stenosis on Graft and Patient Survival in Kidney Transplant Recipients Using the TASC II Classification
Authors: Rijkse Elsaline , Kimenai Hendrikus J.A.N. , Roodnat Joke I. , Ten Raa Sander , Bijdevaate Diederik C. , van Dam Jacob L. , Muller Kelly , IJzermans Jan N.M. , van der Zijden Marcus A. , Minnee Robert C. 
Published: February 2019

Background.
Patients with end-stage renal disease and aortoiliac stenosis are often considered ineligible for kidney transplantation, although kidney transplantation has been acknowledged as the best therapy for end-stage renal disease. The clinical outcomes of kidney transplantation in patients with aortoiliac stenosis are not well-studied. This study aimed to assess the impact of aortoiliac stenosis on graft and patient survival.

Methods.
This retrospective, single-center study included kidney transplant recipients transplanted between January 1, 2000, and December 31, 2016, who received contrast-enhanced imaging. Patients with aortoiliac stenosis were classified using the Trans-Atlantic Inter-Society Consensus (TASC) II classification and categorized as having TASC II A/B lesions or having TASC II C/D lesions. Patients without aortoiliac stenosis were functioning as controls.

Results.
A total number of 374 patients was included in this study (n = 88 with TASC II lesions, n = 286 as controls). Death-censored graft survival was similar to the controls. Patient and uncensored graft survival was decreased in patients with TASC II C/D lesions (log-rank test P < 0.001). Patients with TASC II C/D lesions had a higher risk of 90-day mortality (hazard ratio, 3.96; 95% confidence interval, 1.12–14.04). In multivariable analysis, having a TASC II C/D lesion was an independent risk factor for mortality (hazard ratio, 3.25; 95% confidence interval, 1.87–5.67; P < 0.001). Having any TASC II lesion was not a risk factor for graft loss (overall P = 0.282).

Conclusions.
Kidney transplantation in patients with TASC II A/B is feasible and safe without increased risk of perioperative mortality. TASC II C/D decreases patient survival. Death-censored graft survival is unaffected.
Use of Eculizumab for Active Antibody-mediated Rejection That Occurs Early Post–kidney Transplantation: A Consecutive Series of 15 Cases
Authors: Tan Ek Khoon , Bentall Andrew , Dean Patrick G. , Shaheen Mohammed F. , Stegall Mark D. , Schinstock Carrie A. 
Published: February 2019

Background.
Active antibody-mediated rejection (AMR) that occurs during the amnestic response within the first month posttransplant is a rare but devastating cause of early allograft loss after kidney transplant. Prior reports of eculizumab treatment for AMR have been in heterogeneous patient groups needing salvage therapy or presenting at varied time points. We investigated the role of eculizumab as primary therapy for active AMR early posttransplant.

Methods.
We performed a retrospective observational study of a consecutive cohort of solitary kidney transplant recipients who were transplanted between January 1, 2014, and January 31, 2018, and had AMR within the first 30 days posttransplant and treated with eculizumab ± plasmapheresis.

Results.
Fifteen patients had early active AMR at a median (interquartile range [IQR]) of 10 (7–11) days posttransplant and were treated with eculizumab ± plasmapheresis. Thirteen cases were biopsy proven, and 2 cases were presumed on the basis of donor-specific antibody trends and allograft function. Within 1 week of treatment, the median estimated glomerular filtration rate increased from 21 to 34 mL/min (P = 0.001); and persistent active AMR was only found in 16.7% (2/12) of biopsied patients within 4–6 months. No graft losses occurred, and at last follow-up (median [IQR] of 13 [12–19] mo), the median IQR estimated glomerular filtration rate increased to 52 (46–60) mL/min.

Conclusions.
Prompt eculizumab treatment as primary therapy is safe and effective for early active AMR after kidney transplant or abrupt increases in donor-specific antibodies when biopsy cannot be performed for diagnosis confirmation.
Outcomes After Declining Increased Infectious Risk Kidney Offers for Pediatric Candidates in the United States
Authors: Bowring Mary G. , Jackson Kyle R. , Wasik Heather , Neu Alicia , Garonzik-Wang Jacqueline , Durand Christine , Desai Niraj , Massie Allan B. , Segev Dorry L. 
Published: February 2019

Background.
Kidneys from infectious risk donors (IRD) confer substantial survival benefit in adults, yet the benefit of IRD kidneys to pediatric candidates remains unclear in the context of high waitlist prioritization.

Methods.
Using 2010–2016 Scientific Registry of Transplant Recipients data, we studied 2417 pediatric candidates (age <18 y) who were offered an IRD kidney that was eventually used for transplantation. We followed candidates from the date of first IRD kidney offer until the date of death or censorship and used Cox regression to estimate mortality risk associated with IRD kidney acceptance versus decline, adjusting for age, sex, race, diagnosis, and dialysis time.

Results.
Over the study period, 2250 (93.1%) pediatric candidates declined and 286 (11.8%) accepted an IRD kidney offer; 119 (41.6%) of the 286 had previously declined a different IRD kidney. Cumulative survival among those who accepted versus declined the IRD kidney was 99.6% versus 99.4% and 96.3% versus 97.8% 1 and 6 years post decision, respectively (P = 0.1). Unlike the substantial survival benefit seen in adults (hazard ratio = 0.52), among pediatric candidates, we did not detect a survival benefit associated with accepting an IRD kidney (adjusted hazard ratio: 0.791.723.73, P = 0.2). However, those who declined IRD kidneys waited a median 9.6 months for a non-IRD kidney transplant (11.2 mo among those <6 y, 8.8 mo among those on dialysis). Kidney donor profile index (KDPI) of the eventually accepted non-IRD kidneys (median = 13, interquartile range = 6–23) was similar to KDPI of the declined IRD kidneys (median = 16, interquartile range = 9–28).

Conclusions.
Unlike in adults, IRD kidneys conferred no survival benefit to pediatric candidates, although they did reduce waiting times. The decision to accept IRD kidneys should balance the advantage of faster transplantation against the risk of infectious transmission.
Human loss-of-function variants suggest that partial LRRK2 inhibition is a safe therapeutic strategy for Parkinson’s disease
Authors: Whiffin Nicola , Armean Irina M. , Kleinman Aaron , Marshall Jamie L. , Minikel Eric V. , Karczewski Konrad J. , Cummings Beryl B. , Francioli Laurent , Laricchia Kristen , Wang Qingbo , Guan Anna , Alipanahi Babak , Morrison Peter , Baptista Marco A.S. , Merchant Kalpana M. ,   Genome Aggregation Database Production Team,   Genome Aggregation Database Consortium, Ware James S. , Havulinna Aki S. , Iliadou Bozenna , Lee Jung-Jin , Nadkarni Girish N. , Whiteman Cole ,   the 23andMe Research Team, Daly Mark , Esko Tõnu , Hultman Christina , Loos Ruth J.F. , Milani Lili , Palotie Aarno , Pato Carlos , Pato Michele , Saleheen Danish , Sullivan Patrick F. , Alföldi Jessica , Cannon Paul , MacArthur Daniel G. 
Published: February 2019

AbstractHuman genetic variants causing loss-of-function (LoF) of protein-coding genes provide natural in vivo models of gene inactivation, which are powerful indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson’s disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. Whilst preclinical studies in model organisms have raised some on-target toxicity concerns5–8, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here we systematically analyse LoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9 and over 4 million participants in the 23andMe genotyped dataset, to assess their impact at a molecular and phenotypic level. After thorough variant curation, we identify 1,358 individuals with high-confidence predicted LoF variants in LRRK2, several with experimental validation. We show that heterozygous LoF of LRRK2 reduces LRRK2 protein level by ~50% but is not associated with reduced life expectancy, or with any specific phenotype or disease state. These data suggest that therapeutics that downregulate LRRK2 levels or kinase activity by up to 50% are unlikely to have major on-target safety liabilities. Our results demonstrate the value of large scale genomic databases and phenotyping of human LoF carriers for target validation in drug discovery.
Ontology-based prediction of cancer driver genes
Authors: Althubaiti Sara , Karwath Andreas , Dallol Ashraf , Noor Adeeb , Alkhayyat Shadi Salem , Alwassia Rolina , Mineta Katsuhiko , Gojobori Takashi , Beggs Andrew D , Schofield Paul N , Gkoutos Georgios V , Hoehndorf Robert 
Published: February 2019

AbstractIdentifying and distinguishing cancer driver genes among thousands of candidate mutations remains a major challenge. Accurate identification of driver genes and driver mutations is critical for advancing cancer research and personalizing treatment based on accurate stratification of patients. Due to inter-tumor genetic heterogeneity, many driver mutations within a gene occur at low frequencies, which make it challenging to distinguish them from non-driver mutations. We have developed a novel method for identifying cancer driver genes. Our approach utilizes multiple complementary types of information, specifically cellular phenotypes, cellular locations, functions, and whole body physiological phenotypes as features. We demonstrate that our method can accurately identify known cancer driver genes and distinguish between their role in different types of cancer. In addition to confirming known driver genes, we identify several novel candidate driver genes. We demonstrate the utility of our method by validating its predictions in nasopharyngeal cancer and colorectal cancer using whole exome and whole genome sequencing.
The high persister phenotype ofPseudomonas aeruginosais associated with increased fitness and persistence in cystic fibrosis airways
Authors: Mojsoska Biljana , Cameron David R. , Bartell Jennifer A. , Haagensen Janus Anders Juul , Sommer Lea M. , Lewis Kim , Molin Søren , Johansen Helle Krogh 
Published: February 2019

AbstractDespite intensive antibiotic treatment of cystic fibrosis (CF) patients,Pseudomonas aeruginosaoften persists in patient airways for decades, and can do so without the development of antibiotic resistance. Using a high-throughput screening assay of survival after treatment with high concentrations of ciprofloxacin, we have determined the prevalence of high-persister variants (Hip) in a large patient cohort. In a screen of 467 longitudinal clinical isolates ofP. aeruginosafrom 40 CF patients, we classified 25.7% as Hip. Hip were identified in 26 patients, but only a few bacterial lineages were dominated by Hip. Instead, the emergence of Hip increased over time, suggesting that CF airways treated with ciprofloxacin select for Hip with an increased fitness in this environment. We generally observed diverse genetic changes in the Hip isolate population (as many co-occurring routes to increased fitness exist), but interestingly elevated mutation counts in the RpoN gene of 18 Hip isolates suggest that this sigma factor plays a role in shaping levels of antibiotic tolerance. To probe the impact of the Hip phenotype in a CF-similar environment, we tested the fitness properties of otherwise genotypically and phenotypically similar low-persister (Lop) and Hip isolates in co-culture using a specialized flow-cell biofilm system mimicking pharmacokinetic/-dynamic antibiotic dosing. Hip survived ciprofloxacin treatment far better than Lop isolates. The results of this investigation provide novel insights into persister dynamics and fitness contributions to survival in the CF lung, and show that the Hip phenotype of antibiotic susceptible bacteria plays an important role in long-term infections.SignificanceAntibiotic resistance is emphasized as a rapidly increasing health threat, but antibiotic tolerance via the occurrence of persister cells in antibiotic-treated bacterial populations is clinically and publicly neglected. In 40 CF patients representing a well-established human infection model – long-term lung infections byPseudomonas aeruginosa– we show the emergence and accumulation of persister variants in a clinical population heavily reliant on antibiotic therapy. We observe that the high-persister (Hip) phenotype is independent of resistance and likely the consequence of numerous genetic alterations, complicating surveillance and inhibition in the clinic. Furthermore, we find Hip are selected for over time, survive better than ‘normal’ bacteria, and can outcompete them in CF-similar conditions, ultimately affecting 65% of patients in an early disease cohort.
Protein kinase C is a key target for attenuation of Leigh syndrome by rapamycin
Authors: Martin-Perez Miguel , Ito Takashi K. , Grillo Anthony S. , Valente Anthony S. , Han Jeehae , Entwisle Samuel , Huang Heather Z. , Kim Dayae , Yajima Masanao , Kaeberlein Matt , Villén Judit 
Published: February 2019

AbstractLeigh syndrome is a fatal neurometabolic disorder caused by defects in mitochondrial function. mTOR inhibition with rapamycin attenuates disease progression in a mouse model of Leigh syndrome (Ndufs4 KO mouse); however, the mechanism of rescue is unknown. Here we assessed the impact of rapamycin on the brain proteome and phosphoproteome of Ndufs4 KO mice. We report that rapamycin remodels the brain proteome to alter mitochondrial structure, inhibits signaling through both mTOR complexes, and inhibits multiple protein kinase C (PKC) isoforms. Administration of PKC inhibitors was sufficient to increase survival, delay neurological deficits, and prevent hair loss in Ndufs4 KO mice. Thus, PKC may be a viable therapeutic target for treating severe mitochondrial disease.One Sentence SummaryProteomic and phosphoproteomic analysis of mouse brain identifies PKC as a key target to treat mitochondrial disease
Clinical significance of C4d deposition in renal tissues from patients with primary Sjögren’s syndrome—A preliminary study
Authors: Xia Wenli , Gao Bixia , Duan Lin , Li Yan , Wen Yubing , Chen Limeng , Li Xuemei , Zheng Falei , Li Mingxi 
Published: February 2019

AbstractObjectivesTo evaluate renal expression of C4d, a complement component in the classical/mannose binding lectin (MBL) pathway, in patients with primary Sjögren’s syndrome (pSS)-associated renal impairments.MethodsWe retrospectively reviewed the clinical and pathological data from 39 patients with pSS presenting with renal impairments. C4d was examined in paraffin-embedded biopsy tissues using immunohistochemistry. Glomerular C4d positive was defined when >75% glomeruli were globally stained. Tubulointerstitial C4d (TI-C4d) were scored semi-quantitatively as 0 (absent), 1 (spotty or weak), 2 (patchy) and 3 (diffuse). A TI-C4d score ≥2 was considered TI-C4d positive and included in the TI-C4d+ group and vice versa. Peritubular capillary (PTC) C4d was scored as 0 (absent), 1 (0∼10%, minimal), 2 (10%∼50%, focal), and 3 (>50%, diffuse).ResultsGlomerular C4d deposition was observed in all 8 patients with pSS-related membranous nephropathy (MN) without obvious C1q deposition. Two of 5 patients with mesangial proliferative glomerulonephritis and 1 of 2 patients with IgA nephropathy had mild mesangial C4d deposition. Sixteen patients (6 glomerular dominant and 10 tubulointerstitial dominant) presented TI-C4d score ≥2. Patients in the TI-C4d+ group exhibited a higher serum creatinine level at the time of renal biopsy (TI-C4d+ 132.5 [89.7, 165.5] vs. TI-C4d- 83.0 [70.7, 102.0] μmol/L, P=0.008). PTC C4d was observed in 12 patients, with each of minimal, focal and diffuse staining being noted in 4 patients.ConclusionsThe MBL pathway of complement activation was potentially involved in pSS-related MN. Tubulointerstitial C4d might be a pathological marker of severe renal injury in patients with pSS-related renal impairments.
Analyzing time-aggregated networks: the role of bootstrapping, permutation, and simulation
Authors: Bonnell T.R. , Vilette C. 
Published: February 2019

AbstractNetworks are often used to describe adaptive social systems, where individual (node) behaviour generates network-level structures that influence subsequent individual-level behaviour. To address questions about the dynamics of network structure in these systems, there is a need to analyze networks through time. Various statistical methods exist for estimating the behaviour of networks in time, in terms of both time-ordered and time-aggregated networks. In this paper, we discuss three main analytical steps for the analysis of time-aggregated network data: 1) aggregation choices, 2) null-model comparisons, and 3) constructing, parameterizing, and making inferences from time series models. We then present a custom R package, netTS, which facilitates these steps. Observed grooming data from a group of vervet monkeys, a highly social primate species, is used as an example to highlight three potential analyses: 1) quantifying the stability of network-level social structures through time, 2) identifying keystone nodes driving/maintaining network structures, and 3) quantifying the interdependence between node behaviour through time. In particular, we highlight the role of bootstrapping, permutation, and simulation as critical components in the analysis of time-aggregated networks.
Increased Neurite Orientation-Dispersion and Density in the TgCRND8 Mouse Model of Amyloidosis: Inverse Relation with Functional Connectome Clustering and Modulation by Interleukin-6
Authors: Colon-Perez Luis M. , Ibanez Kristen R. , Suarez Mallory , Torroella Kristin , Acuna Kelly , Ofori Edward , Levites Yona , Vaillancourt David E. , Golde Todd E. , Chakrabarty Paramita , Febo Marcelo 
Published: February 2019

ABSTRACTExtracellular β-amyloid (Aβ) plaque deposits and inflammatory immune activation are thought to alter various aspects of tissue microstructure, such as extracellular free water, fractional anisotropy and diffusivity, as well as the density and geometric arrangement of axonal processes. Quantifying these microstructural changes in Alzheimer’s disease and related neurodegenerative dementias could serve to accurately monitor or predict disease course. In the present study we used high-field diffusion magnetic resonance imaging (dMRI) to determine how Aβ and inflammatory interleukin-6 (IL6), alone or in combination, affectin vivotissue microstructure in the TgCRND8 mouse model of Alzheimer’s-type Aβ deposition. TgCRND8 and non-transgenic (nTg) mice expressing brain-targeted IL6 or enhanced glial fibrillary protein (EGFP controls) were scanned at 8 months of age using a 2-shell, 54-gradient direction dMRI sequence at 11.1 Tesla. Images were processed using the free water elimination method and the neurite orientation dispersion and density imaging (NODDI) model. DTI and NODDI processing in TgCRND8 mice revealed a microstructure pattern consistent with reduced white matter integrity along with an increase in density and geometric complexity of axonal and dendritic processes. This included reduced FA, mean diffusivity (MD), and free water (FW), and increased ‘neurite’ density (NDI) and orientation dispersion (ODI). IL6 produced a ‘protective-like’ effect on FA in TgCRND8 mice, although there were minimal microstructure changes in these mice compared IL6 expressing nTg mice. In addition, we found that NDI and ODI had an inverse relationship with the functional connectome clustering coefficient, which was affected by Aβ and IL6. The relationship between NODDI and graph theory metrics suggests that increasing the density and orientation dispersion of neurites may relate to diminished functional network organization in the brain.
Inverted translational control of eukaryotic gene expression by ribosome collisions
Authors: Park Heungwon , Subramaniam Arvind R. 
Published: February 2019

AbstractThe canonical model of eukaryotic translation posits that efficient translation initiation increases protein expression and mRNA stability. Contrary to this dogma, we show that increasing initiation rate can decrease both protein expression and stability of certain mRNAs in the budding yeast,S. cerevisiae. These mRNAs contain a stretch of poly-basic residues that cause ribosome stalling. Using computational modeling, we predict that the observed decrease in gene expression at high initiation rates occurs when ribosome collisions at stalls stimulate abortive termination of the leading ribosome and cause endonucleolytic mRNA cleavage. We test our prediction by identifying critical roles for the collision-associated quality control factors, Asc1 and Hel2 (RACK1 and ZNF598 in humans, respectively). Remarkably, hundreds ofS. cerevisiaemRNAs that contain ribosome-stall sequences also exhibit lower translation efficiency. We propose that these mRNAs have undergone evolutionary selection for inefficient initiation to escape collision-stimulated reduction in gene expression.