bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trajectory Analysis of Cognitive Outcomes in Children With Perinatal HIV
Authors: Patel Payal B. , Apornpong Tanakorn , Puthanakit Thanyawee , Thongpibul Kulvadee , Kosalaraksa Pope , Hansudewechakul Rawiwan , Kanjanavanit Suparat , Ngampiyaskul Chiawat , Luesomboon Wicharn , Wongsawat Jurai , Sun Ly Penh , Chettra Kea , Saphonn Vonthanak , Mellins Claude A. , Malee Kathleen , Spudich Serena , Ananworanich Jintanat , Kerr Stephen J. , Paul Robert 
Published: September 2019

Background:
Children with perinatal HIV (pHIV) may display distinct long-term cognitive phenotypes. We used group-based trajectory modeling to identify clusters of children with pHIV after similar developmental trajectories and predictors of belonging to select cognitive trajectory groups.

Methods:
Participants included children, 4–17 years of age, with pHIV in Thailand and Cambodia. Cognitive measures included translated versions of Intelligence Quotient tests, Color Trails Tests and Beery-Buktenica Developmental Test of Visual-Motor Integration conducted semiannually over 3–6 years. The best fit of trajectory groups was determined using maximum likelihood estimation. Multivariate logistic regression identified baseline factors associated with belonging to the lowest scoring trajectory group.

Results:
Group-based trajectory analyses revealed a 3-cluster classification for each cognitive test, labeled as high, medium and low scoring groups. Most trajectory group scores remained stable across age. Verbal IQ declined in all 3 trajectory groups and the high scoring group for Children’s Color Trails Test 1 and 2 showed an increase in scores across age. Children in the lowest scoring trajectory group were more likely to present at an older age and report lower household income.

Conclusions:
Group-based trajectory modeling succinctly classifies cohort heterogeneity in cognitive outcomes in pHIV. Most trajectories remained stable across age suggesting that cognitive potential is likely determined at an early age with the exception of a small subgroup of children who displayed developmental gains in select cognitive domains and may represent those with better cognitive reserve. Poverty and longer duration of untreated HIV may predispose children with pHIV to suboptimal cognitive development.
Adoptive immunotherapy with autologous T-cell infusions reduces opioid requirements in advanced cancer patients
Authors: Zhou Xinna , Qiao Guoliang , Ren Jun , Wang Xiaoli , Wang Shuo , Zhu Siyu , Yuan Yanhua , Morse Michael A. , Hobeika Amy , Lyerly Herbert Kim 
Published: September 2019

Abstract
Relief of cancer-related pain remains challenging despite the availability of a range of opioid and nonopioid medications. Animal models demonstrate that T lymphocytes may mediate analgesia by producing endogenous opioids, but definitive clinical data are limited. Transfer of ex vivo adoptive cellular therapy (ACT) is being tested as an anticancer therapy. We retrospectively reviewed the medical charts of 357 patients with various malignancies who received 3 intravenous infusions of autologous cytokine-activated T-cell–enriched products. Among these were 55 patients who required opioids for moderate or severe cancer-related pain. Opioid dosage and cancer pain score were recorded daily for 2 consecutive weeks before and 2 weeks after the ACT infusions. The average oral morphine equivalent doses and cancer pain scores were significantly decreased after the ACT infusions. The proportion of patients with breakthrough pain also declined. Moreover, higher frequencies of expanded CD3+, CD3+/CD4+, and CD3+/CD8+ T cells within the ACT product were associated with favorable analgesic effects. Transient elevations in CD3+ and CD3+/CD8+T-cell subpopulations and decreases in CD4+CD25+ Treg were observed in patients' blood after the ACT. In conclusion, ACT was capable of reducing cancer pain severity and opioid consumption and favorably modulating peripheral blood T-cell populations.
Automated Insulin Delivery: The Artificial Pancreas Technical Challenges
Authors: Hernando M. Elena , García-Sáez Gema , Gómez Enrique J. , Pérez-Gandía Carmen , Rodríguez-Herrero Agustín 
Published: September 2019

Background:
The automation of glucose control has been an important goal of diabetes treatment for many decades. The first artificial pancreas experiences were in-hospital, closely supervised, small-scale, and short-term studies that demonstrated their superiority over continuous subcutaneous insulin infusion therapy. At present, long-term outpatient studies are being conducted in free-living scenarios.

Areas of Uncertainty:
The integration of multiple devices increases patients' burden and the probability of technical risks. Control algorithms must be robust to manage disturbance variables, such as physical exercise, meal composition, stress, illness, and circadian variations in insulin sensitivity. Extra layers of safety could be achieved through remote supervision. Dual-hormone systems reduce the incidence and duration of hypoglycemia, but the availability of stable pumpable glucagon needs to be solved. Faster insulin analogues are expected to improve all types of artificial pancreas.

Therapeutic Advances:
Artificial pancreas safety and feasibility are being demonstrated in outpatient studies. Artificial pancreas use increases the time of sensor-measured glucose in near-normoglycemia and reduces the risk of hyperglycemia and hypoglycemia. The benefits are observed both in single- and dual-hormone algorithms and in full- or semi-closed loop control. A recent meta-analysis including 41 randomized controlled trials showed that artificial pancreas use achieves a reduction of time in hyperglycemia (2 hours less than control treatment) and in hypoglycemia (20 minutes less); mean levels of continuous glucose sensor fell by 8.6 mg/dL over 24 hours and by 14.6 mg/dL overnight. The OpenAPS community uses Do It Yourself artificial pancreas in the real world since 2013, and a recent retrospective cross-over study (n = 20) compared continuous glucose sensor readings before and after initiation: mean levels of blood glucose fell by 7.4 mg/dL over 24 hours and time in range increased from 75.8% to 82.2% (92 minutes more).

Conclusions:
The outpatient use of artificial pancreas is safe and improves glucose control in outpatients with type 1 diabetes compared with the use of any type of insulin-based treatment. The availability of open-source solutions and data sharing is needed to foster the development of new artificial pancreas approaches and to promote the wide use of Big Data tools for knowledge discovery, decision support, and personalization.
VGF: a biomarker and potential target for the treatment of neuropathic pain?
Authors: Soliman Nadia , Okuse Kenji , Rice Andrew S.C. 
Published: September 2019

Abstract
Neuropathic pain (NP) remains an area of considerable unmet medical need. A persistent challenge in the management of NP is to target the specific mechanisms leading to a change from normal to abnormal sensory perception while ensuring that the defensive pain perception remains intact. Targeting VGF-derived neuropeptides may offer this opportunity. VGF was first identified in 1985 and is highly expressed after nerve injury and inflammation in neurons of both the peripheral and central nervous system. Subsequent studies implicate the vgf gene and its products in pain pathways. This narrative review was supported by a systematic search to identify, select, and critically appraise all relevant research investigating the role of VGF-derived neuropeptides in pain pathways. It predominantly focuses on in vivo investigations of the role of VGF in the initiation and maintenance of NP. VGF expression levels are very low under normal physiological conditions and nerve injury results in rapid and robust upregulation, increasing mechanical and thermal hypersensitivity. The identification of the 2 complement receptors with which VGF neuropeptides interact suggests a novel interplay of neuronal and immune signalling mediators. The understanding of the molecular mechanisms and signalling events by which VGF-derived active neuropeptides exert their physiological actions is in its infancy. Future work should aim to improve understanding of the downstream consequences of VGF neuropeptides thereby providing novel insights into pain mechanisms potentially leading to the identification of novel therapeutic targets.
Renal Protection Against Ischemia Reperfusion Injury: Hemoglobin-based Oxygen Carrier-201 Versus Blood as an Oxygen Carrier in Ex Vivo Subnormothermic Machine Perfusion
Authors: Bhattacharjee Rabindra N. , Patel Sanjay V.B. , Sun Qizhi , Jiang Larry , Richard-Mohamed Mahms , Ruthirakanthan Aushanth , Aquil Shahid , Al-Ogaili Rafid , Juriasingani Smriti , Sener Alp , Luke Patrick P.W. 
Published: September 2019

Background.
The optimal method of oxygen delivery to donor kidneys during ex vivo machine perfusion has not been established. We have recently reported the beneficial effects of subnormothermic (22°C) blood perfusion in the preservation of porcine donation after circulatory death kidneys. Since using blood as a clinical perfusate has limitations, including matching availability and potential presence of pathogen, we sought to assess hemoglobin-based oxygen carrier (HBOC-201) in oxygen delivery to the kidney for renal protection.

Methods.
Pig kidneys (n = 5) were procured after 30 minutes of warm in situ ischemia by cross-clamping the renal arteries. Organs were flushed with histidine tryptophan ketoglutarate solution and subjected to static cold storage or pulsatile perfusion with an RM3 pump at 22°C for 4 hours with HBOC-201 and blood. Thereafter, kidneys were reperfused with normothermic (37°C) oxygenated blood for 4 hours. Blood and urine were subjected to biochemical analysis. Total urine output, urinary protein, albumin/creatinine ratio, flow rate, resistance were measured. Acute tubular necrosis, apoptosis, urinary kidney damage markers, neutrophil gelatinase-associated lipocalin 1, and interleukin 6 were also assessed.

Results.
HBOC-201 achieved tissues oxygen saturation equivalent to blood. Furthermore, upon reperfusion, HBOC-201 treated kidneys had similar renal blood flow and function compared with blood-treated kidneys. Histologically, HBOC-201 and blood-perfused kidneys had vastly reduced acute tubular necrosis scores and degrees of terminal deoxynucleotidyl transferase 2'-deoxyuridine, 5'-triphosphate nick end labeling staining versus kidneys treated with cold storage. Urinary damage markers and IL6 levels were similarly reduced by both blood and HBOC-201.

Conclusions.
HBOC-201 is an excellent alternative to blood as an oxygen-carrying molecule in an ex vivo subnormothermic machine perfusion platform in kidneys.
Too Much, Too Little, or Just Right? The Importance of Allograft Portal Flow in Deceased Donor Liver Transplantation
Authors: Matsushima Hajime , Sasaki Kazunari , Fujiki Masato , Uso Teresa Diago , Aucejo Federico , Kwon Choon Hyuck David , Eghtesad Bijan , Miller Charles , Quintini Cristiano , Hashimoto Koji 
Published: September 2019

Background.
While portal flow (PF) plays an important role in determining graft outcomes in living donor liver transplantation, its impact in deceased donor liver transplantation (DDLT) is unclear. The aim of this study was to investigate the correlations between graft PF and graft outcomes in DDLT.

Methods.
We retrospectively investigated 1001 patients who underwent DDLT between January 2007 and June 2017 at our institution. The patients were divided into 3 groups according to hazard ratio for 1-year graft loss at each PF value, which was standardized with graft weight. Graft and recipient outcomes were compared between the groups.

Results.
The low-PF group (PF < 65 mL/min/100 g, n = 210, P = 0.011) and the high-PF group (PF ≥ 155 mL/min/100 g, n = 159, P = 0.018) showed significantly poorer 1-year graft survival compared with the intermediate-PF group (PF ≥ 65 mL/min/100 g and < 155 mL/min/100 g, n = 632). The patients in the low-PF group had severe reperfusion injury and were more frequently complicated with primary nonfunction (P = 0.013) and early allograft dysfunction (P < 0.001) compared with the other groups. In contrast, the patients in the high-PF group had milder reperfusion injury, but had lower intraoperative hepatic artery flow with higher incidence of hepatic artery thrombosis (P = 0.043) and biliary complication (P = 0.041) compared with the other groups.

Conclusions.
These results suggest that intraoperative PF plays an important role in determining early graft outcomes after DDLT.
A unified sequence catalogue of over 280,000 genomes obtained from the human gut microbiome
Authors: Almeida Alexandre , Nayfach Stephen , Boland Miguel , Strozzi Francesco , Beracochea Martin , Shi Zhou Jason , Pollard Katherine S. , Parks Donovan H. , Hugenholtz Philip , Segata Nicola , Kyrpides Nikos C. , Finn Robert D. 
Published: September 2019

AbstractComprehensive reference data is essential for accurate taxonomic and functional characterization of the human gut microbiome. Here we present the Unified Human Gastrointestinal Genome (UHGG) collection, a resource combining 286,997 genomes representing 4,644 prokaryotic species from the human gut. These genomes contain over 625 million protein sequences used to generate the Unified Human Gastrointestinal Protein (UHGP) catalogue, a collection that more than doubles the number of gut protein clusters over the Integrated Gene Catalogue. We find that a large portion of the human gut microbiome remains to be fully explored, with over 70% of the UHGG species lacking cultured representatives, and 40% of the UHGP missing meaningful functional annotations. Intra-species genomic variation analyses revealed a large reservoir of accessory genes and single-nucleotide variants, many of which were specific to individual human populations. These freely available genomic resources should greatly facilitate investigations into the human gut microbiome.
RobNorm: Model-Based Robust Normalization Method for Labeled Quantitative Mass Spectrometry Proteomics Data
Authors: Wang Meng , Jiang Lihua , Jian Ruiqi , Chan Joanne Y. , Liu Qing , Snyder Michael P. , Tang Hua 
Published: September 2019

AbstractMotivationData normalization is an important step in processing proteomics data generated in mass spectrometry (MS) experiments, which aims to reduce sample-level variation and facilitate comparisons of samples. Previously published methods for normalization primarily depend on the assumption that the distribution of protein expression is similar across all samples. However, this assumption fails when the protein expression data is generated from heterogenous samples, such as from various tissue types. This led us to develop a novel data-driven method for improved normalization to correct the systematic bias meanwhile maintaining underlying biological heterogeneity.MethodsTo robustly correct the systematic bias, we used the density-power-weight method to down-weigh outliers and extended the one-dimensional robust fitting method described in the previous work of (Windham, 1995, Fujisawa and Eguchi, 2008) to our structured data. We then constructed a robustness criterion and developed a new normalization algorithm, called RobNorm.ResultsIn simulation studies and analysis of real data from the genotype-tissue expression (GTEx) project, we compared and evaluated the performance of RobNorm against other normalization methods. We found that the RobNorm approach exhibits the greatest reduction in systematic bias while maintaining across-tissue variation, especially for datasets from highly heterogeneous samples.Availabilityhttps://github.com/mwgrassgreen/RobNormContacthuatang@stanford.eduandmpsnyder@stanford.edu
Laminar-specific cortico-cortical loops in mouse visual cortex
Authors: Young Hedi , Belbut Beatriz , Baeta Margarida , Petreanu Leopoldo 
Published: September 2019

AbstractMany theories propose recurrent interactions across the cortical hierarchy, but it is unclear if cortical circuits are selectively wired to implement looped computations. Using subcellular channelrhodopsin-2-assisted circuit mapping in mouse visual cortex, we compared feedforward (FF) or feedback (FB) cortico-cortical input to cells projecting back to the input source (looped neurons) with cells projecting to a different cortical or subcortical area (non-looped neurons). Despite having different laminar innervation patterns, FF and FB afferents showed similar cell-type selectivity, making stronger connections with looped neurons versus non-looped neurons in layer (L) 5 and L6, but not in L2/3. FB inputs preferentially innervated the apical tufts of looped L5 neurons, but not their perisomatic dendrites. Our results reveal that interareal cortical connections are selectively wired into monosynaptic excitatory loops involving L6 and the apical dendrites of L5 neurons, supporting a role of these circuit elements in hierarchical recurrent computations.
An atlas of the tissue and blood metagenome in cancer reveals novel links between bacteria, viruses and cancer
Authors: Borchmann Sven 
Published: September 2019

ABSTRACTHost tissue infections by bacteria and viruses can cause cancer. Massively parallel sequencing now routinely generates datasets large enough to contain detectable traces of bacterial and viral nucleic acids of taxa that colonize the examined tissue or are integrated into the host genome. However, this hidden resource has not been comprehensively studied in large patient cohorts.In the present study, 3000 whole genome sequencing datasets are leveraged to gain insight into novel links between viruses, bacteria and cancer. The resulting map confirms known links and expands current knowledge by identifying novel associations. Moreover, the detection of certain bacteria or viruses is associated with profound differences in patient and tumor phenotypes, such as patient age, tumor stage, survival, somatic mutations in cancer genes or gene expression profiles.Overall, these results provide a detailed, unprecedented map of links between viruses, bacteria and cancer that can serve as a reference for future studies.
Surface association induces cytotoxic alkyl-quinolones in Pseudomonas aeruginosa
Authors: Vrla Geoffrey D. , Esposito Mark , Zhang Chen , Kang Yibin , Seyedsayamdost Mohammad R. , Gitai Zemer 
Published: September 2019

AbstractSurface attachment, an early step in the colonization of multiple host environments, activates the virulence of the human pathogen P. aeruginosa. However, the signaling pathways and downstream toxins specifically induced by surface association to stimulate P. aeruginosa virulence are not fully understood. Here, we demonstrate that alkyl-quinolone (AQ) secondary metabolites are rapidly induced upon surface association and represent a major class of surface-dependent cytotoxins. AQ cytotoxicity is direct and independent of other AQ functions like quorum sensing or PQS-specific activities like iron sequestration. Furthermore, the regulation of AQ production can explain the surface-dependent virulence regulation of the quorum sensing receptor, LasR, and the pilin-associated candidate mechanosensor, PilY1. PilY1 regulates surface-induced AQ production by repressing the AlgR-AlgZ two-component system. AQs also contribute to the known cytotoxicity of secreted outer membrane vesicles. These findings collectively explain previously mysterious aspects of virulence regulation and provide new avenues for the development of anti-infectives.
Ongoing surveillance protects tanoak whilst conserving biodiversity: applying optimal control theory to a spatial simulation model of sudden oak death
Authors: Bussell E.H. , Cunniffe N.J. 
Published: September 2019

AbstractThe sudden oak death epidemic in California is spreading uncontrollably. Large-scale eradication has been impossible for some time. However, small-scale disease management could still slow disease spread. Although empirical evidence suggests localised control could potentially be successful, mathematical models have said little about such management. By approximating a detailed, spatially-explicit simulation model of sudden oak death with a simpler, mathematically-tractable model, we demonstrate how optimal control theory can be used to unambiguously characterise effective time-dependent disease management strategies. We focus on protection of tanoak, a tree species which is culturally and ecologically important, but also highly susceptible to sudden oak death. We identify management strategies to protect tanoak in a newly-invaded forest stand, whilst also conserving biodiversity. We find that thinning of bay laurel is essential early in the epidemic. We apply model predictive control, a feedback strategy in which both the approximating model and the control are repeatedly updated as the epidemic progresses. Adapting optimal control strategies in this way is vital for effective disease management. This feedback strategy is robust to parameter uncertainty, limiting loss of tanoak in the worst-case scenarios. However, the methodology requires ongoing surveillance to re-optimise the approximating model. This introduces an optimal level of surveillance to balance the high costs of intensive surveys against improved management resulting from better estimates of disease progress. Our study shows how detailed simulation models can be coupled with optimal control theory and model predictive control to find effective control strategies for sudden oak death. We demonstrate that control strategies for sudden oak death must depend on local management goals, and that success relies on adaptive strategies that are updated via ongoing disease surveillance. The broad framework allowing the use of optimal control theory on complex simulation models is applicable to a wide range of systems.
Inhibition of the Myocardin-Related Transcription Factor pathway increases efficacy of Trametinib in NRAS-mutant melanoma cell lines
Authors: Appleton Kathryn M. , Palsuledesai Charuta C. , Misek Sean A. , Blake Maja , Zagorski Joseph , Dexheimer Thomas S. , Neubig Richard R. 
Published: September 2019

ABSTRACTThe Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (∼50% BRAFV600 mutations and ∼30% NRAS mutations). While targeted therapies have yielded success in BRAFV600 mutant melanoma patients, such therapies have been ineffective in NRAS mutant melanomas in part due to their cytostatic effects and primary resistance in this patient population. Here, we demonstrate that increased Rho/MRTF-pathway activation correlates with high intrinsic resistance to the MEK inhibitor, trametinib, in a panel of NRAS mutant melanoma cell lines. Combination of trametinib with the Rho/MRTF-pathway inhibitor, CCG-222740, synergistically reduced cell viability in NRAS mutant melanoma cell lines in vitro. Furthermore, the combination of CCG-222740 with trametinib induced apoptosis and reduced clonogenicity in SK-Mel-147 cells which have a high level of trametinib resistance. These findings suggest a role of the Rho/MRTF-pathway in intrinsic trametinib resistance in a subset of NRAS mutant melanoma cell lines and highlights the potential of concurrently targeting the Rho/MRTF-pathway and MEK in NRAS mutant melanomas.