bluuebunny/crossref_metadata_2025 huggingface dataset:
High crystalloid volumes negate benefit of hemostatic resuscitation in pediatric wartime trauma casualties
Authors: Schauer Steven G. , April Michael D. , Becker Tyson E. , Cap Andrew P. , Borgman Matthew A.
Published: January 2020

BACKGROUND

Recent data for adult trauma patients suggest improved survival when using hemostatic resuscitation, which includes limiting crystalloids and using closer to 1:1 ratios for both fresh frozen plasma (FFP) and platelets (PLTs) relative to packed red blood cells (PRBCs). Pediatric studies have shown similar but mixed results and often lack measuring crystalloids. We seek to evaluate in-hospital survival based on crystalloid administration and different blood product ratios in pediatric casualties during the recent conflicts.

METHODS

We queried the Department of Defense Trauma Registry for all pediatric encounters in Iraq and Afghanistan from January 2007 to January 2016 and included those with at least 40 mL/kg of total blood products administered provided that they received at least 1 U of PRBC. We grouped children as younger (0–7 years) and older (8–17 years). We grouped low versus high ratios for FFP/PRBC (≤1:2 vs. >1:2) and PLT/PRBC (≤1:6 vs. >1.6). We used a threshold of 40 mL/kg to for high versus low crystalloid resuscitation.

RESULTS

During this time, there were 3,439 encounters in the registry with 521 (15.1%) that met the inclusion criteria. The median age of casualties that met the inclusion was 10 years (interquartile range, 5–13), most were male (73.5%), with a moderate median injury severity score (17; interquartile range, 13–25). We performed regression modeling with adjustments for mechanism of injury, composite injury severity score, and total blood product volume (mL/kg based), grouping children based on high versus low fluid resuscitation. In the low-volume crystalloid group, we found that higher (>1:2) FFP/PRBC was associated with improved survival (odds ratio [OR], 3.42). However, in the high fluid crystalloid resuscitation group, we found that that higher ratios for PLT/PRBC (>1:6) overall (OR, 0.46) and the FFP/PRBC (>1:2) in younger children (OR, 0.28) was associated with worse survival. The remaining associations were not statistically significant.

CONCLUSION

We found an association with survival in massively transfused pediatric trauma patients who received both a high FFP/PRBC ratio and low crystalloid administration. The benefit of this high ratio is negated, in patients receiving high crystalloid volumes, particularly among smaller children. Future studies on hemostatic resuscitation evaluating blood product ratios should also account for crystalloid and colloid administration.

LEVEL OF EVIDENCE

Retrospective, comparative, level III.
Surveillance for HCC After Liver Transplantation: Increased Monitoring May Yield Aggressive Treatment Options and Improved Postrecurrence Survival
Authors: Lee David D. , Sapisochin Gonzalo , Mehta Neil , Gorgen Andre , Musto Kaitlyn R. , Hajda Hana , Yao Francis Y. , Hodge David O. , Carter Rickey E. , Harnois Denise M.
Published: January 2020

Background.

Currently, no surveillance guidelines for hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) exist. In this retrospective, multicenter study, we have investigated the role of surveillance imaging on postrecurrence outcomes.

Methods.

Patients with recurrent HCC after LT from 2002 to 2016 were reviewed from 3 transplant centers (University of California San Francisco, Mayo Clinic Florida, and University of Toronto). For this study, we proposed the term cumulative exposure to surveillance (CETS) as a way to define the cumulative sum of all the protected intervals that each surveillance test provides. In our analysis, CETS has been treated as a continuous variable in months.

Results.

Two hundred twenty-three patients from 3 centers had recurrent HCC post-LT. The median follow-up was 31.3 months, and median time to recurrence was 13.3 months. Increasing CETS was associated with improved postrecurrence survival (hazard ratio, 0.94; P < 0.01) as was treatment of recurrence with resection or ablation (hazard ratio, 0.31; P < 0.001). An receiver operating characteristic curve (area under the curve, 0.64) for CETS covariate showed that 252 days of coverage (or 3 surveillance scans) within the first 24 months provided the highest probability for aggressive postrecurrence treatment.

Conclusions.

In this review of 223 patients with post-LT HCC recurrence, we found that increasing CETS does lead to improved postrecurrence survival as well as a higher probability for aggressive recurrence treatment. We found that 252 days of monitoring (ie, 3 surveillance scans) in the first 24 months was associated with the ability to offer potentially curative treatment.
Antidepressant Effect of Adjunct Repetitive Transcranial Magnetic Stimulation in Inpatients 60 Years and Older
Authors: Qiao Ying , Wang JunJie , Zhu JunJuan , Cui HuiRu , Tang YingYing , Xu LiHua , Tang XiaoChen , Wei YanYan , Hui Li , Li ChunBo , Jia QiuFang , Zhu HongLiang , Wen Hui , Wang JiJun , Zhang TianHong
Published: January 2020

Background

Repetitive transcranial magnetic stimulation (rTMS) is now an established, safe, and effective treatment for adults with depression. However, specific research in rTMS for use in elderly patients with acute depression is scarce.

Objective

The aim of the present study was to investigate the efficacy of add-on rTMS in a clinical sample of older adults experiencing an acute phase of depression.

Method

This study examined 114 patients (54 elderly [aged ≥60] and 60 adults [aged 18–59]) with acute depression who were drug free at baseline. They were treated with at least 10 sessions of rTMS for 4 weeks along with 1 antidepressant. Symptoms of depression were measured using the Hamilton Rating Scale for Depression at baseline and after 2 and 4 weeks of treatment. Clinical improvement and rates of response and remission were compared across groups.

Results

Significant improvement was noted after 2 and 4 weeks of treatment in both adult and elderly groups. Higher remission rates were found in adult patients but with no differences in response. The stimulation intensity and course of illness were significant predictors of remission after 4 weeks of rTMS treatment in the elderly.

Conclusions

The add-on rTMS treatment for elderly depression patients is promising with respect to safety and feasibility. This preliminary evidence supports the application of rTMS to this group during acute episodes.
Prospective Single Center Cohort Study for Early Diagnosis of Cardiac Dysfunction in Swiss Childhood Cancer Survivors: A Study Protocol
Authors: Schindera Christina , Kuehni Claudia E. , Pavlovic Mladen , Haegler-Laube Eva , Waespe Nicolas , Roessler Jochen , Suter Thomas M. , von der Weid Nicolas X.
Published: January 2020

Introduction

Cardiovascular disease is the leading nonmalignant cause of late deaths in childhood cancer survivors. Cardiovascular disease and cardiac dysfunction can remain asymptomatic for many years, but eventually lead to progressive disease with high morbidity and mortality. Early detection and intervention are therefore crucial to improve outcome. In our study, we aim to 1) assess the prevalence of early cardiac dysfunction in adult childhood cancer survivors using conventional and speckle tracking echocardiography, 2) determine the association between cardiac dysfunction and treatment-related risk factors (anthracyclines, alkylating agents, steroids, cardiac radiation) and modifiable cardiovascular risk factors (abdominal obesity, hypertension), 3) investigate the development of cardiac dysfunction longitudinally in a defined cohort, 4) study the association between cardiac dysfunction and other health outcomes like pulmonary, endocrine, and renal diseases, quality of life, fatigue, strength and endurance, and physical activity, and 5) gain experience conducting a clinical study of childhood cancer survivors that will be extended to a national, multicenter study of cardiac complications.

Methods

We will invite ≥5 year childhood cancer survivors who were treated at the University Children’s Hospital Bern, Switzerland with any chemotherapy and/or cardiac radiation since 1976 and who are ≥18 years of age at time of study for a cardiac assessment at the University Hospital Bern. This includes overall 544 childhood cancer survivors, of whom about half were treated with anthracyclines and/or cardiac radiation and half with any other chemotherapy. The standardized cardiac assessment includes a medical history focusing on signs of cardiovascular disease and its risk factors, a physical examination, anthropometry, vital parameters, the 1-minute sit-to-stand test, and an echocardiography including speckle tracking.

Results

We will invite 544 eligible childhood cancer survivors for a cardiac assessment with a median age at study of 32.5 years and a median times since diagnosis of 25.0 years. Three hundred survivors (55%) are at high risk and 244 survivors (45%) are at standard risk for cardiac dysfunction.

Discussion

The results of this study will show the prevalence of early cardiac dysfunction in Swiss childhood cancer survivors, inform whether speckle tracking echocardiography is more sensitive to cardiac dysfunction than conventional echocardiography, and give a detailed picture of risk factors for cardiac dysfunction. The results will help improve primary treatment and follow-up care of children suffering from cancer.

Trial registration

Prospectively registered in ClinicalTrials.gov, Identifier: NCT03790943, registration date 25.06.2018.
Ideal Cardiovascular Health in Urban Jamaica: Prevalence Estimates and Relationship to Community Property Value, Household Assets and Educational Attainment
Authors: McKenzie Joette A. , Younger-Coleman Novie O. , Tulloch-Reid Marshall K. , Govia Ishtar , Bennett Nadia R. , McFarlane Shelly R. , Walters Renee , Francis Damian K. , Webster-Kerr Karen , Grant Andriene , Davidson Tamu , Wilks Rainford J. , Williams David R. , Ferguson Trevor S.
Published: January 2020

BACKGROUND

Ideal cardiovascular health (ICH) is associated with greater longevity and reduced morbidity, but no research on ICH has been conducted in Jamaica. We estimated the prevalence of ICH in urban Jamaica and evaluated associations between ICH and community, household and individual socioeconomic status (SES).

METHODS

Cross-sectional study using data from 360 men and 665 women, age ≥20 years in urban Jamaica. ICH was defined as having seven characteristics: current non-smoking, healthy diet, moderate physical activity, and normal body mass index, blood pressure, glucose, and cholesterol. Logistic regression, weighted for survey design, quantified association between the outcome (≥5 ICH characteristics [ICH-5]), and exposure variables (tertiles of community median land value [MLV], tertiles of household assets and educational attainment).

RESULTS

Prevalence of ICH (7 characteristics) was 0.51%, while prevalence of ICH-5 was 22.9% (male 24.5%, female 21.5%, p=0.447). In sex-specific multivariable models adjusted for age, education, and household assets, men in the lower tertiles of community MLV had lower odds of ICH-5 compared to men in the upper tertile (lowest tertile: OR 0.33, 95%CI 0.12-0.91, p=0.032; middle tertile: OR 0.46 (0.20-1.04) p=0.062). Women from communities in the lower and middle tertiles of MLV also had lower odds of ICH-5, but association was not statistically significant. Educational attainment was inversely associated with ICH-5 among men and positively associated among women. No significant association was seen for household assets.

CONCLUSION

Prevalence of ICH is low in urban Jamaica. Living in poorer communities was associated with lower odds of ICH-5 among men. Higher education was associated with higher odds of ICH-5 among women but lowers odds among men.
Locus coeruleus pathology in progressive supranuclear palsy, and its relation to disease severity
Authors: Kaalund Sanne Simone , Passamonti Luca , Allinson Kieren SJ , Murley Alexander G , Robbins Trevor W , Spillantini Maria Grazia , Rowe James B
Published: January 2020

The locus coeruleus is the major source of noradrenaline to the brain and contributes to a wide range of physiological and cognitive functions including arousal, attention, autonomic control, and adaptive behaviour. Neurodegeneration and pathological aggregation of tau protein in the locus coeruleus are early features of progressive supranuclear palsy (PSP). This pathology is proposed to contribute to the clinical expression of disease, including the PSP Richardson’s syndrome. We test the hypothesis that tau pathology and neuronal loss are associated with clinical heterogeneity and severity in PSP.

We used immunohistochemistry in post mortem tissues from 31 patients with a clinical diagnosis of PSP (22 with Richardson’s syndrome) and 6 control cases. We quantified the presence of hyperphosphorylated tau, the number of pigmented cells indicative of noradrenergic neurons, and the percentage of pigmented neurons with tau-positive inclusions. Ante mortem assessment of clinical severity using the PSP rating scale was available within 1.8 (±0.9) years for 23 patients.

We found an average 49% reduction of pigmented neurons in PSP patients relative to controls. The loss of pigmented neurons correlated with disease severity, even after adjusting for disease duration and the interval between clinical assessment and death. The degree of neuronal loss was associated with tau-positive inclusions, with an average of 44% of pigmented neurons displaying tau-inclusions.

Degeneration and tau pathology in the locus coeruleus are related to clinical heterogeneity of PSP. The noradrenergic deficit in the locus coeruleus is a candidate target for pharmacological treatment. Recent developments in ultra-high field magnetic resonance imaging to quantify in vivo structural integrity of the locus coeruleus may provide biomarkers for noradrenergic experimental medicines studies in PSP.
Prognostic Imaging Biomarkers for Diabetic Kidney Disease (iBEAt): Study protocol
Authors: Gooding Kim M , Lienczewski Chrysta , Papale Massimo , Koivuviita Niina , Maziarz Marlena , Andersson Anna-Maria Dutius , Sharma Kanishka , Pontrelli Paola , Hernandez Alberto Garcia , Bailey Julie , Tobin Kay , Saunavaara Virva , Zetterqvist Anna , Shelley David , Teh Irvin , Ball Claire , Puppala Sapna , Ibberson Mark , Karihaloo Anil , Metsärinne Kaj , Banks Rosamonde , Gilmour Peter S , Mansfield Michael , Gilchrist Mark , de Zeeuw Dick , Heerspink Hiddo J.L. , Nuutila Pirjo , Kretzler Matthias , Wellberry-Smith Matthew , Gesualdo Loreto , Andress Dennis , Grenier Nicolas , Shore Angela C , Gomez Maria F. , Sourbron Steven ,   iBEAt investigators
Published: January 2020

Diabetic kidney disease (DKD) is traditionally classified based on albuminuria and reduced kidney function (estimated glomerular filtration rate (eGFR)), but these have limitations as prognostic biomarkers due to the heterogeneity of DKD. Novel prognostic markers are needed to improve stratification of patients based on risk of disease progression.

The iBEAT study, part of the BEAt-DKD consortium, aims to determine whether renal imaging biomarkers (magnetic resonance imaging (MRI) and ultrasound (US)) provide insight into the pathogenesis and heterogeneity of DKD (primary aim), and whether they have potential as prognostic biomarkers in DKD progression (secondary aim).

iBEAT is a prospective multi-centre observational cohort study recruiting 500 patients with type 2 diabetes (T2D) and eGFR > 30ml/min/1.73m2. At baseline each participant will undergo quantitative renal MRI and US imaging with central processing for MRI images. Blood sampling, urine collection and clinical examinations will be performed and medical history obtained at baseline, and these assessments will be repeated annually for 3 years. Biological samples will be stored in a central laboratory for later biomarker and validation studies. All data will be stored in a central data depository. Data analysis will explore the potential associations between imaging biomarkers and renal function, and whether the imaging biomarkers may improve the prediction of DKD progression rates.

Embedded within iBEAT are ancillary substudies that will (1) validate imaging biomarkers against renal histopathology; (2) validate MRI based renal blood flow against water-labelled positron-emission tomography (PET); (3) develop machine-learning methods for automated processing of renal MRI images; (4) examine longitudinal changes in imaging biomarkers; (5) examine whether the glycocalyx, microvascular function and structure are associated with imaging biomarkers and eGFR decline; (6) a pilot study to examine whether the findings in T2D can be extrapolated to type 1 diabetes.

The iBEAT study, the largest DKD imaging study to date, will provide invaluable insights into the progression and heterogeneity of DKD, and aims to contribute to a more personalized approach to the management of DKD in patients with type 2 diabetes.
Common genetic risk variants identified in the SPARK cohort implicate DDHD2 as a novel autism risk gene
Authors: Matoba Nana , Liang Dan , Sun Huaigu , Aygün Nil , McAfee Jessica C. , Davis Jessica E. , Raffield Laura M. , Qian Huijun , Piven Joseph , Li Yun , Kosuri Sriam , Won Hyejung , Stein Jason L.
Published: January 2020

Background

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder. Large genetically informative cohorts of individuals with ASD have led to the identification of three common genome-wide significant (GWS) risk loci to date. However, many more common genetic variants are expected to contribute to ASD risk given the high heritability. Here, we performed a genome-wide association study (GWAS) using the Simons Foundation Powering Autism Research for Knowledge (SPARK) dataset to identify additional common genetic risk factors and molecular mechanisms underlying risk for ASD.

Methods

We performed an association study on 6,222 case-pseudocontrol pairs from SPARK and meta-analyzed with a previous GWAS. We integrated gene regulatory annotations to map non-coding risk variants to their regulated genes. Further, we performed a massively parallel reporter assay (MPRA) to identify causal variant(s) within a novel risk locus.

Results

We identified one novel GWS locus from the SPARK GWAS. The meta-analysis identified four significant loci, including an additional novel locus. We observed significant enrichment of ASD heritability within regulatory regions of the developing cortex, indicating that disruption of gene regulation during neurodevelopment is critical for ASD risk. The MPRA identified one variant at the novel locus with strong impacts on gene regulation (rs7001340), and expression quantitative trait loci data demonstrated an association between the risk allele and decreased expression of DDHD2 (DDHD domain containing 2) in both adult and pre-natal brains.

Conclusions

By integrating genetic association data with multi-omic gene regulatory annotations and experimental validation, we fine-mapped a causal risk variant and demonstrated that DDHD2 is a novel gene associated with ASD risk.
Crowdsourcing digital health measures to predict Parkinson’s disease severity: the Parkinson’s Disease Digital Biomarker DREAM Challenge
Authors: Sieberts Solveig K. , Schaff Jennifer , Duda Marlena , Pataki Bálint Ármin , Sun Ming , Snyder Phil , Daneault Jean-Francois , Parisi Federico , Costante Gianluca , Rubin Udi , Banda Peter , Chae Yooree , Chaibub Neto Elias , Dorsey E. Ray , Aydın Zafer , Chen Aipeng , Elo Laura L. , Espino Carlos , Glaab Enrico , Goan Ethan , Golabchi Fatemeh Noushin , Görmez Yasin , Jaakkola Maria K. , Jonnagaddala Jitendra , Klén Riku , Li Dongmei , McDaniel Christian , Perrin Dimitri , Perumal Thanneer M. , Rad Nastaran Mohammadian , Rainaldi Erin , Sapienza Stefano , Schwab Patrick , Shokhirev Nikolai , Venäläinen Mikko S. , Vergara-Diaz Gloria , Zhang Yuqian ,   the Parkinson’s Disease Digital Biomarker Challenge Consortium, Wang Yuanjia , Guan Yuanfang , Brunner Daniela , Bonato Paolo , Mangravite Lara M. , Omberg Larsson
Published: January 2020

Mobile health, the collection of data using wearables and sensors, is a rapidly growing field in health research with many applications. Deriving validated measures of disease and severity that can be used clinically or as outcome measures in clinical trials, referred to as digital biomarkers, has proven difficult. In part due to the complicated analytical approaches necessary to develop these metrics. Here we describe the use of crowdsourcing to specifically evaluate and benchmark features derived from accelerometer and gyroscope data in two different datasets to predict the presence of Parkinson’s Disease (PD) and severity of three PD symptoms: tremor, dyskinesia and bradykinesia. Forty teams from around the world submitted features, and achieved drastically improved predictive performance for PD status (best AUROC=0.87), as well as tremor (best AUPR=0.75), dyskinesia (best AUPR=0.48) and bradykinesia (best AUPR=0.95) severity.
Nivolumab and Ipilimumab in Metastatic Melanoma Are Associated with Distinct Immune Landscape Changes and Response-Associated Immunophenotypes
Authors: Woods DM , Laino AS , Winters A , Alexandre J , Rao V , Adavani SS , Weber JS , Chattopadhyay PK
Published: January 2020

The reshaping of the immune landscape by nivolumab (NIVO) and ipilimumab (IPI) and its relation to patient outcomes is not well-described. We used high-parameter flow cytometry and a novel computational platform, CytoBrute, to define immunophenotypes of up to 15 markers to assess peripheral blood samples from metastatic melanoma patients receiving sequential NIVO>IPI or IPI>NIVO. The two treatments were associated with distinct immunophenotypic changes and had differing profiles associated with response. Only two immunophenotypes were shared but had opposing relationships to response/survival. To understand the impact of sequential treatment on response/survival, phenotypes that changed after the initial treatment and differentiated response in the other cohort were identified. Immunophenotypic changes occurring post-NIVO were predominately associated with response to IPI>NIVO, but changes occurring post-IPI were predominately associated with progression with NIVO>IPI. Among these changes, CD4+CD38+CD39+CD127-GARP- T-cell subsets were increased after IPI treatment and were negatively associated with response/survival for the NIVO>IPI cohort.
Controlling water hyacinth infestation in Lake Tana using Fungal pathogen from Laboratory level upto pilot scale
Authors: Admas Adugnaw , Sahile Samuel , Agidie Aklilu , Menale Hailu , Gedefaw Tadelo , Teshome Menberu
Published: January 2020

Water hyacinth (Eichhornia crassipes) is one of the most dangerous aquatic weeds for Lake Tana and other water body in Ethiopia. To reduce its invasion biological, chemical and physical control methods can be used. Use of natural biological enemies of the weed to discourage its propagation is one of the best recommended options by scientfic society. Among them, there are more fungi naturally a pathogen for water hyacinth and other plants. To use those patogenes to manage water hyacinth infestation in Lake Tana infected plant material by fungi were collected from three weredas (Amba Gyorgese, Dabat and Debarke) around Gondar at 20 Peasant associations (PAs) since Novmber 2015. The collection was done from infected Faba bean leaves and roots. All isolated fungus was attempted to infect the collected healthy water hyacinth in laboratory and green house. Among isolated fungus species Rhizoctonia solani, Aspergillus flatus, Tricothcium roseum, Fusarium spp and Aspergillus niger fungi show high moderate disease severity on the healthy water hyacinth at temporarey green house and laboratory. Disease severity scale was recorded using modified NAHEMA et al. (200). By following those experiments to show its efficiency, the effective pathogens on laboratory and green house were released to 16 m2 open ponds since September 2016, in University of Gondar. In this study, we have recorded scientific data that shows the fungi were high potencial to attack healthy water hyacinth at above 26 oc and at less than 25 % humidity. From this research also we have observed the most infected water hyacinth by fungi have not produced flower and it can not re generate by seed in the next propagation sesaon.Finally, before directly release the fungi on Lake Tana its impacts were studied in the Goregora, at Kuame Michel kebela for a year in open ponds and in controlled wet land areas that not linked to the Lake by taking some common aquatic plants and fish from the Lake. Fortunatelly, those fungi have not impact on aquatic plant like Echinochloa and Cyperus papyrus grass, water quality and fish.
Dispersal limitation and fire feedbacks maintain mesic savannas in Madagascar
Authors: Goel Nikunj , Van Vleck Erik , Aleman Julie C. , Staver A. Carla
Published: January 2020

Madagascar is regarded by some as one of the most degraded landscapes on Earth, with estimates suggesting that 90% of forests have been lost to indigenous Tavy farming. However, the extent of this degradation has been challenged: paleoecological data, phylogeographic analysis, and species diversity maps indicate that pyrogenic savannas in Central Madagascar pre-date human arrival, even though rainfall is sufficient to allow forest expansion into Central Madagascar. These observations raise a question—if savannas in Madagascar are not anthropogenic, how then are they maintained in regions where the climate can support forest? Observation reveals that the savanna-forest boundary coincides with a dispersal barrier—the escarpment of the Central Plateau. Using a stepping-stone model, we show that in a limited dispersal landscape, a stable savanna-forest boundary can form due to fire-vegetation feedbacks. This novel phenomenon, referred to as range pinning, could explain why eastern lowland forests have not expanded into the mesic savannas of the Central Highlands. This work challenges the view that highland savannas in Madagascar are derived by human-lit fires and, more importantly, suggests that partial dispersal barriers and strong non-linear feedbacks can pin biogeographical boundaries over a wide range of environmental conditions, providing a temporary buffer against climate change.
Chemical constituents involved in e-cigarette, or vaping product use-associated lung injury (EVALI)
Authors: Muthumalage Thivanka , Friedman Michelle R. , McGraw Matthew D. , Friedman Alan E. , Rahman Irfan
Published: January 2020

Background

The Centers for Disease Control (CDC) declared e-cigarette (e-cig), or vaping product use-associated lung injury (EVALI) a national outbreak due to the high incidence of emergency department admissions and deaths. Investigators have identified vitamin E acetate (VEA) as the plausible cause for EVALI, based on compounds found in bronchoalveolar lavage fluid.

Objectives

We defined the chemical constituents present in e-cig cartridges associated with EVALI and compared constituents to medical-grade and cannabidiol (CBD) containing cartridges.

Methods

We measured chemicals and elemental metals in e-liquid and vapor phases of e-cig counterfeit cartridges by Gas Chromatography (GC) and Mass Spectrometry (MS), EPA method TO-15 by GCMS, and ICP-MS analysis.

Results

We have identified chemical constituents in e-cig vaping tetrahydrocannabinol (THC)-containing counterfeit cartridges compared to medical-grade and cannabidiol (CBD) containing cartridges. Apart from VEA and THC, other potential toxicants correlated with EVALI included solvent-derived hydrocarbons, silicon conjugated compounds, various terpenes, pesticides/plasticizers/polycaprolactones, and metals. These chemicals are known to cause symptoms, such as cough, shortness of breath or chest pain, nausea, vomiting or diarrhea, fatigue, fever, or weight loss, all symptoms presenting in patients with EVALI.

Conclusion

This study provides insights into understanding the chemical-induced disease mechanism of acute lung injury.
Removable cranial window for sustained wide-field optical imaging in mouse neocortex
Authors: Cha Susie S. , Bucklin Mark E. , Han Xue
Published: January 2020

Attempts to image neocortical regions on the surface of mouse brain typically use a small glass disc attached to the cranial surface. This approach, however, is often challenged by progressive deterioration in optical quality and permits limited tissue access after its initial implantation. Here we describe a design and demonstrate a two-stage cranial implant device developed with a remarkably versatile material, polydimethylsiloxane, which facilitates longitudinal imaging experiments in mouse cortex. The system was designed considering biocompatibility and optical performance. This enabled us to achieve sustained periods of optical quality, extending beyond a year in some mice, and allows imaging at high spatio-temporal resolution using wide-field microscopy. Additionally, the two-part system, consisting of a fixed headplate with integrated neural access chamber and optical insert, allowed flexible access to the underlying tissue offering an expansive toolbox of neuromanipulation possibilities. Finally, we demonstrate the technical feasibility of rapid adaptation of the system to accommodate varying applications requiring long-term ability to visualize and access neural tissue. This capability will drastically reduce wasted time and resources for experiments of any duration, and will facilitate previously infeasible studies requiring long-term observation such as for research in aging or the progression chronic neurological disorders.
Should I shrink or should I flow? – body size adjustment to thermo-oxygenic niche
Authors: Walczyńska Aleksandra , Gudowska Agnieszka , Sobczyk Łukasz
Published: January 2020

Organisms adjust their size according to temperature and supposedly also respond to its negative covariate, oxygen. To what extent is size a response to temperature or oxygen? We analyzed the thermo-oxygenic niche for the community of 188 rotifer species. Evolution toward ranges of thermal tolerance occurred separately from evolution toward their optima. Body size was adjusted to both temperature and oxygen, but the cues for body size response differed; size was either driven by optimal temperatures or by the oxygen tolerance range. Animals are clearly separated into generalists or specialists, and their evolutionary body size adjustment is realized through differential responses to environmental factors. Oxygen is as important as temperature in the evolution of body size and ecological niche preference. An important conclusion from this study is that oxygen deprivation following global warming seems to be as problematic for the studied organisms as the temperature increase itself.
Quantifying Epithelial Plasticity as a Platform to Reverse Epithelial Injury
Authors: Nishida Kristine , Ghosh Baishakhi , Chandrala Lakshmana , Mahmud Saborny , Chen Si , Khosla Atulya Aman , Katz Joseph , Sidhaye Venkataramana K.
Published: January 2020

Epithelial surfaces lining the lung serve as the primary environmental gaseous interface, and are subject to common life-limiting diseases, including COPD (Chronic Obstructive Pulmonary Disease). Despite the critical role of epithelial cells in pulmonary health and disease, quantitative models are lacking but are required given the large patient to patient variability to characterize the epithelial plasticity that follows injury. We have identified a series of assessments to quantitatively identify the changes that occur in the epithelium and to identify targets that reverse injury. The injured epithelium has decreased ciliary function and monolayer height, which in the case of cells derived from COPD patients results in an overall disorganization of structure. Injury causes the cells to shift to an unjammed state, with corresponding increases in the velocity correlation length implicating cell shape and stiffness as fundamental to the injury response. Specific inhibitors of actin polymerization (LatA), of MAPK/ERK kinase (U0126) and Nrf-2 pathway activation (CDDO-Me) push the epithelium back towards a jammed state with decreased cell movement and correlation length, as well as improve barrier function and CBF. These studies attest to cell intrinsic properties that allow for a transition to an unjammed state, and that quantitative phenotypic analysis can identify potential specific pharmacologic targets in a given patient and provide insight into basic mechanisms of cellular damage.

One Sentence Summary

Environmental toxins undermine tissue integrity by manipulating transitions from jammed to unjammed states, thereby mimicking or inducing disease.
Distinct components of photoperiodic light are differentially encoded by the mammalian circadian clock
Authors: Tackenberg Michael C. , Hughey Jacob J. , McMahon Douglas G.
Published: January 2020

Seasonal light cycles influence multiple physiological functions and are mediated through photoperiodic encoding by the circadian system. Despite our knowledge of the strong connection between seasonal light input and downstream circadian changes, less is known about the specific components of seasonal light cycles that are encoded and induce persistent changes in the circadian system. Using combinations of three T cycles (23, 24, 26 hr.) and two photoperiods per T cycle (Long and Short, with duty cycles scaled to each T cycle), we investigate after-effects of entrainment to these six light cycles. We measure locomotor behavior duration (α), period (τ), and entrained phase angle (Ψ)in vivo, and SCN phase distribution (σϕ), τ, and Ψex vivoin order to refine our understanding of critical light components for influencing particular circadian properties. We find that photoperiod and T cycle length both drive determination ofin vivoΨ but differentially influence after-effects in α and τ, with photoperiod driving changes in α and photoperiod length and T cycle length combining to influence τ. Using skeleton photoperiods, we demonstrate thatin vivoΨ is determined by both parametric and non-parametric components, while changes in α are driven non-parametrically. Within theex vivoSCN, we find that Ψ and σϕof the PER2∷LUCIFERASE rhythm follow closely with their likely behavioral counterparts (Ψ and α of the locomotor activity rhythm), while also confirming previous reports of τ after-effects of gene expression rhythms showing negative correlations with behavioral τ after-effects in response to T cycles. We demonstrate that within-SCN σϕchanges, thought to underly α changesin vivo, are induced primarily non-parametrically. Taken together, our results demonstrate distinct components of seasonal light input differentially influence Ψ, α, and τ, and suggest the possibility of separate mechanisms driving the persistent changes in circadian behaviors mediated by seasonal light.
25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner
Authors: Wong Man Ying , Lewis Michael , Doherty James J. , Shi Yang , Sullivan Patrick M. , Qian Mingxing , Covey Douglas F. , Petsko Gregory A. , Holtzman David M. , Paul Steven M. , Luo Wenjie
Published: January 2020

Genome-wide association studies associated with Alzheimer’s disease (AD) have implicated pathways related to both lipid homeostasis and innate immunity in the pathophysiology of AD. However, the exact cellular and chemical mediators of neuroinflammation in AD remain poorly understood. The oxysterol 25-hydroxycholesterol (25-HC) is an important immunomodulator produced by peripheral macrophages with wide-ranging effects on cell signaling and innate immunity. Genetic variants of the enzyme responsible for 25-HC production, cholesterol 25-hydroxylase (CH25H), have been found to be associated with AD. In the present study, we found that the CH25H expression is upregulated in human AD brain tissue and in transgenic mouse brain tissue bearing amyloid-β (Aβ) plaques or tau pathology. Treatment with the toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) markedly upregulates CH25H expression in the mouse brainin vivo. LPS also stimulates CH25H expression and 25-HC secretion in cultured mouse primary microglia. We also found that LPS-induced microglial production of the pro-inflammatory cytokine IL1β is markedly potentiated by 25-HC and attenuated by genetic deletion of CH25H. Microglia expressing apolipoprotein E4 (apoE4), a genetic risk factor for AD, produce greater amounts of 25-HC than apoE3-expressing microglia following treatment with LPS. Remarkably, treatment of microglia with 25-HC results in a much greater level of IL1β secretion in LPS-activated apoE4-expressing microglia than in apoE2- or apoE3-expressing microglia. Blocking potassium efflux or inhibiting caspase-1 prevents 25-HC-potentiated IL1β release in apoE4-expressing microglia, indicating the involvement of caspase-1/NLRP3 inflammasome activity. 25-HC may function as a microglial secreted inflammatory mediator in brain, promoting IL1β-mediated neuroinflammation in an apoE isoform-dependent manner (E4≫E2/E3) and thus may be an important mediator of neuroinflammation in AD.
Sex differences in cardiometabolic traits at four life stages: cohort study with repeated metabolomics
Authors: Bell Joshua A. , Santos Ferreira Diana L. , Fraser Abigail , Soares Ana Luiza G. , Howe Laura D. , Lawlor Deborah A. , Carslake David , Smith George Davey , O’Keeffe Linda M.
Published: January 2020

Background

Males experience higher rates of coronary heart disease (CHD) than females, but the circulating traits underpinning this difference are poorly understood. We examined sex differences in detailed cardiometabolic traits measured at four life stages, spanning childhood to middle adulthood.

Methods and Results

Data were from the Avon Longitudinal Study of Parents and Children cohort study. 229 traits quantified from targeted metabolomics (nuclear magnetic resonance spectroscopy) including lipoprotein subclass-specific cholesterol and triglycerides, amino acids, glucose, and inflammatory glycoprotein acetyls were measured repeatedly in offspring (Generation 1 (G1)) born in 1991-92 and once in their parents (Generation 0 (G0)). Measurements in G1 were once in childhood (mean age 8y), twice in adolescence (16y and 18y) and once in early adulthood (25y), and in G0 once in middle adulthood (50y). Linear regression models were used to examine differences in standardized traits for males compared with females on each occasion (serial cross-sectional associations). 7,727 G1s (49% male) and 6,500 G0s (29% male) contributed to analyses. At age 8y, total lipids in very-low-density lipoproteins (VLDL) were lower in males than females; levels were higher in males than females at age 16y and were higher still by age 18y and age 50y (in G0) for medium-or-larger subclasses. Larger sex differences at older ages were most pronounced for triglycerides in VLDL – e.g. male levels were 0.19 standard deviation (SD) units (95% CI=0.12, 0.26) higher at age 18y, 0.50 SD (95% CI=0.42, 0.57) higher at age 25y, and 0.62 SD (95% CI=0.55, 0.68) higher at age 50y. Cholesterol in VLDL and low-density lipoproteins (LDL) was generally lower in males, with inconsistent sex differences across ages. Apolipoprotein-B was generally lower in males than females. Branched chain amino acids were consistently higher in males after age 8y with the largest sex difference of all traits at all ages seen for leucine at age 50y (1.53 SD, 95% CI=1.47, 1.58 higher in males compared with females). Males had consistently lower glycoprotein acetyls across ages.

Conclusions

Our results suggest that males begin to have higher VLDL triglycerides in adolescence, and that this sex difference is larger at older ages. Sex differences in other CHD-related traits, including LDL cholesterol, apolipoprotein-B, and inflammatory glycoproteins, show the opposite pattern with age, with higher levels among females. Higher triglyceride content may therefore be a key factor underpinning the higher age-adjusted rate of CHD among males; causal analyses of this and other traits are needed to understand whether they differentially affect CHD risk among males and females.
Association Between Reduced Handgrip Strength and Commonly Prescribed Medications
Authors: Love Bryan L. , Mitchell Erin M. , Norris LeAnn B.
Published: January 2020

Decreased handgrip-strength has become an increasingly important measure of overall health status and fitness. This was a cross-sectional analysis among adult participants in the 2011-2012 NHANES survey. Handgrip-strength was assessed using a digital dynamometer and a standard protocol, and medication use was assessed by self-report and verification by the interviewer. Mean handgrip-strength among participants with no medication use was 87.2kg in males and 57.2kg in females. Handgrip strength decreased significantly in both men and women (ptrend<0.001 for both) with increasing medication use after adjustment for age, sex, height, arm circumference, and BMI. Statins, ACE-inhibitors, ARBs, diuretics, calcium channel blockers, and sulfonylureas showed a consistent and significant decrease in grip strength in linear regression models. In this nationally representative survey of adults in the US, we observed a negative relationship between handgrip strength and polypharmacy. Further, several specific medications, mostly cardiovascular drug classes, were associated with reduced handgrip-strength.
Immune-checkpoint engagement as predictive biomarkers in clear cell renal cell carcinoma and melanoma
Authors: Sánchez-Magraner Lissete , Miles James , Baker Claire , Applebee Christopher J , Lee Dae-Jin , Elsheikh Somaia , Lashin Shaimaa , Withers Katriona , Watts Andrew , Parry Richard , Edmead Christine , Lopez Jose Ignacio , Mehta Raj , Ward Stephen G , Parker Peter J. , Larijani Banafshé
Published: January 2020

Many cancers are termed immuno-evasive due to expression of immuno-modulatory ligands. Programmed death ligand-1 (PD-L1) and cluster of differentiation 80/86 (CD80/86) interact with their receptors, programmed death receptor-1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4), on tumour infiltrating leukocytes, thus eliciting immunosuppression. Immunotherapies aimed at blocking these interactions are revolutionising cancer treatments, albeit in an inadequately described patient subset.

Our prognostic assay, utilising amplified two-site time-resolved Förster resonance energy transfer (iFRET), quantifies PD-1/ PD-L1 and CTLA-4/ CD80 cell-cell interactions in single cell assays and tumour biopsies. iFRET efficiencies demonstrate, in cell-cell engagement models, that receptor-ligand interactions are significantly lower with anti-PD-1 or anti-CTLA-4 blocking antibodies. In patient samples, iFRET detects immune-cell/tumour-cell interaction variance in different cancers. These results revealed inter-cancer, inter-patient and intra-tumoural heterogeneity of engaged immune-checkpoints, contradicting their ligand expression patterns. Exploiting spatio-temporal interactions of immune-checkpoint proteins defined biomarker functionality for determining whether checkpoint inhibitors are appropriate treatments.

Statement of Significance

Quantitative photophysics exploitation in determining immune-checkpoint engagement, as predictive biomarkers in cancers led to revealing inter-cancer, inter-patient and intra-tumoural heterogeneity of the engaged immune-checkpoints. This receptor-ligand interaction did not reflect simple expression patterns of these immuno-modulatory proteins. Our findings may affect immunotherapies aimed at blocking these intercellular interactions in patients.
Comparison of a second-generation trabecular bypass (iStentinject) to ab interno trabeculectomy (Trabectome) byexact matching
Authors: Yousef Yousef Al , Strzalkowska Alicja , Hillenkamp Jost , Rosentreter André , Loewen Nils A.
Published: January 2020

Purpose

To achieve a highly balanced comparison of trabecular bypass stenting (IS2, iStent inject)with ab interno trabeculectomy (T, Trabectome) byexact matching. In a similar study, IS1 (1st generation iStent) had shown a loss of effect at 6 months.

Methods

53 IS2 eyes were matched to 3446 T eyes. Patients were matched using exact matching by baseline IOP, the number of glaucoma medications, and glaucoma type and using nearest neighbor matching by age. Individuals without a close match were excluded. All surgeries were combined with phacoemulsification.

Results

A total of 78 eyes (39 in each group) could be matched as exact pairs with a baseline IOP of 18.3±5.1 mmHg and glaucoma medications of 2.7±1.2 in each. IOP in IS2 was reduced to 14.6±4.2 mmHg at 3 months and in T to a minimum of 13.1±3.2 mmHg at 1 month. In IS2, IOP began to rise again at 6 months, eventually exceeding baseline. At 24 months, IOP in IS2 was 18.8±9.0 mmHg and in T 14.2±3.5 mmHg. IS2 had a higher average IOP than T at all postoperative visits (p<0.05 at 1, 12, 18 months). Glaucoma medications decreased to 2.0±1.5 in IS2 and to 1.5±1.4 in T.

Conclusion

T resulted in a larger and sustained IOP reduction compared to IS2 where a rebound occurred after six months to slightly above preoperative values. This time course fits bioreactivity data of the IS1.
IRESbase: a Comprehensive Database of Experimentally Validated Internal Ribosome Entry Sites
Authors: Zhao Jian , Li Yan , Wang Cong , Zhang Haotian , Zhang Hao , Jiang Bin , Guo Xuejiang , Song Xiaofeng
Published: January 2020

Internal Ribosome Entry Sites (IRESs) are functional RNA elements that can directly recruit ribosomes to an internal position of the mRNA in a cap-independent manner to initiate translation. Recently, IRES elements have attracted much attention for their critical roles in various processes including translation initiation of a new type of RNA, circular RNA, with no 5′ cap to support classical cap-dependent translation. Thus, an integrative data resource of IRES elements with experimental evidences will be useful for further studies. In this study, we present a comprehensive database of IRESs (IRESbase) by curating the experimentally validated functional minimal IRES elements from literature and annotating their host linear and circular RNA information. The current version of IRESbase contains 1328 IRESs, including 774 eukaryotic IRESs and 554 viral IRESs from 11 eukaryotic organisms and 198 viruses. As our database collected only IRES of minimal length with functional evidences, the median length of IRESs in IRESbase is 174 nucleotides. By mapping IRESs to human circRNAs and lncRNAs, 2191 circRNAs and 168 lncRNAs were found to contain at least one entire or partial IRES sequences. The IRESbase is available athttp://reprod.njmu.edu.cn/cgi-bin/iresbase/index.php.
SREBP1 regulates mitochondrial metabolism in oncogenicKRASexpressing NSCLC
Authors: Ruiz Christian F. , Montal Emily D. , Haley John A. , Haley John D.
Published: January 2020

Cancer cells require extensive metabolic reprogramming in order to provide the bioenergetics and macromolecular precursors needed to sustain a malignant phenotype. MutantKRASis a driver oncogene that is well known for its ability to regulate the ERK and PI3K signaling pathways. However, it is now appreciated that KRAS can promote tumor growth via upregulation of anabolic metabolism. We recently showed that oncogenic KRAS promotes a gene expression program ofde novo lipogenesisin non-small cell lung cancer (NSCLC). To define the mechanism(s) responsible, we focused on the lipogenic transcription factor SREBP1. We observed that KRAS increases SREBP1 expression and genetic knockdown of SREBP1 significantly inhibited cell proliferation of mutantKRAS-expressing cells. Unexpectedly, lipogenesis was not significantly altered in cells subject to SREBP1 knockdown. Carbon tracing metabolic studies showed a significant decrease in oxidative phosphorylation and RNA-seq data revealed a significant decrease in mitochondrial encoded subunits of the electron transport chain (ETC). Taken together, these data support a novel role, distinct from lipogenesis, of SREBP1 on mitochondrial function in mutantKRASNSCLC.