bluuebunny/crossref_metadata_2025 huggingface dataset:
Mistrust and inconsistency during COVID-19: considerations for resource allocation guidelines that prioritise healthcare workers
Authors: Cheung Alexander T M , Parent Brendan
Published: October 2020

As the USA contends with another surge in COVID-19 cases, hospitals may soon need to answer the unresolved question of who lives and dies when ventilator demand exceeds supply. Although most triage policies in the USA have seemingly converged on the use of clinical need and benefit as primary criteria for prioritisation, significant differences exist between institutions in how to assign priority to patients with identical medical prognoses: the so-called ‘tie-breaker’ situations. In particular, one’s status as a frontline healthcare worker (HCW) has been a proposed criterion for prioritisation in the event of a tie. This article outlines two major grounds for reconsidering HCW prioritisation. The first recognises trust as an indispensable element of clinical care and mistrust as a hindrance to any public health strategy against the virus, thus raising concerns about the outward appearance of favouritism. The second considers the ways in which proponents of HCW prioritisation deviate from the very ‘ethics frameworks’ that often preface triage policies and serve to guide resource allocation—a rhetorical strategy that may undermine the very ethical foundations on which triage policies stand. By appealing to trust and consistency, we re-examine existing arguments in favour of HCW prioritisation and provide a more tenable justification for adjudicating on tie-breaker events during crisis standards of care.
Metabolomic profiling identifies plasma sphingosine 1-phosphate levels associated with welding exposures
Authors: Gao Shangzhi , Zhuo Zhu , Hutchinson John , Su Li , Christiani David C
Published: October 2020

Background

Despite a number of known health hazards of welding fume exposure, it is unclear how exposure affects the human metabolome.

Objective

We assessed the metabolic profiles of welders before and after a 6-hour welding shift, controlling for circadian rhythm of metabolism on a non-welding day.

Methods

Welders were recruited from a training centre in Quincy, Massachusetts, in 2006 and 2010–2012 and donated blood samples on a welding shift day before and after work, as well as on a non-welding day spent in an adjacent classroom. In total, we collected 509 samples from 74 participants. Liquid chromatography–mass spectrometry quantified 665 metabolites from thawed plasmas. Metabolites with significant time (afternoon compared with morning) and day (welding/classroom) interactions were identified by two-way analysis of variance, and the overnight changes were evaluated.

Results

Sphingosine 1-phosphate (S1P) and sphingasine 1-phosphate (SA1P) exhibited significant interaction effects between day and time with false discovery rate-adjusted p values of 0.03 and <0.01, respectively. S1P, SA1P and sphingosine shared similar trends over time: high relative levels in the morning of a non-welding day declining by afternoon, but with lower starting levels on a welding day and no decline. There was no obvious pattern related to current smoking status.

Conclusion

S1P and SA1P profiles were different between welding day and classroom day. The S1P pathway was disrupted on the day of welding exposure. The levels of S1P, SA1P and sphingosine were highly correlated over time. S1P is a signalling lipid with many vital roles; thus, the underlying mechanism and clinical implications of this alteration need further investigation.
Transmuscular quadratus lumborum block reduces opioid consumption and prolongs time to first opioid demand after laparoscopic nephrectomy
Authors: Dam Mette , Hansen Christian , Poulsen Troels Dirch , Azawi Nessn Htum , Laier Gunnar Hellmund , Wolmarans Morné , Chan Vincent , Bendtsen Thomas Fichtner , Børglum Jens
Published: October 2020

Background

Robotic and hand-assisted laparoscopic nephrectomies are often associated with moderate to severe postoperative pain. The aim of the current study was to investigate the analgesic efficacy of the transmuscular quadratus lumborum (TQL) block for patients undergoing robotic or hand-assisted laparoscopic nephrectomy.

Methods

Fifty patients were included in this single-center study. All patients were scheduled for elective hand-assisted or robotic laparoscopic nephrectomy under general anesthesia. Preoperatively, patients were randomly allocated to TQL block bilaterally with ropivacaine 60 mL 0.375% or 60 mL saline and all patients received standard multimodal analgesia and intravenous patient-controlled analgesia. Primary outcome was postoperative oral morphine equivalent (OME) consumption 0–12 hours. Secondary outcomes were postoperative OME consumption up to 24 hours, pain scores, time to first opioid, nausea/vomiting, time to first ambulation and hospital length of stay (LOS).

Results

Mean (95% CI) OME consumption was significantly lower in the intervention group at 12 hours after surgery 50 (28.5 to 71.5) mg versus control 87.5 (62.7 to 112.3) mg, p=0.02. At 24 hours, 69.4 (43.2 to 95.5) mg versus 127 (96.7 to 158.6) mg, p<0.01. Time to first opioid was significantly prolonged in the intervention group median (IQR) 4.4 (2.8–17.6) hours compared with 0.3 (0.1–1.0) hours in the control group, p<0.001. No significant intergroup differences were recorded for time to first ambulation, pain scores, nausea/vomiting nor for LOS.

Conclusion

Preoperative bilateral TQL block significantly reduced postoperative opioid consumption by 43% and significantly prolonged time to first opioid.

Trial registration number

NCT03571490.
Factors associated with lower knowledge of HIV and STI transmission, testing and treatment among MSM in Ireland: findings from the MSM Internet Survey Ireland (MISI) 2015
Authors: Carey Cian , O'Donnell Kate , Davoren Martin , Quinlan Mick , Igoe Derval , Barrett Peter
Published: October 2020

Background

Poor knowledge regarding STI and HIV transmission, testing and treatment among men who have sex with men (MSM) may be contributing to their disproportionate burden of STIs. However, factors which predispose MSM to having this low knowledge are less understood.

Aim

The aim of this study was to identify factors associated with having lower knowledge of HIV and STI transmission, testing and treatment among MSM.

Methods

The MSM Internet Survey Ireland 2015 was a self-completed online national survey available to MSM living in Ireland. Thirteen factual statements were used to assess participants’ knowledge of HIV and STI transmission, testing and treatment. Respondents were defined as having ‘lower knowledge’ if they indicated prior knowledge of fewer than 11 true statements. Multivariable-adjusted logistic regression was used to identify factors associated with having lower knowledge.

Results

3090 MSM completed the survey, of whom 2905 (94%) were included in this study. Thirty-six per cent (n=1055) had lower knowledge of HIV and STI transmission, testing and treatment. The factors associated with having lower knowledge included being 18–24 years of age (vs >40 years; adjusted OR (aOR) 1.98, 95% CI 1.50 to 2.61), born in Ireland (vs outside Ireland; aOR 1.62, 95% CI 1.25 to 2.10) and being out to none of their contacts (vs out to most/all; aOR 1.69, 95% CI 1.20 to 2.37). Knowledge was also lower among those who never tested for HIV (vs tested negative within last 12 months; aOR 2.32, 95% CI 1.88 to 2.86) and among MSM who never visited an MSM-specific health promotion website (vs visited website; aOR 1.81, 95% CI 1.45 to 2.25).

Conclusion

A range of demographic factors, sexual health variables and use of MSM-specific sexual health promotion materials are associated with low knowledge regarding HIV and STI transmission, testing and treatment among MSM in Ireland. Engagement with the main national MSM-specific sexual health promotion website was associated with higher knowledge levels.
Carbon availability limits the denitrification potential of sandy loam soil from corn agroecosystems with long-term tillage and residue management
Authors: Ejack Leanne , Whalen Joann K. , Madramootoo Chandra A.
Published: October 2020

Conservation tillage and crop residues should increase the soluble organic carbon and nitrate concentration in agricultural soil, which increases the denitrification potential. Basal denitrification (72 h laboratory incubation) was 2.1–2.7 times higher in a sandy loam soil under 15 yr of conservation tillage than conventional tillage and 1.8–2.0 times higher with high-residue (additional input 8.6–9.4 Mg dry matter·ha−1·yr−1) than low-residue inputs. Adding glucose and nitrate increased the soil denitrification potential 3- to 14-fold. Denitrification was limited by carbon availability, even in soil with 15 yr of conservation tillage and high-residue inputs.
MULTISCALE ENTROPY ALGORITHMS AND THEIR APPLICATIONS IN CARDIAC DISEASES DISCRIMINATION
Authors: WAN XIANGKUI , ZHU BINRU , JIN ZHIYAO , ZHANG MINGRUI , LI YAN
Published: October 2020

In recent years, the number of cardiac disease patients has been increasing. Modern medical research has shown that the complexity of electrocardiogram (ECG) signals is related to cardiovascular diseases. This paper investigates the difference in complexity of ECG data from the people with different cardiovascular diseases, such as atrial fibrillation (AF), ventricular arrhythmia (VA) and congestive heart failure (CHF). The empirical mode decomposition (EMD) and multiscale entropy method are used to analyze the ECG data, and a mathematical model established by a support vector machine is used to identify different diseases. The accuracy recognition rate of the AF recognition is 96.25%, and that of the CHF and VA reach 90.26% and 92.20%, respectively. The experimental results show that the recognition method proposed in this paper is successful.
REDUCED CHICKEN EMBRYO DWARFING EFFECT IS RELATED TO INFECTIOUS BRONCHITIS VIRUS TW2575/98 REPLICATION EFFICIENCY
Authors: Tsai Cheng-Ta , Lee Ming-Chang , Wang Ching-Ho
Published: October 2020

An attenuated infectious bronchitis virus (TW2575/98) vaccine strain was successfully developed after 75 serial passages in embryonated chicken eggs. However, the in ovo vaccination for disease control was not applied in practice because this vaccine strain is highly pathogenic to chicken embryos (CEs) causing early death, dwarfing and other harmful effects. We compared the differences in virus replication, pathological changes, and tissue tropism between the wild virus and attenuated vaccine strain in CEs inoculated with different viral titer levels, i.e. 0.1, 1 and 10 EID[Formula: see text]/egg. The wild virus caused dwarfing effect at high titer inoculation, whereas the attenuated vaccine strain caused the dwarfing effect only at a lower viral inoculation accompanied by the earlier infection establishment and embryonic death at high and medium titers. There were no significant differences in the pathological changes in CEs infected by both wild and attenuated strains. Detected by immunohistochemistry, the viral antigens of both strains could be found mainly at the epithelium of the chorioallantoic membrane, lung parabronchus, renal tubules and some in the spleen and heart serosa. These findings indicated that the early embryonic death and dwarfing is not related to the change in cell/tissue tropism of the vaccine strain, rather on the early infection establishment and viral load. We suggest that the vaccine strain inoculated titer could be adjusted to an optimal low level for in ovo vaccination to overcome the poor hatching rate for its higher virulence to chicken embryos.
Identifying pathfinder elements for gold in bulk-rock geochemical data from the Cripple Creek Au–Te deposit: a statistical approach
Authors: Kadel-Harder Irene M. , Spry Paul G. , McCombs Audrey L. , Zhang Haozhe
Published: October 2020

The Cripple Creek alkaline igneous rock-related, low-sulfidation epithermal gold telluride deposit, Colorado, is hosted in the 10 km wide Oligocene alkaline volcanic Cripple Creek diatreme in Proterozoic rocks. Gold occurs as native gold, Au-tellurides, and in the structure of arsenian pyrite, in potassically altered high-grade veins, and as disseminations in the host rocks.

Correlation coefficients, principal component analysis, hierarchical cluster analysis and random forests were used to analyse major and trace element compositions of 995 rock samples primarily from low-grade gold mineralization in drill core from three currently operating pits (Wild Horse Extension, Globe Hill and Schist Island) in the northwestern part of the Cripple Creek diatreme. These methods suggest that Ag, As, Bi, Te and W are the best pathfinders to gold mineralization in low-grade disseminated ore. Although Mo correlates with gold in other studies and is spatially related to gold veins, molybdenite post-dated the formation of gold and is likely related to a late-stage porphyry overprint. These elements, in conjunction with mineralogical studies, indicate that tellurides, fluorite, quartz, carbonates, roscoelite, tennantite-tetrahedrite, pyrite, sphalerite, muscovite, monazite, bastnäsite and hübnerite serve as exploration guides to ore.
Model Checking a Logic for True Concurrency
Authors: Baldan Paolo , Padoan Tommaso
Published: October 2020

We study the model-checking problem for a logic for true concurrency, whose formulae predicate about events in computations and their causal dependencies. The logic, which represents the logical counterpart of history-preserving bisimilarity, is naturally interpreted over event structures or any formalism that can be given a causal semantics, like Petri nets. It includes least and greatest fixpoint operators and thus it can express properties of infinite computations. Since the event structure associated with a system is typically infinite (even if the system is finite state), already the decidability of model-checking is non-trivial. We first develop a local model-checking technique based on a tableau system, for which, over a class of event structures satisfying a suitable regularity condition, referred to as strong regularity, we prove termination, soundness, and completeness. The tableau system allows for a clean and intuitive proof of decidability, but a direct implementation of the procedure can be extremely inefficient. For easing the development of a more efficient model-checking technique, we move to an automata-theoretic framework. Given a formula and a strongly regular event structure, we show how to construct a parity tree automaton whose language is non-empty if and only if the event structure satisfies the formula. The automaton is usually infinite. We discuss how it can be quotiented to an equivalent finite automaton, where emptiness can be checked effectively. To show the applicability of the approach, we discuss how it instantiates to finite safe Petri nets, providing also a corresponding proof-of-concept model-checking tool.
The October 2020 issue
Authors: Uhlig Steve
Published: October 2020

This October 2020 issue contains five technical papers, the third paper of our education series, as well as three editorial notes.
Mobile web browsing under memory pressure
Authors: Qazi Ihsan Ayyub , Qazi Zafar Ayyub , Benson Theophilus A. , Murtaza Ghulam , Latif Ehsan , Manan Abdul , Tariq Abrar
Published: October 2020

Mobile devices have become the primary mode of Internet access. Yet, differences in mobile hardware resources, such as device memory, coupled with the rising complexity of Web pages can lead to widely different quality of experience for users. In this work, we analyze how device memory usage affects Web browsing performance. We quantify the memory footprint of popular Web pages over different mobile devices, mobile browsers, and Android versions, analyze the induced memory distribution across different browser components (e.g., JavaScript engine and compositor), investigate how performance gets impacted under memory pressure and propose optimizations to reduce the memory footprint of Web browsing. We show that these optimizations can improve performance and reduce chances of browser crashes in low memory scenarios.
Using deep programmability to put network owners in control
Authors: Foster Nate , McKeown Nick , Rexford Jennifer , Parulkar Guru , Peterson Larry , Sunay Oguz
Published: October 2020

Controlling an opaque system by reading some "dials" and setting some "knobs," without really knowing what they do, is a hazardous and fruitless endeavor, particularly at scale. What we need are transparent networks, that start at the top with a high-level intent and map all the way down, through the control plane to the data plane. If we can specify the behavior we want in software, then we can check that the system behaves as we expect. This is impossible if the implementation is opaque. We therefore need to use open-source software or write it ourselves (or both), and have mechanisms for checking actual behavior against the specified intent. With fine-grain checking (e.g., every packet, every state variable), we can build networks that are more reliable, secure, and performant. In the limit, we can build networks that run autonomously under verifiable, closed-loop control. We believe this vision, while ambitious, is finally within our reach, due to
deep programmability
across the stack, both vertically (control and data plane) and horizontally (end to end). It will emerge naturally in some networks, as network owners take control of their software and engage in open-source efforts; whereas in enterprise networks it may take longer. In 5G access networks, there is a pressing need for our community to engage, so these networks, too, can operate autonomously under verifiable, closed-loop control.
Geospatial forecasting of COVID-19 spread and risk of reaching hospital capacity
Authors: Bobashev Georgiy , Segovia-Dominguez Ignacio , Gel Yulia R. , Rineer James , Rhea Sarah , Sui Hui
Published: October 2020

Prompt surveillance and forecasting of COVID-19 spread are of critical importance for slowing down the pandemic and for the success of any public mitigation efforts. However, as with any infectious disease with rapid transmission and high virulence, lack of COVID-19 observations for near-real-time forecasting is still the key challenge obstructing operational disease prediction and control. In this context, we can follow the two approaches to forecasting COVID-19 dynamics: based on mechanistic models and based on machine learning. Mechanistic models are better in capturing an epidemiological curve, using a low amount of data, and describing the overall trajectory of the disease dynamics, hence, providing long-term insights into where the disease might go. Machine learning, in turn, can provide more precise data-driven forecasts especially in the short-term horizons, while suffering from limited interpretability and usually requiring backlog history on the infectious disease. We propose a unified reinforcement learning framework that combines the two approaches. That is, long-term trajectory forecasts are used in machine learning techniques to forecast local variability which is not captured by the mechanistic model.
Editors’ Choice—Uncovering the Role of Alkaline Pretreatment for Hydroxide Exchange Membrane Fuel Cells
Authors: Shi Lin , Setzler Brian P. , Hu Keda , Weiss Catherine M. , Matz Stephanie , Xue Yanrong , Xu Zhiyuan , Zhuang Zhongbin , Gottesfeld Shimshon , Yan Yushan
Published: October 2020

Alkaline pretreatment is perceived as an essential step for high-performance hydroxide exchange membrane fuel cells (HEMFCs), but its exact function is not fully understood. Here we show that alkaline pretreatment is only necessary when carboxylates are generated from platinum- or palladium-catalyzed oxidation of primary alcohol solvents during membrane electrode assembly (MEA) fabrication. When alkaline pretreatment is needed, bicarbonates are a better choice than the most commonly used hydroxide bases. We further demonstrate that MEAs with Pt/Pd-free catalysts, which can be used in HEMFCs, exhibit a better performance without the alkaline pretreatment: a voltage of 0.64 V at 1.0 A cm−2 and a peak power density of 0.69 W cm−2 in H2/O2. The optimization or elimination of the alkaline pretreatment will simplify the fabrication process for fuel cells and thus reduces their manufacturing costs.
Platinum Nanoparticle-Decorated ZnO Nanorods Improved the Performance of Methanol Gas Sensor
Authors: Young Sheng-Joue , Chu Yen-Lin
Published: October 2020

In this study, the crystallinities, structures, and optical properties of zinc oxide (ZnO) and platinum nanoparticles (Pt NPs)-decorated ZnO nanorods (Pt/ZnO NRs) were investigated by an X-ray diffraction, a field-emission scanning electron microscopy, and a photoluminescence spectrometry. The Pt NPs-decorated ZnO NRs were prepared by direct current (DC) magnetron sputtering for 0 and 30 s. The ZnO and Pt/ZnO NR-based gas sensors are consistent, stable, and repeatable. The sensitivities of the ZnO and Pt/ZnO NR sensors were 1.34% and 121.03%, respectively, at a concentration of 1000 ppm methanol gas and at an operating temperature of 270 °C. The Pt NPs-decorated ZnO NRs exhibit enhanced sensor characteristics of methanol gas.
Differential responses of bone to angiotensin II and angiotensin(1-7): beneficial effects of ANG(1-7) on bone with exposure to high glucose
Authors: Sha Nan-Nan , Zhang Jia-Li , Poon Christina Chui-Wa , Li Wen-Xiong , Li Yue , Wang Yi-Fei , Shi Wei , Lin Fu-Hui , Lin Wen-Ping , Wang Yong-Jun , Zhang Yan
Published: October 2020

Osteoporosis, diabetes, and hypertension are common concurrent chronic disorders. This study aimed to explore the respective effects of angiotensin II (ANG II) and angiotensin(1-7) [ANG(1-7)], active peptides in the renin-angiotensin system, on osteoblasts and osteoclasts under high-glucose level, as well as to investigate the osteo-preservative effects of ANG II type 1 receptor (AT1R) blocker and ANG(1-7) in diabetic spontaneously hypertensive rats (SHR). ANG II and ANG(1-7), respectively, decreased and increased the formation of calcified nodules and alkaline phosphatase activity in MC3T3-E1 cells under high-glucose level, and respectively stimulated and inhibited the number of matured osteoclasts and pit resorptive area in RANKL-induced bone marrow macrophages. Olmesartan and Mas receptor antagonist A779 could abolish those effects. ANG II and ANG(1-7), respectively, downregulated and upregulated the expressions of osteogenesis factors in MC3T3-E1 cells. ANG II promoted the expressions of cathepsin K and MMP9 in RAW 264.7 cells, whereas ANG(1-7) repressed these osteoclastogenesis factors. ANG II rapidly increased the phosphorylation of Akt and p38 in RAW 264.7 cells, whereas ANG(1-7) markedly reduced the phosphorylation of p38 and ERK under high-glucose condition. After treatments of diabetic SHR with valsartan and ANG(1-7), a significant increase in trabecular bone area, bone mineral density, and mechanical strength was only found in the ANG(1-7)-treated group. Treatment with ANG(1-7) significantly suppressed the increase in renin expression and ANG II content in the bone of SHR. Taken together, ANG II/AT1R and ANG(1-7)/Mas distinctly regulated the differentiation and functions of osteoblasts and osteoclasts upon exposure to high-glucose condition. ANG(1-7) could protect SHR from diabetes-induced osteoporosis.
Effects of carbohydrate restriction on postprandial glucose metabolism, β-cell function, gut hormone secretion, and satiety in patients with Type 2 diabetes
Authors: Skytte Mads J. , Samkani Amirsalar , Astrup Arne , Frystyk Jan , Rehfeld Jens F. , Holst Jens J. , Madsbad Sten , Burling Keith , Fenger Mogens , Thomsen Mads N. , Larsen Thomas M. , Krarup Thure , Haugaard Steen B.
Published: October 2020

Dietary carbohydrate restriction may improve the phenotype of Type 2 diabetes (T2D) patients. We aimed to investigate 6 wk of carbohydrate restriction on postprandial glucose metabolism, pancreatic α- and β-cell function, gut hormone secretion, and satiety in T2D patients. Methods In a crossover design, 28 T2D patients (mean HbA1c: 60 mmol/mol) were randomized to 6 wk of carbohydrate-reduced high-protein (CRHP) diet and 6 wk of conventional diabetes (CD) diet (energy-percentage carbohydrate/protein/fat: 30/30/40 vs. 50/17/33). Twenty-four-hour continuous glucose monitoring (CGM) and mixed-meal tests were undertaken and fasting intact proinsulin (IP), 32,33 split proinsulin concentrations (SP), and postprandial insulin secretion rates (ISR), insulinogenic index (IGI), β-cell sensitivity to glucose ( Bup), glucagon, and gut hormones were measured. Gastric emptying was evaluated by postprandial paracetamol concentrations and satiety by visual analog scale ratings. A CRHP diet reduced postprandial glucose area under curve (net AUC) by 60% ( P < 0.001), 24 h glucose by 13% ( P < 0.001), fasting IP and SP concentrations (both absolute and relative to C-peptide, P < 0.05), and postprandial ISR (24%, P = 0.015), while IGI and Bup improved by 31% and 45% (both P < 0.001). The CRHP diet increased postprandial glucagon net AUC by 235% ( P < 0.001), subjective satiety by 18% ( P = 0.03), delayed gastric emptying by 15 min ( P < 0.001), decreased gastric inhibitory polypeptide net AUC by 29% ( P < 0.001), but had no significant effect on glucagon-like-peptide-1, total peptide YY, and cholecystokinin responses. A CRHP diet reduced glucose excursions and improved β-cell function, including proinsulin processing, and increased subjective satiety in patients with T2D.
AMPK mediates regulation of voltage-gated calcium channels by leptin in isolated neurons from arcuate nucleus
Authors: Bermeo K. , Castro H. , Arenas I. , Garcia D. E.
Published: October 2020

Our results readily support the hypothesis that AMPK is responsible for the maintenance of the calcium current and mediates the fine-tuning modulation of the leptin response. The novelty of these results strengthens the critical role of AMPK in the general energy balance and homeostasis.
Beyond the tubule: pathological variants of LRP2, encoding the megalin receptor, result in glomerular loss and early progressive chronic kidney disease
Authors: Charlton Jennifer R. , Tan Weizhen , Daouk Ghaleb , Teot Lisa , Rosen Seymour , Bennett Kevin M. , Cwiek Aleksandra , Nam Sejin , Emma Francesco , Jouret François , Oliveira João Paulo , Tranebjærg Lisbeth , Frykholm Carina , Mane Shrikant , Hildebrandt Friedhelm , Srivastava Tarak , Storm Tina , Christensen Erik Ilsø , Nielsen Rikke
Published: October 2020

Pathogenic variants in the LRP2 gene, encoding the multiligand receptor megalin, cause a rare autosomal recessive syndrome: Donnai-Barrow/Facio-Oculo-Acoustico-Renal (DB/FOAR) syndrome. Because of the rarity of the syndrome, the long-term consequences of the tubulopathy on human renal health have been difficult to ascertain, and the human clinical condition has hitherto been characterized as a benign tubular condition with asymptomatic low-molecular-weight proteinuria. We investigated renal function and morphology in a murine model of DB/FOAR syndrome and in patients with DB/FOAR. We analyzed glomerular filtration rate in mice by FITC-inulin clearance and clinically characterized six families, including nine patients with DB/FOAR and nine family members. Urine samples from patients were analyzed by Western blot analysis and biopsy materials were analyzed by histology. In the mouse model, we used histological methods to assess nephrogenesis and postnatal renal structure and contrast-enhanced magnetic resonance imaging to assess glomerular number. In megalin-deficient mice, we found a lower glomerular filtration rate and an increase in the abundance of injury markers, such as kidney injury molecule-1 and N-acetyl-β-d-glucosaminidase. Renal injury was validated in patients, who presented with increased urinary kidney injury molecule-1, classical markers of chronic kidney disease, and glomerular proteinuria early in life. Megalin-deficient mice had normal nephrogenesis, but they had 19% fewer nephrons in early adulthood and an increased fraction of nephrons with disconnected glomerulotubular junction. In conclusion, megalin dysfunction, as present in DB/FOAR syndrome, confers an increased risk of progression into chronic kidney disease.
Experimental Investigation of Thermal Conductivity and Specific Heat of the Calcium Phosphate Ore for a Drying Application
Authors: El Hallaoui Zhor , Moudakkar T. , Vaudreuil S. , Bounahmidi T. , Abderafi S.
Published: October 2020

This paper discusses an experimental investigation to determine regression models for thermal properties of phosphate particles and to analyze the performances of the phosphate flash dryer. For this purpose, the specific heat capacity and thermal conductivity of phosphate particles were experimentally determined by the modulated differential scanning calorimetry (MDSC) and the modified transient plane source method (MTPS), respectively. Multiple regression models were developed to correlate the specific heat and thermal conductivity to moisture content, particle size, and temperature. Experimental results showed that the measured thermal conductivity and dry specific heat were found in the range of 0.07–0.61 W/m K and 510–630 J/kg·K, respectively. Furthermore, the specific heat increased almost linearly with temperature but decreased with particle size, while the thermal conductivity increased with moisture content and temperature but decreased with particle size. These correlations were integrated to the phosphate flash dryer mathematical model and used to analyze the thermal behavior of phosphate drying. Simulation results were compared to experimental data obtained on a bench-scale dryer, where the model exhibits an average error of 2% and 4% for moisture content and air temperature estimation, showing good fitting for practical data.
Corrosion Localization Analysis in T‐Shape Pipe Junction Based on Multielectrode Current Measurements
Authors: Vasyliev Georgii S.
Published: October 2020

The water flow rate and galvanic current distribution in the T‐shape junction of steel pipes were investigated using the multielectrode array approach. The inner surface of polypropylene pipes junction was divided into 15 separate sections, and a steel plate was placed in every section to form a single inner surface. The tap water flow rate varied between 0.28 and 0.57 m/s, and the water distribution in the junction was between 5 : 1 and 1 : 5. The galvanic current flowing through each steel electrode was mapped on the 3D model of the T‐shape junction. Two differential aeration pairs were found with high anodic current densities.
Comparative Analysis of Visual Performance and Astigmatism Tolerance with Monofocal, Bifocal, and Extended Depth-of-Focus Intraocular Lenses Targeting Slight Myopia
Authors: Xu Jie , Zheng Tianyu , Lu Yi
Published: October 2020

Purpose. To compare the visual performance and astigmatism tolerance of 3 intraocular lens (IOL) groups: monofocal, bifocal, and extended depth-of-focus (EDOF) IOLs targeting slight myopia. Methods. Overall, there were 60 cataract surgery eyes from 60 patients with implantation of a monofocal, bifocal, or EDOF IOL (20 eyes in each IOL group). The EDOF IOLs targeted slight myopia (−0.25 D to −0.75 D). Intragroup comparison of visual acuity, defocus curve, objective optical quality, contrast sensitivity, visual function questionnaire scores, patients’ overall satisfaction, and the astigmatism tolerance was performed 3 months after surgery. Results. The EDOF group provided equivalently excellent distance visual outcomes (0.06 ± 0.12) as the monofocal (0.06 ± 0.09) and bifocal (0.03 ± 0.09) groups

P
=
0.554

, better intermediate vision than the other 2 groups

P
<
0.05

, and similarly satisfactory near visual outcomes (0.23 ± 0.16 at 20 cm, and 0.17 ± 0.14 at 33 cm) as the bifocal group (0.28 ± 0.14 at 20 cm and 0.08 ± 0.10 at 33 cm)

P
>
0.05

. The contrast sensitivity of EDOF IOL was slightly decreased compared to that of monofocal IOL, but it was better than that of bifocal IOL. The EDOF group showed significantly higher satisfaction than the bifocal group did when preoperative corneal astigmatism was 0.75 D or greater

P

=

0.009

. A significant negative correlation between the corneal astigmatism and patient satisfaction was observed in only the bifocal group. Conclusions. The EDOF IOLs targeting slight myopia offered satisfactory visual outcomes at an extended range from far to near distances. The EDOF and monofocal IOLs showed a better tolerance to astigmatism than did the bifocal IOL.
Acute Confusional Migraine: Unusual Great Masquerader—Case Report and Literature Review
Authors: Tanous Bashar , Tahtouh Raad , Sardar Sundus , Mohamed Sara , Sukik Aseel , Habib Mhd-Baraa , Sajid Jamal , Mohamed Mouhand F. H.
Published: October 2020

Background. Acute confusional migraine (ACM) is a rare variant of migraine, mainly prevalent in children and adolescents. It is not currently indexed as a distinct variant of migraine likely since only a few cases were reported in the adult population. We report a case of delayed ACM diagnosis in a young man and present a concise-related literature review. Case Presentation. A thirty-eight-year-old man with a past medical history of migraine, not on any treatment, presented with headaches accompanied by confusion. Over a two-year period before the current presentation, he experienced two episodes of confusion, which required hospital admission for evaluation: once mislabeled as a psychiatric illness and diagnosed as a migrainous infarct in the second hospitalization. In the current presentation, he reported a similar history of headache accompanied by confusion. The examination was remarkable for disorientation; otherwise, no focal deficit was elicited. Laboratory testing, cerebrospinal fluid, and neurological imaging were all unremarkable. His symptoms improved spontaneously within less than twenty-four hours, similar to his previous presentations. After two-year history of episodic confusion and after excluding other plausible causes of confusion, guided by proposed diagnostic criteria, we diagnosed him as a case of ACM. The patient remains well at the follow-up of two months after discharge. Discussion and Conclusion. ACM is a rare variant of migraine and is often a challenge for clinicians to diagnose appropriately. Until recent years, the disease was thought to be limited to children and adolescents. However, recently few reports also expanded the incidence of this entity to the adult population. There is a significant gap in knowledge about proper identification and treatment of this condition, leading to delayed or overlooked ACM diagnosis. Moreover, the recent edition of the International Classification of Headache Disorders (ICHD-3) does not account for this entity, thereby further adding to physicians’ lack of awareness regarding this migraine subtype. The authors emphasize that clinicians be aware of this entity and adequately utilize the existing proposed diagnostic criteria for ACM until standardized and validated tools are available. We also believe that this entity should be acknowledged in the subsequent migraine guidelines and classifications.
Brain Tumor Stem Cell Dependence on Glutaminase Reveals a Metabolic Vulnerability through the Amino Acid Deprivation Response Pathway
Authors: Restall Ian J. , Cseh Orsolya , Richards Laura M. , Pugh Trevor J. , Luchman H. Artee , Weiss Samuel
Published: October 2020

Cancer cells can metabolize glutamine to replenish TCA cycle intermediates, leading to a dependence on glutaminolysis for cell survival. However, a mechanistic understanding of the role that glutamine metabolism has on the survival of glioblastoma (GBM) brain tumor stem cells (BTSC) has not yet been elucidated. Here, we report that across a panel of 19 GBM BTSC lines, inhibition of glutaminase (GLS) showed a variable response from complete blockade of cell growth to absolute resistance. Surprisingly, BTSC sensitivity to GLS inhibition was a result of reduced intracellular glutamate triggering the amino acid deprivation response (AADR) and not due to the contribution of glutaminolysis to the TCA cycle. Moreover, BTSC sensitivity to GLS inhibition negatively correlated with expression of the astrocytic glutamate transporters EAAT1 and EAAT2. Blocking glutamate transport in BTSCs with high EAAT1/EAAT2 expression rendered cells susceptible to GLS inhibition, triggering the AADR and limiting cell growth. These findings uncover a unique metabolic vulnerability in BTSCs and support the therapeutic targeting of upstream activators and downstream effectors of the AADR pathway in GBM. Moreover, they demonstrate that gene expression patterns reflecting the cellular hierarchy of the tissue of origin can alter the metabolic requirements of the cancer stem cell population.

Significance:

Glioblastoma brain tumor stem cells with low astrocytic glutamate transporter expression are dependent on GLS to maintain intracellular glutamate to prevent the amino acid deprivation response and cell death.
Activatable Zymography Probes Enable In Situ Localization of Protease Dysregulation in Cancer
Authors: Soleimany Ava P. , Kirkpatrick Jesse D. , Su Susan , Dudani Jaideep S. , Zhong Qian , Bekdemir Ahmet , Bhatia Sangeeta N.
Published: October 2020

Recent years have seen the emergence of conditionally activated diagnostics and therapeutics that leverage protease-cleavable peptide linkers to enhance their specificity for cancer. However, due to a lack of methods to measure and localize protease activity directly within the tissue microenvironment, the design of protease-activated agents has been necessarily empirical, yielding suboptimal results when translated to patients. To address the need for spatially resolved protease activity profiling in cancer, we developed a new class of in situ probes that can be applied to fresh-frozen tissue sections in a manner analogous to immunofluorescence staining. These activatable zymography probes (AZP) detected dysregulated protease activity in human prostate cancer biopsy samples, enabling disease classification. AZPs were leveraged within a generalizable framework to design conditional cancer diagnostics and therapeutics and showcased in the Hi-Myc mouse model of prostate cancer, which models features of early pathogenesis. Multiplexed screening against barcoded substrates yielded a peptide, S16, that was robustly and specifically cleaved by tumor-associated metalloproteinases in the Hi-Myc model. In situ labeling with an AZP incorporating S16 revealed a potential role of metalloproteinase dysregulation in proliferative, premalignant Hi-Myc prostatic glands. Systemic administration of an in vivo imaging probe incorporating S16 perfectly classified diseased and healthy prostates, supporting the relevance of ex vivo activity assays to in vivo translation. We envision AZPs will enable new insights into the biology of protease dysregulation in cancer and accelerate the development of conditional diagnostics and therapeutics for multiple cancer types.

Significance:

Visualization of protease activity within the native tissue context using AZPs provides new biological insights into protease dysregulation in cancer and guides the design of conditional diagnostics and therapeutics.
Transcriptomic Analysis of Diffuse Intrinsic Pontine Glioma (DIPG) Identifies a Targetable ALDH-Positive Subset of Highly Tumorigenic Cancer Stem-like Cells
Authors: Surowiec Rachel K. , Ferris Sarah F. , Apfelbaum April , Espinoza Carlos , Mehta Ranjit K. , Monchamp Karamoja , Sirihorachai Veerin R. , Bedi Karan , Ljungman Mats , Galban Stefanie
Published: October 2020

Understanding the cancer stem cell (CSC) landscape in diffuse intrinsic pontine glioma (DIPG) is desperately needed to address treatment resistance and identify novel therapeutic approaches. Patient-derived DIPG cells demonstrated heterogeneous expression of aldehyde dehydrogenase (ALDH) and CD133 by flow cytometry. Transcriptome-level characterization identified elevated mRNA levels of MYC, E2F, DNA damage repair (DDR) genes, glycolytic metabolism, and mTOR signaling in ALDH+ compared with ALDH−, supporting a stem-like phenotype and indicating a druggable target. ALDH+ cells demonstrated increased proliferation, neurosphere formation, and initiated tumors that resulted in decreased survival when orthotopically implanted. Pharmacologic MAPK/PI3K/mTOR targeting downregulated MYC, E2F, and DDR mRNAs and reduced glycolytic metabolism. In vivo PI3K/mTOR targeting inhibited tumor growth in both flank and an ALDH+ orthotopic tumor model likely by reducing cancer stemness. In summary, we describe existence of ALDH+ DIPGs with proliferative properties due to increased metabolism, which may be regulated by the microenvironment and likely contributing to drug resistance and tumor recurrence.

Implications:

Characterization of ALDH+ DIPGs coupled with targeting MAPK/PI3K/mTOR signaling provides an impetus for molecularly targeted therapy aimed at addressing the CSC phenotype in DIPG.
SHOC2 Is a Critical Modulator of Sensitivity to EGFR–TKIs in Non–Small Cell Lung Cancer Cells
Authors: Terai Hideki , Hamamoto Junko , Emoto Katsura , Masuda Takeshi , Manabe Tadashi , Kuronuma Satoshi , Kobayashi Keigo , Masuzawa Keita , Ikemura Shinnosuke , Nakayama Sohei , Kawada Ichiro , Suzuki Yusuke , Takeuchi Osamu , Suzuki Yukio , Ohtsuki Sumio , Yasuda Hiroyuki , Soejima Kenzo , Fukunaga Koichi
Published: October 2020

EGFR mutation-positive patients with non–small cell lung cancer (NSCLC) respond well to treatment with EGFR–tyrosine kinase inhibitors (EGFR–TKI); however, treatment with EGFR–TKIs is not curative, owing to the presence of residual cancer cells with intrinsic or acquired resistance to this class of drugs. Additional treatment targets that may enhance the efficacy of EGFR–TKIs remain elusive. Using a CRISPR/Cas9-based screen, we identified the leucine-rich repeat scaffold protein SHOC2 as a key modulator of sensitivity to EGFR–TKI treatment. On the basis of in vitro assays, we demonstrated that SHOC2 expression levels strongly correlate with the sensitivity to EGFR–TKIs and that SHOC2 affects the sensitivity to EGFR–TKIs in NSCLC cells via SHOC2/MRAS/PP1c and SHOC2/SCRIB signaling. The potential SHOC2 inhibitor celastrol phenocopied SHOC2 depletion. In addition, we confirmed that SHOC2 expression levels were important for the sensitivity to EGFR–TKIs in vivo. Furthermore, IHC showed the accumulation of cancer cells that express high levels of SHOC2 in lung cancer tissues obtained from patients with NSCLC who experienced acquired resistance to EGFR–TKIs. These data indicate that SHOC2 may be a therapeutic target for patients with NSCLC or a biomarker to predict sensitivity to EGFR–TKI therapy in EGFR mutation-positive patients with NSCLC. Our findings may help improve treatment strategies for patients with NSCLC harboring EGFR mutations.

Implications:

This study showed that SHOC2 works as a modulator of sensitivity to EGFR–TKIs and the expression levels of SHOC2 can be used as a biomarker for sensitivity to EGFR–TKIs.
Timed Ang2-Targeted Therapy Identifies the Angiopoietin–Tie Pathway as Key Regulator of Fatal Lymphogenous Metastasis
Authors: Gengenbacher Nicolas , Singhal Mahak , Mogler Carolin , Hai Ling , Milde Laura , Pari Ashik Ahmed Abdul , Besemfelder Eva , Fricke Claudine , Baumann Daniel , Gehrs Stephanie , Utikal Jochen , Felcht Moritz , Hu Junhao , Schlesner Matthias , Offringa Rienk , Chintharlapalli Sudhakar R. , Augustin Hellmut G.
Published: October 2020

Recent clinical and preclinical advances have highlighted the existence of a previously hypothesized lymphogenous route of metastasis. However, due to a lack of suitable preclinical modeling tools, its contribution to long-term disease outcome and relevance for therapy remain controversial. Here, we established a genetically engineered mouse model (GEMM) fragment–based tumor model uniquely sustaining a functional network of intratumoral lymphatics that facilitates seeding of fatal peripheral metastases. Multiregimen survival studies and correlative patient data identified primary tumor–derived Angiopoietin-2 (Ang2) as a potent therapeutic target to restrict lymphogenous tumor cell dissemination. Mechanistically, tumor-associated lymphatic endothelial cells (EC), in contrast to blood vascular EC, were found to be critically addicted to the Angiopoietin–Tie pathway. Genetic manipulation experiments in combination with single-cell mapping revealed agonistically acting Ang2–Tie2 signaling as key regulator of lymphatic maintenance. Correspondingly, acute presurgical Ang2 neutralization was sufficient to prolong survival by regressing established intratumoral lymphatics, hence identifying a therapeutic regimen that warrants further clinical evaluation.

Significance:

Exploiting multiple mouse tumor models including a unique GEMM-derived allograft system in combination with preclinical therapy designs closely matching the human situation, this study provides fundamental insight into the biology of tumor-associated lymphatic EC and defines an innovative presurgical therapeutic window of migrastatic Ang2 neutralization to restrict lymphogenous metastasis.

This article is highlighted in the In This Issue feature, p. 211
Comparison between Prophylactic versus Therapeutic Doses of Low-Molecular-Weight Heparin in Severely Ill Coronavirus Disease 2019 Patients in Relation to Disease Progression and Outcome
Authors: Elmelhat Ahmed , Elbourai Essam , Dewedar Hany , Elgergawi Taghrid , Alkhanbouli Maryam , Ahmed Salwa , Malik Zoiya , Nugud Alaa , Mohammed Shadha , Mohammad Hozaifah , Husain Abdullah
Published: October 2020

Introduction: The predominant coagulation abnormalities in patients with coronavirus disease 2019 (COVID-19) suggest a hypercoagulable state and are consistent with uncontrolled clinical observations of an increased risk of venous thromboembolism. Aim and Objectives: To compare the effect of prophylactic versus therapeutic doses of enoxaparin in the treatment of severe cases of COVID-19 infection. Materials and Methods: This was a retrospective observational study conducted at Latifa hospital, Dubai. Fifty-nine patients enrolled from March to June 2020 and divided into 2 groups: patients who received the prophylactic dose of enoxaparin (group 1) and patients who received the therapeutic dose of enoxaparin (group 2). Results: The mean age of all cases was 47.2 ± 10.4 years, while the mean weight was 76.4 ± 13.4 kg. Males represented 79.7% of cases. Blood group “O” was the most frequent blood group (40.9%). None of the cases were smokers or using alcohol. Bronchial asthma, lung diseases, diabetes mellitus, hypertension, CKD, cardiac disease, thyroid disease, and immunodeficiency were present in 1.7, 1.7, 39, 27.1, 5.1, 1.7, 5.1, and 1.7% respectively. There was no significant difference between both study groups regarding personal and medical characteristics, except for hypertension where 35.9% of group 2 (therapeutic) cases were hypertensive compared to 10% of group 1 cases (prophylactic). There was a significant difference between both study groups regarding inflammatory markers improvement duration, duration of MV and O2 support duration, with longer duration among (therapeutic) group 2 cases compared to group 1 cases (prophylactic). There was a highly significant difference between both study groups regarding ICU admission, as 64% of group 1 cases were admitted compared to 25% of group 1 cases. Similarly, 38.5% of group 2 cases needed MV compared to only 10% of group 1 cases, which was statistically significant. There was no significant difference between both groups regarding bleeding tendency and mortality (p value 0.54). Conclusion: Our results showed that use of prophylactic dose of enoxaparin might have some benefits compared to the therapeutic dose in terms of less duration of ICU and hospital stay, duration of oxygen support, need and duration of MV, and normalization of inflammatory markers. However, there was no significant difference between the 2 regimens regarding the mortality.