bluuebunny/crossref_metadata_2025_split huggingface dataset:
Geographic Variation in the Utilization of and Mortality After Emergency General Surgery Operations in the Northeastern and Southeastern United States
Authors: Becher Robert D. , Jin Lan , Warren Joshua L. , Gill Thomas M. , DeWane Michael P. , Davis Kimberly A. , Zhang Yawei 
Published: June 2020

Objective:
To define geographic variations in emergency general surgery (EGS) care, we sought to determine how much variability exists in the rates of EGS operations and subsequent mortality in the Northeastern and Southeastern United States (US).

Summary Background Data:
While some geographic variations in healthcare are normal, unwarranted variations raise questions about the quality, appropriateness, and cost-effectiveness of care in different areas.

Methods:
Patients ≥18 years who underwent 1 of 10 common EGS operations were identified using the State Inpatient Databases (2011–2012) for 6 states, representing Northeastern (New York) and Southeastern (Florida, Georgia, Kentucky, North Carolina, Mississippi) US. Geographic unit of analysis was the hospital service area (HSA). Age-standardized rates of operations and in-hospital mortality were calculated and mapped. Differences in rates across geographic areas were compared using the Kruskal–Wallis test, and variance quantified using linear random-effects models. Variation profiles were tabulated via standardized rates of utilization and mortality to compare geographically heterogenous areas.

Results:
227,109 EGS operations were geospatially analyzed across the 6 states. Age-standardized EGS operation rates varied significantly by region (Northeast rate of 22.7 EGS operations per 10,000 in population versus Southeast 21.9; P < 0.001), state (ranging from 9.9 to 29.1; P < 0.001), and HSA (1.9–56.7; P < 0.001). The geographic variability in age-standardized EGS mortality rates was also significant at the region level (Northeast mortality rate 7.2 per 1000 operations vs Southeast 7.4; P < 0.001), state-level (ranging from 5.9 to 9.0 deaths per 1000 EGS operations; P < 0.001), and HSA-level (0.0–77.3; P < 0.001). Maps and variation profiles visually exhibited widespread and substantial differences in EGS use and morality.

Conclusions:
Wide geographic variations exist across 6 Northeastern and Southeastern US states in the rates of EGS operations and subsequent mortality. More detailed geographic analyses are needed to determine the basis of these variations and how they can be minimized.
Therapeutic effectiveness of interferon-alpha 2b against COVID-19: the Cuban experience
Authors: Pereda R , González D , Rivero HB , Rivero JC , Pérez A , López LR , Mezquia N , Venegas R , Betancourt JR , Domínguez RE 
Published: June 2020

ABSTRACTBackgroundEffective therapies are needed to control the SARS-Cov-2 infection pandemic and reduce mortality associated with COVID-19. Several clinical studies have provided evidence for the antiviral effects of type I interferons (IFNs) in patients with respiratory coronaviruses. This study assessed the therapeutic efficacy of IFN-α2b in patients infected with SARS-CoV-2 during the first month after the outbreak began in Cuba.MethodThis multicenter prospective observational study was conducted in 16 hospitals in 8 Cuban provinces. Participants were patients with confirmed SARS-CoV-2 infection detected from throat swab specimens by real time RT-PCR who gave informed consent and had no contraindications for IFN treatment. Patients received therapy as per the Cuban COVID protocol, that included a combination of oral antivirals (lopinavir/ritonavir and chloroquine) with intramuscular administration of IFN-α2b (Heberon® Alpha R, Center for Genetic Engineering and Biotechnology, Havana), 3 times per week, for 2 weeks. The primary endpoint was the proportion of patients discharged from hospital (without clinical and radiological symptoms and non-detectable virus by RT-PCR). The secondary endpoint was the case fatality rate (CFR), defined as the number of confirmed deaths divided by the number of confirmed cases.ResultsFrom March 11th to April 14th, 814 patients were confirmed SARS-CoV-2 positive in Cuba, 761 (93.4%) were treated with Heberon® Alpha R and 53 received the approved protocol without IFN treatment. The proportion of fully recovered patients was higher in the IFN-treated compared with non-IFN treated group (95.4% vs 26.1%, p<0.01). The CFR for all patients was 2.95%, and for those patients who received IFN-α2b the CFR was reduce to 0.92. The estimated global CFR is 6.34% and 4.05% for the Americas reported by WHO and PAHO, respectively. In this study, 82 patients (10.1%) required intensive care and, of these, 42 (5.5%) were treated with IFN.ConclusionsThis report provides preliminary evidence for the therapeutic effectiveness of IFNα-2b for COVID-19 and suggests that the use of Heberon® Alpha R may contribute to complete recovery.
The First Complete Zoroastrian-Parsi Mitochondrial Reference Genome and genetic signatures of an endogamous non-smoking population
Authors: Patell Villoo Morawala , Pasha Naseer , Krishnasamy Kashyap , Mittal Bharti , Gopalakrishnan Chellappa , Mugasimangalam Raja , Sharma Naveen , Gupta Arati-Khanna , Bhote-Patell Perviz , Rao Sudha , Jain Renuka ,   The Avestagenome Project
Published: June 2020

AbstractThe present-day Zoroastrian-Parsis have roots in ancient pastoralist migrations from circumpolar regions leading to their settlement on the Eurasian Steppes and later, as Indo-Iranians in the Fertile Crescent. After migrating from the Persian province of Pars to India, the Zoroastrians from Pars (“Parsis”) practiced endogamy, thereby preserving their genetic identity and social practices. The study was undertaken to gain an insight into the genetic consequences of migration on the community, the practice of endogamy, to decipher the phylogenetic relationships with other groups, and elucidate the disease linkages to their individual haplotypesWe generated thede novothe Zoroastrian-Parsi Mitochondrial Reference Genome (AGENOME-ZPMS-HV2a-1), which is the first complete mitochondrial reference genome assembled for this group. Phylogenetic analysis of an additional 99 Parsi mitochondrial genome sequences showed the presence of HV, U, T, A and F (belonging to the macrohaplogroup N) and Z and other M descendents of the macrohaplogroup M (M5, M39, M33, M44’52, M24, M3, M30, M2, M4’30, M2, M35 and M27) and a largely Persian origin for the Parsi community. We assembled individual reference genomes for each major haplogroup and the Zoroastrian-Parsi Mitochondrial Consensus Genome (AGENOME-ZPMCG V1.0), which is the first consensus genome assembled for this group. We report the existence of 420 mitochondrial genetic variants, including 12 unique variants, in the 100 Zoroastrian-Parsi mitochondrial genome sequences. Disease association mapping showed 217 unique variants linked to longevity and 41 longevity-associated disease phenotypes across the majority of haplogroups.Analysis of the coding genes, tRNA genes, and the D-loop region revealed haplogroup-specific disease associations for Parkinson’s disease, Alzheimer’s disease, cancers, and rare diseases. No known mutations linked to lung cancer were found in our study. Mutational signatures linked to tobacco carcinogens, specifically, the C>A and G>T transitions, were observed at extremely low frequencies in the Parsi cohort, suggestive of an association between the cultural norm prohibiting smoking and its reflection in the genetic signatures. In sum, the Parsi mitochondrial genome provides an exceptional resource for determining details of their migration and uncovering novel genetic signatures for wellness and disease.
Evidence for reduced long-term potentiation-like visual cortical plasticity in schizophrenia and bipolar disorder
Authors: Valstad Mathias , Roelfs Daniël , Slapø Nora B. , Timpe Clara M.F. , Rai Ahsan , Matziorinis Anna Maria , Beck Dani , Richard Geneviève , Sæther Linn Sofie , Haatveit Beathe , Nordvik Jan Egil , Hatlestad-Hall Christoffer , Einevoll Gaute T. , Mäki-Marttunen Tuomo , Haram Marit , Ueland Torill , Lagerberg Trine V. , Steen Nils Eiel , Melle Ingrid , Westlye Lars T. , Jönsson Erik G. , Andreassen Ole A. , Moberget Torgeir , Elvsåshagen Torbjørn 
Published: June 2020

AbstractBackgroundSeveral lines of research suggest that impairments in long-term potentiation (LTP)-like synaptic plasticity might be a key pathophysiological mechanism in schizophrenia (SZ) and bipolar disorder type I (BDI) and II (BDII). Using modulations of visually evoked potentials (VEP) of the electroencephalogram, impaired LTP-like visual cortical plasticity has been implicated in patients with BDII, while there has been conflicting evidence in SZ, a lack of research in BDI, and mixed results regarding associations with symptom severity, mood states, and medication.MethodsWe measured the VEP of patients with SZ spectrum disorders (n=31), BDI (n=34), BDII (n=33), and other BD spectrum disorders (n=2), and age-matched healthy control participants (n=200) before and after prolonged visual stimulation.ResultsCompared to healthy controls, modulation of VEP component N1b, but not C1 or P1, was impaired both in patients within the SZ spectrum (χ2=35.1, p=3.1×10−9) and BD spectrum (χ2=7.0, p=8.2×10−3), including BDI (χ2=6.4, p=0.012), but not BDII (χ2=2.2, p=0.14). N1b modulation was also more severely impaired in SZ spectrum than BD spectrum patients (χ2=14.2, p=1.7×10−4). The reduction in N1b modulation was related to PANSS total scores (χ2=10.8, p=1.0×10−3), and nominally to number of psychotic episodes (χ2=4.9, p=0.027).Conclusions.These results suggest that LTP-like plasticity is impaired in SZ and BDI, but not BDII, and related to psychotic symptom severity. Adding to previous genetic, pharmacological, and anatomical evidence, these results implicate aberrant synaptic plasticity as a mechanism underlying SZ and BD.
Analysis of single-cell RNA-seq data from ovarian cancer samples before and after chemotherapy links stress-related transcriptional profile with chemotherapy resistance
Authors: Zhang Kaiyang , Erkan Erdogan Pekcan , Dai Jun , Andersson Noora , Kaipio Katja , Lamminen Tarja , Mansuri Naziha , Huhtinen Kaisa , Carpén Olli , Hynninen Johanna , Hietanen Sakari , Oikkonen Jaana , Häkkinen Antti , Hautaniemi Sampsa , Vähärautio Anna 
Published: June 2020

AbstractChemotherapy resistance is the greatest contributor to cancer mortality and the most urgent unmet challenge in oncology. In order to reveal transcriptomics changes due to platinum-based chemotherapy we analyzed single-cell RNA-seq data from fresh tissue samples taken at the time of diagnosis and after neoadjuvant chemotherapy from 11 high-grade serous ovarian cancer (HGSOC) patients. With a novel clustering method accounting for patient-specific variability and technical confounders, we identified 12 clusters. Of these, a stress-related transcriptional profile was enriched during chemotherapy and associated significantly to poor progression-free survival (PFS) and disease-free interval (DFI) in deconvoluted bulk RNA-seq data analysis of treatment-naive samples in TCGA cohort. Pan-cancer cell line analysis suggests that patients with high stress-related transcriptional profile may benefit from MEK1/2 inhibitors instead of platinum. Further, high proportion of stromal components and high interaction score between tumor and stromal suggest the tumor cells with high-stress profile actively interact with and potentially recruit stromal cells to their microenvironment already prior to chemotherapy, potentially facilitating protection from chemotherapeutic treatments. In summary, we have identified a stress-related transcriptional profile, which is present at the time of diagnosis, enriched during platinum treatment, independent predictor for poor PFS and DFI, and, based onin vitrodata, targetable with MEK1/2 inhibitors.Translational relevanceWe discovered a stress-related transcriptional profile that is significantly enriched in fresh tissue samples after chemotherapy and is significantly associated with poor progression-free survival in an independent patient cohort. The survival association is independent of age, tumor purity or BRCAness. Therefore, this chemotherapy resistance associated profile is intrinsic and could thus be targeted already in treatment-naive patients. The translation potential of the stress-related transcriptomics profile was further supported by pan-cancer cell line analysis that showed that cell lines with high stress-related transcriptional profile are not affected by platinum, corroborating our results, whereas they were more sensitive to MEK1/2 inhibitors. Taken together, the stress-related transcriptional profile, quantifiable with a set of 35 marker genes, provides a basis for improved prediction of platinum response as well as novel avenues to treat this patient group more effectively.
Identification of Wee1 as Target in Combination with Avapritinib for the Treatment of Gastrointestinal Stromal Tumor
Authors: Ye Shuai , Sharipova Dinara , Kozinova Marya , Klug Lilli , D’Souza Jimson , Belinsky Martin G. , Johnson Katherine J. , Einarson Margret B. , Devarajan Karthik , Zhou Yan , Litwin Samuel , Heinrich Michael C. , DeMatteo Ronald , von Mehren Margaret , Duncan James S. , Rink Lori 
Published: June 2020

AbstractManagement of gastrointestinal stromal tumor (GIST) has been revolutionized by the identification of activating mutations in KIT and PDGFRA, and the clinical application of receptor tyrosine kinase (RTK) inhibitors in the advanced disease setting. Stratification of GIST into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in the majority of GIST, resistance to these agents remains a significant clinical problem. Development of effective treatment strategies for refractory GIST subtypes requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases that are essential in GIST. Using Multiplexed Inhibitor Beads and Mass Spectrometry, we explored the majority of the kinome in GIST specimens from the three most common molecular subtypes to identify novel kinase targets. Kinome profiling revealed distinct signatures in GIST subtypes and identified kinases that are universally activated in all GIST, as well as kinases that are unique to each subtype. Kinome profiling in combination with loss-of-function assays identified a significant role for the G2-M tyrosine kinase, Wee1, in GIST cell survival.In vitroandin vivostudies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib inKITandPDGFRA-mutant GIST cell lines, and notable efficacy of MK-1775 as a single agent in thePDGFRA-mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.
Swine viral detection by adapted Next-Generation Sequencing (NGS) for RNA and DNA species reveals first detection of porcine circovirus type 3 (PCV3) in Chile
Authors: Rubilar Paulina S. , Tognarelli Javier , Fernández Jorge , Valdés Cristóbal , Broitman Felipe , Mandakovic Dinka , Pulgar Rodrigo 
Published: June 2020

AbstractThe outbreak and propagation of COVID-19 have posed a significant challenge to our society, highlighting the relevance of epidemiological monitoring of animal pathogens closely related to humans due to potential zoonosis. To find previously undetected viruses inside Chilean swine farms, we collected non-invasive samples from animals suspected to undergo any viral disease. After screening by Next Generation Sequencing (NGS) adapted to identify viral species with RNA and DNA genomes simultaneously, different viral species were successfully detected. Among viruses with an RNA genome, Porcine Rotavirus A (RVA), Porcine Astrovirus type 5 (PAstV-5) and Porcine Feces-Associated IASV-like virus (PfaIV) were identified; whereas among viruses with DNA genome, Porcine Parvovirus 1 (PPV1), Porcine Circovirus type 1 (PCV1) and Porcine Circovirus type 3 (PCV3) were found. PCV3, a recently described pathogenic virus, was detected for the first time in Chile in different samples from mummified tissue of stillbirths. The whole genome sequence of PCV3 was completed using conventional PCR and Sanger sequencing and compared with previously reported genomes. To the best of our knowledge, this is the first time that an adapted NGS system is used for the screening of DNA and RNA viral species simultaneously inside the Chilean swine industry. This adapted NGS system might be useful for the detection of swine viral emerging diseases worldwide.
Altered Thalamocortical Connectivity in Six-Week Old Infants at High Familial Risk for Autism Spectrum Disorder
Authors: Nair Aarti , Jalal Rhideeta , Liu Janelle , Tsang Tawny , McDonald Nicole M. , Jackson Lisa , Ponting Carolyn , Jeste Shafali S. , Bookheimer Susan Y. , Dapretto Mirella 
Published: June 2020

ABSTRACTConverging evidence from neuroimaging studies has revealed altered connectivity in cortical-subcortical networks in youth and adults with autism spectrum disorder (ASD). Comparatively little is known about the development of cortical-subcortical connectivity in infancy, before the emergence of overt ASD symptomatology. Here we examined early functional and structural connectivity of thalamocortical networks in infants at high familial risk for ASD (HR) and lowrisk controls (LR). Resting-state functional connectivity (rs-fcMRI) and diffusion tensor imaging (DTI) data were acquired 52 six-week-old infants. Functional connectivity was examined between six cortical seeds –prefrontal, motor, somatosensory, temporal, parietal, and occipital regions– and bilateral thalamus. We found significant thalamic-prefrontal underconnectivity, as well as thalamic-occipital and thalamic-motor overconnectivity in HR infants, relative to LR infants. Subsequent structural connectivity analyses also revealed atypical white matter integrity in thalamic-occipital tracts in HR infants, compared to LR infants. Notably, aberrant rs-fcMRI and DTI connectivity indices at 6 weeks predicted atypical social development between 6 and 36 months of age, as assessed with eye-tracking and diagnostic measures. These findings indicate that thalamocortical connectivity is disrupted at both the functional and structural level in HR infants as early as six weeks of age, providing a possible early marker of risk for ASD.
Structural basis for polyglutamate chain initiation and elongation by TTLL family enzymes
Authors: Mahalingan Kishore K. , Keenen E. Keith , Strickland Madeleine , Li Yan , Liu Yanjie , Ball Haydn L. , Tanner Martin E. , Tjandra Nico , Roll-Mecak Antonina 
Published: June 2020

AbstractGlutamylation, introduced by TTLL enzymes, is the most abundant modification of brain tubulin. Essential effector proteins read the tubulin glutamylation pattern, and its misregulation causes neurodegeneration. TTLL glutamylases posttranslationally add glutamates to internal glutamates in tubulin C-terminal tails (branch initiation, through an isopeptide bond), and additional glutamates can extend these (elongation). TTLLs are thought to specialize for initiation or elongation, but the mechanistic basis for regioselectivity is unknown. We present cocrystal structures of murine TTLL6 bound to tetrahedral intermediate analogs that delineate key active-site residues that make this an elongase. We show that TTLL4 is exclusively an initiase, and through combined structural and phylogenetic analyses, engineer TTLL6 into a branch-initiating enzyme. TTLL glycylases add glycines posttranslationally to internal glutamates, and we find that the same active-site residues discriminate between initiase and elongase glycylases. These active-site specializations of TTLL glutamylases and glycylases ultimately yield the chemical complexity of cellular microtubules.
Predictive usefulness of PCR testing in different patterns of Covid-19 symptomatology - Analysis of a French cohort of 12,810 outpatients
Authors:   AP-HP / Universities / Inserm COVID-19 research collaboration members, Caroline Apra , Charlotte Caucheteux , Arthur Mensch , Jenny Mansour , Mélodie Bernaux , Agnès Dechartres , Erwan Debuc , Xavier Lescure , Aurélien Dinh , Youri Yordanov , Patrick Jourdain , Arthur Mensch , Charlotte Caucheteux , Caroline Apra , Jenny Mansour , Nicolas Paris , Alexandre Gramfort 
Published: June 2020

AbstractPolymerase Chain reaction (PCR) is a key tool to diagnose Covid-19. Yet access to PCR is often limited. In this paper, we develop a clinical strategy for prescribing PCR to patients based on data from COVIDOM, a French cohort of 54,000 patients with clinically suspected Covid-19 including 12,810 patients tested by PCR. Using a machine learning algorithm (a decision tree), we show that symptoms alone are sufficient to predict PCR outcome with a mean average precision of 86%. We identify combinations of symptoms that are predictive of PCR positivity (90% for anosmia/ageusia) or negativity (only 30% of PCR+ for a subgroup with cardiopulmonary symptoms): in both cases, PCR provides little added diagnostic value. We deduce a prescribing strategy based on clinical presentation that can improve the global efficiency of PCR testing.
Covid-19 Incidence Rate Evolution Modeling using Dual Wave Gaussian-Lorentzian Composite Functions
Authors: Poomari Radhakrishnan 
Published: June 2020

AbstractModeling the evolution of Covid-19 incidence rate is critical to deciding and assessing non-medical intervention strategies that can lead to successful containment of the pandemic. This research presents a mathematical model to empirically assess measures related to various pandemic containment strategies, their similarities and a probabilistic estimate on the evolution of Covid-19 incidence rates. The model is built on the principle that, the exponential rise and decay of the number of confirmed Covid-19 infections can be construed as a set of concurrent non-linear waves. These waves can be characterized by a linear combination of Gaussian and Cauchy Lorentz functions collectively termed as Gaussian-Lorentzian Composite (GLC) function. The GLC function is used for non-linear approximation of officially confirmed Covid-19 incidence rates in each country. Results of fitting GLC based models to incidence rate trends of 20 different countries proves that the models can empirically explain the growth and decay trajectory Covid-19 infections in a given population.