bluuebunny/crossref_metadata_2025 huggingface dataset:
A fast, semi-analytical model for the Venusian binary cloud system
Authors: Dai L-K , Zhang X , Cui J
Published: July 2022

The Venusian clouds originate from the binary condensation of H2SO4 and H2O. The two components strongly interact with each other via chemistry and cloud formation. Previous works adopted sophisticated microphysical approaches to understand the clouds. Here, we show that the observed vapour and cloud distributions on Venus can be well explained by a semi-analytical model. Our model assumes local thermodynamical equilibrium for water vapour but not for sulphuric acid vapour, and includes the feedback of cloud condensation and acidity to vapour distributions. The model predicts strong supersaturation of the H2SO4 vapour above 60 km, consistent with our recent cloud condensation model. The semi-analytical model is 100 times faster than the condensation model and 1000 times faster than the microphysical models. This allows us to quickly explore a large parameter space of the sulphuric acid gas-cloud system. We found that the cloud mass loading in the upper clouds has an opposite response of that in the lower clouds to the vapour mixing ratios in the lower atmosphere. The transport of water vapour influences the cloud acidity in all cloud layers, while the transport of sulphuric acid vapour only dominates in the lower clouds. This cloud model is fast enough to be coupled with the climate models and chemistry models to understand the cloudy atmospheres of Venus and Venus-like extra-solar planets.
The impact of two non-transiting planets and stellar activity on mass determinations for the super-Earth CoRoT-7b
Authors: Anna John Ancy , Collier Cameron Andrew , Wilson Thomas G
Published: July 2022

CoRoT-7 is an active star, whose orbiting planets and their masses have been under debate since their initial detection. In the previous studies, CoRoT-7 was found to have two planets, CoRoT-7b and CoRoT-7c with orbital periods 0.85 and 3.69 d, and a potential third planet with a period ∼9 d. The existence of the third planet has been questioned later as potentially being an activity-induced artefact. Moreover, mass of the transiting planet CoRoT-7b has been estimated to have widely different values owing to the activity level of the parent star, the consequent RV ‘jitter’, and the methods used to rectify this ambiguity. Here. we present an analysis of the HARPS archival RV (RV) data of CoRoT-7 using a new wavelength-domain technique, scalpels, to correct for the stellar activity-induced spectral line-shape changes. Simultaneous modelling of stellar activity and orbital motions, identified using the ℓ1- periodogram, shows that scalpels effectively reduce the contribution of stellar variability to the RV signal and enhance the detectability of exoplanets around active stars. Using kima nested-sampling package (Faria et al.), we modelled the system incorporating a Gaussian Process together with scalpels. The resultant posterior distributions favoured a three-planet system comprising two non-transiting planets, CoRoT-7c and CoRoT-7d with orbital periods 3.697 ± 0.005 and 8.966 ± 1.546 d, in addition to the known transiting planet. The transiting planet CoRoT-7b is found to be a rocky super-Earth with a mass of Mb = 6.06 ± 0.65M⊕. The determined masses of Mc = 13.29 ± 0.69M⊕ and Md = 17.14 ± 2.55M⊕ suggest the non-transiting planets CoRoT-7c and CoRoT-7d to be structurally similar to Uranus and Neptune.
On the distribution of Bayesian evidence
Authors: Keeley Ryan E , Shafieloo Arman
Published: July 2022

We look at the distribution of the Bayesian evidence for mock realizations of supernova and baryon acoustic oscillation data. The ratios of Bayesian evidence of different models are often used to perform model selection. The significance of these Bayes factors is then interpreted using scales such as the Jeffreys or Kass & Raftery scale. First, we demonstrate how to use the evidence itself to validate the model, that is to say how well a model fits the data, regardless of how well other models perform. The basic idea is that if, for some real data set, a model’s evidence lies outside the distribution of evidence that result when the same fiducial model that generates the data sets is used for the analysis, then the model in question is robustly ruled out. Further, we show how to assess the significance of a hypothetically computed Bayes factor. We show that the range of the distribution of Bayes factors can greatly depend on the models in question and also the number of data points in the data set. Thus, we have demonstrated that the significance of Bayes factors needs to be calculated for each unique data set.
Skylight: a new code for general-relativistic ray-tracing and radiative transfer in arbitrary space–times
Authors: Pelle Joaquin , Reula Oscar , Carrasco Federico , Bederian Carlos
Published: July 2022

To reproduce the observed spectra and light curves originated in the neighbourhood of compact objects requires accurate relativistic ray-tracing codes. In this work, we present Skylight, a new numerical code for general-relativistic ray-tracing and radiative transfer in arbitrary space–time geometries and coordinate systems. The code is capable of producing images, spectra, and light curves from astrophysical models of compact objects as seen by distant observers. We incorporate two different schemes, namely Monte Carlo radiative transfer integrating geodesics from the astrophysical region to distant observers, and camera techniques with backwards integration from the observer to the emission region. The code is validated by successfully passing several test cases, among them: thin accretion discs and neutron stars hotspot emission.
CKD-MBD biomarkers and CKD progression: an analysis by the joint model
Authors: D'Arrigo Graziella , Mallamaci Francesca , Pizzini Patrizia , Leonardis Daniela , Tripepi Giovanni , Zoccali Carmine
Published: July 2022

Background

Biomarkers of chronic kidney disease–mineral and bone disorder (CKD-MBD) have been implicated in CKD progression in follow-up studies focusing on single measurements of individual biomarkers made at baseline only. The simultaneous relationship between the time trend of these biomarkers over the course of CKD and renal outcomes has never been tested.

Methods

We applied the joint model (JM) to investigate the longitudinal relationship between repeated measurements of CKD-MBD biomarkers and a combined renal endpoint (estimated glomerular filtration rate reduction >30%, dialysis or transplantation) in 729 stage 2–5 CKD patients over a 36-month follow-up.

Results

In the survival submodel of the JM, the longitudinal series of parathyroid hormone (PTH) values was directly and independently related to the risk of renal events [hazard ratio (HR) (1 ln increase in parathyroid hormone (PTH) 2.0 (range 1.5–2.8), P < .001)] and this was also true for repeated measurements of serum phosphate [HR (1 mg/dl) 1.3924 (range 1.1459–1.6918), P = .001], serum calcium [HR (1 mg/dl) 0.7487 (range 0.5843–0.9593), P = .022], baseline fibroblast growth factor 23 [HR (1 pg/ml) 1.001 (range 1.00–1.002), P = .045] and 1,25-dihydroxyvitamin D [HR (1 pg/ml) 0.9796 (range 0.9652–0.9942), P = .006].

Conclusion

Repeated measurements of serum PTH, calcium and phosphate as well as baseline FGF23 and 1,25-dihydroxyvitamin D are independently related with the progression to kidney failure in a cohort of stage 2–5 CKD patients. This longitudinal study generates the hypothesis that interventions at multiple levels on MBD biomarkers can mitigate renal function loss in this population.
Varenicline Treatment for Waterpipe Smoking Cessation
Authors: Chami Hassan A , Zaouk Nour , Makki Maha , Tamim Hani , Shaya Monique , Talih Farid
Published: July 2022

Background

Waterpipe smoking is increasing worldwide with no proven interventions for cessation. We compared abstinence rates with 12-week varenicline therapy versus placebo among habitual waterpipe smokers willing to quit.

Methods

This double-blind placebo-controlled single-center trial, randomized waterpipe smokers from Lebanon who did not smoke other tobacco products to receive varenicline or placebo for 12 weeks. All participants also received three structured 30-minute individual behavioral intervention sessions. The primary outcome was repeated point prevalence abstinence assessed by self-report and verified by exhaled carbon monoxide three times during 12 weeks and analyzed with the intention to treat. End of treatment urine cotinine, weight, blood pressure, anxiety, depression, withdrawal, and adverse symptoms were also assessed.

Results

In total, 152 waterpipe smokers (mean age 38 years [SD = 13], 39% females) willing to quit, who smoked waterpipe exclusively (average 2.3 per day [SD = 1.6] for 16.8 years [SD = 10.8]) were randomized. Seventy-nine participants (52%) with any missing abstinence assessment were considered to have relapsed. Repeat point prevalence abstinence rate was numerically higher among the varenicline group compared to placebo, but the difference did not reach statistical significance when assessed by self-report (16.9 vs. 13.6%, respectively, p = .6) and when further verified by exhaled carbon monoxide (14.1% vs. 9.9%, respectively, p = .4). Abstinence rates were similar in both groups when further verified by urine cotinine at end of treatment. No serious adverse events were reported, adverse symptoms and other outcomes were similar in the varenicline and placebo arms.

Conclusions

Varenicline for 12 weeks was not more effective than placebo to achieve abstinence among daily waterpipe smokers.

Implications

Varenicline in combination with a behavioral intervention did not significantly enhance the quit rate among exclusive waterpipe smokers compared to behavioral intervention plus placebo. We experienced difficulty enrolling exclusive waterpipe smokers willing to quit and observed high dropout rates among participants demonstrating the difficulties of waterpipe smoking cessation.
Phytoplankton phagotrophy across nutrients and light gradients using different measurement techniques
Authors: Costa Mariana R A , Sarmento Hugo , Becker Vanessa , Bagatini Inessa L , Unrein Fernando
Published: July 2022

Mixotrophy is important to ecosystems functioning. Assuming that limiting resources induce phagotrophy in mixotrophs, we used a factorial experimental design to evaluate how nutrient and light affects phagotrophy in two mixotrophic phytoflagellates belonging to different lineages. We estimated cell-specific grazing rates (CSGR) by analyzing prey ingestion using microscopy and flow cytometry (FC). Furthermore, we tested if the acidotropic probe LysoTracker green (LyTG) can be used to differentiate autotrophs from mixotrophs. Cryptomonas marssonii (cryptophyte) had higher CSGR in high-nutrient treatments. Although it seems counterintuitive, phytoflagellates likely uses phagotrophy to obtain organic growth factors instead of inorganic nutrients when photosynthesis is more favorable. In contrast, CSGR in Ochromonas tuberculata (chrysophyte) increased when light decreased, suggesting that it uses phagotrophy to supplement carbon when autotrophic growth conditions are suboptimal. Measurements of CSGR obtained by FC and microscopy were significantly correlated and displayed the same trend among treatments, although FC rates tended to be higher. Fluorescence with LyTG did not differ from the control in the non-phagotrophic chlorophyte. Contrarily, addition of LyTG significantly increased the fluorescence in chrysophytes and cryptophytes, although no differences were observed among treatments. This approach allowed for differentiation between phagotrophic and non-phagotrophic flagellates but failed to quantify mixotrophy.
Rice DWARF AND LOW-TILLERING and the homeodomain protein OSH15 interact to regulate internode elongation via orchestrating brassinosteroid signaling and metabolism
Authors: Niu Mei , Wang Hongru , Yin Wenchao , Meng Wenjing , Xiao Yunhua , Liu Dapu , Zhang Xiaoxing , Dong Nana , Liu Jihong , Yang Yanzhao , Zhang Fan , Chu Chengcai , Tong Hongning
Published: July 2022

Brassinosteroid (BR) phytohormones play crucial roles in regulating internode elongation in rice (Oryza sativa). However, the underlying mechanism remains largely unclear. The dwarf and low-tillering (dlt) mutant is a mild BR-signaling-defective mutant. Here, we identify two dlt enhancers that show more severe shortening of the lower internodes compared to the uppermost internode (IN1). Both mutants carry alleles of ORYZA SATIVA HOMEOBOX 15 (OSH15), the founding gene for dwarf6-type mutants, which have shortened lower internodes but not IN1. Consistent with the mutant phenotype, OSH15 expression is much stronger in lower internodes, particularly in IN2, than IN1. The osh15 single mutants have impaired BR sensitivity accompanied by enhanced BR synthesis in seedlings. DLT physically interacts with OSH15 to co-regulate many genes in seedlings and internodes. OSH15 targets and promotes the expression of the BR receptor gene BR INSENSITIVE1 (OsBRI1), and DLT facilitates this regulation in a dosage-dependent manner. In osh15, dlt, and osh15 dlt, BR levels are higher in seedlings and panicles, but unexpectedly lower in internodes compared with the wild-type. Taken together, our results suggest that DLT interacts with OSH15, which functions in the lower internodes, to modulate rice internode elongation via orchestrating BR signaling and metabolism.
Making the House a Home: The Stimulative Effect of Home Purchases on Consumption and Investment
Authors: Benmelech Efraim , Guren Adam , Melzer Brian T
Published: July 2022

We introduce and quantify a new channel through which the housing market affects household spending: the home purchase channel. Households spend on average $8,000 more on home-related durables and home improvements in the 2 years following a home purchase. Expenditures on nondurables and durables unrelated to the home remain unchanged or decrease modestly. The home purchase channel played a substantial role in the Great Recession, accounting for one-third of the decline in spending on home-related durables and home improvements from 2005 to 2010.

Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online
Immunogenicity 6 months post COVID-19 mRNA vaccination among adolescents with juvenile idiopathic arthritis on treatment with TNF inhibitors
Authors: Dimopoulou Dimitra , Tsolia Maria N , Spyridis Nikos , Maritsi Despoina N
Published: July 2022

Objectives

Mass vaccination is the most effective strategy for controlling the COVID-19 pandemic. This study aimed to evaluate the 6-month immunogenicity after BNT162b2-COVID-19 vaccination in adolescents with JIA on TNFi treatment.

Methods

This single-centre study included adolescents with JIA treated with TNFi for at least 18 months. Patients received two doses of COVID-19 vaccine (Pfizer-BioNTech) from 15 April to 15 May 2021. Quantitative measurement of IgG antibodies to SARS-CoV-2-spike-protein-1 was performed at 1, 3 and 6 months post-vaccination.

Results

Overall, 21 adolescents with JIA in clinical remission at the time of vaccinations were enrolled. None of them discontinued TNFi/MTX treatment at the time of vaccine administration or during the follow-up period. All patients developed a sustained humoral response against SARS-CoV-2 at 1 and 3 months after vaccination (P < 0.05). The antibody levels decreased significantly at 6 months post-vaccination (P < 0.01). The type of JIA did not reveal any differences in the humoral response at 3 (P = 0.894) or 6 months post-vaccination (P = 0.72). No difference was detected upon comparison of the immunogenicity between the different treatment arms (adalimumab vs etanercept) at 3 (P = 0.387) and 6 months (P = 0.526), or TNFi monotherapy vs combined therapy (TNFi plus methotrexate) at 3 (P = 0.623) and 6 months (P = 0.885).

Conclusions

Although mRNA vaccines develop satisfactory immunogenicity at 1 month and 3 months post-vaccination in adolescents with JIA on TNFi, SARS-CoV-2 antibody titres decrease significantly overtime, remaining at lower levels at 6 months. Further collaborative studies are required to determine long-term immunogenicity, real duration of immune protection and the need for a booster vaccine dose.
Long-term cardiovascular outcomes and temporal trends in patients diagnosed with ANCA-associated vasculitis: a Danish nationwide registry study
Authors: Nygaard Louis , Polcwiartek Christoffer , Nelveg-Kristensen Karl Emil , Carlson Nicholas , Kristensen Salome , Torp-Pedersen Christian , Gregersen Jon Waarst
Published: July 2022

Objectives

To examine long-term cardiovascular outcomes and temporal trends among patients with ANCA-associated vasculitis (AAV) using Danish nationwide registries.

Methods

Using a cohort design, we examined patients with granulomatosis with polyangiitis (ICD-10: DM31.3) and microscopic polyangiitis (ICD-10: DM3.17) in Denmark from 1996–2018. Hazard ratios (HRs) of cardiovascular outcomes were compared between patients with AAV and age and gender-matched controls. Counterfactual G-estimation of HRs was performed to estimate 5-year absolute risks. Temporal trends were obtained by grouping cohorts into evenly distributed tertiles according to inclusion year.

Results

A total of 2306 patients with AAV (median age: 62.9yrs, 52.6% male) were matched with 6918 controls. Median follow-up was 9.5yrs. Patients with AAV had a higher rate of ischaemic heart disease [HR 1.86 (1.62–2.15)], myocardial infarction [HR 1.62 (1.26–2.09)], coronary angiogram [HR 1.64 (1.37–1.96)], percutaneous coronary intervention [HR 1.56 (1.17–2.07)] and ventricular arrhythmias/implantable-cardioverter-defibrillator (ICD)-implantations [HR 2.04 (1.16–3.57)]. Similarly, an increased rate of heart failure [HR 2.12 (1.77–2.54)], deep vein thrombosis [HR 3.13 (2.43–4.05)], pulmonary embolism [HR 4.04 (3.07–5.32)], atrial fibrillation [HR 2.08 (1.82–2.39)], ischaemic stroke [HR 1.58 (1.31–1.90)] and in-hospital cardiac arrest [HR 2.27 (1.49–3.48)] was observed. The 5-year risk of all outcomes were significantly higher (excluding ventricular arrhythmia/ICD-implantations). For temporal trends among patients with AAV, a decreased 3-year risk of cardiovascular mortality was observed over time.

Conclusions

Patients with AAV are at increased risk of heart failure, atrial-/ventricular arrhythmias, venous thrombotic events, ischaemic stroke and myocardial infarction. Furthermore, patients with AAV were more frequently examined with coronary procedures and underwent more coronary revascularizations. No temporal changes in ischaemic cardiovascular outcomes were observed, albeit the cardiovascular mortality has decreased over time.
Leverage and Cash Dynamics
Authors: DeAngelo Harry , Gonçalves Andrei S , Stulz René M
Published: July 2022

This article documents new and empirically important interactions between cash-balance and leverage dynamics. Cash ratios typically vary widely over extended horizons, with dynamics remarkably similar to (and complementary with) those of capital structure. Leverage and cash dynamics interact approximately as predicted by the internal-versus-external funding regimes in Myers and Majluf (1984, J. Finan. Econ., 13, 187–221.). Leverage is quite volatile when cash ratios are stable and vice-versa, while net-debt ratios are almost always volatile. Most firms increase leverage sharply as cash balances (internal funds) become scarce. Capital structure models that extend Hennessy and Whited (2005, J. Finan., 60, 1129–1165.) to include cash-balance dynamics explain some, but not all, aspects of the observed relation between cash squeezes and leverage increases.
Bacterial Leaf Blight of Polyscias guilfoylei Caused by a Novel Pathovar of Xanthomonas euvesicatoria
Authors: Wang Liang-Hsuan , Chan Jiun-Jie , Wang Yi-Hsin , Fang Zi-Qing , Lee Shin , Chu Chia-Ching
Published: July 2022

Polyscias guilfoylei is a popular ornamental belonging to the Araliaceae family. The present study identified and characterized bacterial strains causing leaf lesions on P. guilfoylei in a nursery in Taiwan. Strains Pgu1 to Pgu5 were isolated from infected leaf tissues and Koch’s postulates were fulfilled. Observation of Pgu1 under a transmission electron microscope revealed that its cells were single flagellated and rod shaped. Sequencing of Pgu1 to Pgu5’s 16S ribosomal DNA showed that they belong to the genus Xanthomonas. The biochemical and physiological traits of these bacteria were determined, and many of them also resemble those of other xanthomonads. However, the strains were unable to produce yellow pigments typically found in most members of the Xanthomonas genus, even when grown on yeast dextrose calcium carbonate (YDC) agar. Physiological assays and phylogenetic analyses based on multiple loci showed that the isolates were closely associated with members of the species Xanthomonas euvesicatoria and phylogenetically distant from X. hortorum pv. hederae, the currently only known xanthomonad capable of inducing diseases on Polyscias spp. Artificial inoculation into different host plants revealed that a representative strain, Pgu1, is specialized to P. guilfoylei and perhaps other members of the Araliaceae family. Based on the results from the phylogenetic and phenotypic analyses, the present work concludes that these strains belong to a novel pathovar of X. euvesicatoria. The pathovar epithet polysciadis is proposed.
Efficient Elimination of Actinidia Chlorotic Ringspot-Associated Virus from Infected Kiwifruit Shoots Cultured In Vitro
Authors: Wang Yicheng , Sun Jiaxiu , Wang Jingke , Sujata Shrestha , Huang Qianru , Hou Caiting , Wu Yunfeng , Zhao Lei
Published: July 2022

In this study, methods of Actinidia chlorotic ringspot-associated virus (AcCRaV) elimination by shoot tip culture, thermotherapy followed by shoot tip culture, and chemotherapy followed by shoot tip culture were explored. The results showed that the AcCRaV elimination rate was 23.3% when the secondary shoot tip culture method was used and when the shoot tip length was less than 0.5 mm. The AcCRaV elimination rate was 100% when thermotherapy (36°C [day] and 32°C [night]) was applied for 20 days followed by shoot tip culture (shoot tip length less than 1.0 mm). When shoot segments were treated with ribavirin at 15 µg/ml for 2 months followed by shoot tip culture, the elimination rate of AcCRaV was 100% (shoot tip length less than 1.0 mm). When shoot segments were treated with ribavirin at 25 µg/ml for 2 months followed by shoot tip culture, the elimination rate of AcCRaV was 100% (shoot tip length less than 1.5 mm). This is the first report on kiwifruit virus elimination methods.
Anesthetic considerations for endovascular treatment in stroke therapy
Authors: Stolp Jeffrey , Coutinho Jonathan M. , Immink Rogier V. , Preckel Benedikt
Published: July 2022

Purpose of review

The introduction of clot removement by endovascular treatment (EVT) in 2015 has improved the clinical outcome of patients with acute ischemic stroke (AIS) due to a large vessel occlusion (LVO). Anesthetic strategies during EVT vary widely between hospitals, with some departments employing local anesthesia (LA), others performing conscious sedation (CS) or general anesthesia (GA). The optimal anesthetic strategy remains debated. This review will describe the effects of anesthetic strategy on clinical and radiological outcomes and hemodynamic parameters in patients with AIS undergoing EVT.

Recent findings

Small single-center randomized controlled trails (RCTs) found either no difference or favored GA, while large observational cohort studies favored CS or LA. RCTs using LA as separate comparator arm are still lacking and a meta-analysis of observational studies failed to show differences in functional outcome between LA vs. other anesthetic strategies. Advantages of LA were shorter door-to-groin time in patients and less intraprocedural hypotension, which are both variables that are known to impact functional outcome.

The optimal anesthetic approach in patients undergoing EVT for stroke therapy is still unclear, but based on logistics and peri-procedural hemodynamics, LA may be the optimal choice. Multicenter RCTs are warranted comparing LA, CS and GS with strict blood pressure targets and use of the same anesthetic agents to minimize confounding variables.
In Vivo Evidence of Early Instability and Late Stabilization in Motion Segments Immediately Superior to Anterior Cervical Arthrodesis
Authors: Chen Stephen R. , LeVasseur Clarissa M. , Pitcairn Samuel , Munsch Maria A. , Couch Brandon K. , Kanter Adam S. , Okonkwo David O. , Shaw Jeremy D. , Donaldson William F. , Lee Joon Y. , Anderst William J.
Published: July 2022

Study Design.

Prospective cohort study.

Objective.

The aim was to identify patient factors that affect adjacent segment kinematics after anterior cervical discectomy and fusion (ACDF) as measured by biplane radiography.

Summary of Background Data.

The etiology of adjacent segment disease (ASD) may be multifactorial. Previous studies have investigated associations between patient factors and ASD, although few attempted to link patient factors with mechanical changes in the spine that may explain ASD development. Previous studies manually measured intervertebral motion from static flexion/extension radiographs, however, manual measurements are unreliable, and those studies failed to measure intervertebral motion during rotation.

Methods.

Patients had continuous cervical spine flexion/extension and axial rotation movements captured at 30 images per second in a dynamic biplane radiography system preoperatively and 1 year after ACDF. Digitally reconstructed radiographs generated from subject-specific computed tomography scans were matched to the biplane radiographs using a validated tracking process. Dynamic kinematics and preoperative disc height were calculated from this tracking process. Preoperative magnetic resonance imagings were evaluated for disc bulge. Patient age, sex, body mass index, smoking status, diabetes, psychiatric history, presence of an inciting event, and length of symptoms were collected. Multivariate linear regression was performed to identify patient factors associated with 1-year postoperative changes in adjacent segment kinematics.

Results.

Sixty-three patients completed preoperative and postoperative testing. Superior adjacent segment disc height and disc bulge predicted the change in superior adjacent segment range of motion after surgery. Inferior adjacent segment disc bulge, smoking history, and the use of psychiatric medications predicted the change in inferior adjacent segment flexion/extension range of motion after surgery.

Conclusions.

Preexisting adjacent segment disc degeneration, as indicated by disc height and disc bulge, was associated with reduced adjacent segment motion after ACDF, while lack of preexisting adjacent disc degeneration was associated with increased adjacent segment motion after ACDF. These findings provide in vivo evidence supporting early instability and late stabilization in the pathophysiology of disc degeneration.
The Multi-Kinase Inhibitor Lucitanib Enhances the Antitumor Activity of Coinhibitory and Costimulatory Immune Pathway Modulators in Syngeneic Models
Authors: Robillard Liliane , Liao Mingxiang , Nguyen Minh , Harding Thomas C. , Simmons Andrew D. , Dusek Rachel L.
Published: July 2022

Lucitanib is a multi-tyrosine kinase inhibitor whose targets are associated with angiogenesis and other key cancer and immune pathways. Its antiangiogenic properties are understood, but lucitanib’s immunomodulatory activity is heretofore unknown. Lucitanib exhibited such activity in vivo, increasing CD3+, CD8+, and CD4+ T cells and decreasing dendritic cells and monocyte-derived suppressor cells in mouse spleens. Depletion of CD8+ T cells from syngeneic MC38 colon tumor-bearing mice reduced the antitumor efficacy of lucitanib and revealed a CD8+ T-cell-dependent component of lucitanib’s activity. The combination of lucitanib and costimulatory immune pathway agonists targeting 4-1BB, glucocorticoid-induced TNFR (GITR), inducible T-cell co-stimulator (ICOS), or OX40 exhibited enhanced antitumor activity compared with each single agent in immunocompetent tumor models. Lucitanib combined with blockade of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or programmed cell death protein-1 (PD-1) coinhibitory immune pathways also showed enhanced antitumor activity over the single agents in multiple models. In CT26 tumors, lucitanib, alone or combined with anti-PD-1, reduced CD31+ vessels and depleted F4/80+ macrophages. Combination treatment also increased the number of intratumoral T cells. Gene expression in pathways associated with immune activity was upregulated by lucitanib in MC38 tumors and further potentiated by combination with anti-PD-1. Accordingly, lucitanib, alone or combined with anti-PD-1, increased intratumoral CD8+ T-cell abundance. Lucitanib’s antitumor and pharmacodynamic activity, alone or combined with anti-PD-1, was not recapitulated by specific vascular endothelial growth factor receptor-2 (VEGFR2) inhibition. These data indicate that lucitanib can modulate vascular and immune components of the tumor microenvironment and cooperate with immunotherapy to enhance antitumor efficacy. They support the clinical development of lucitanib combined with immune pathway modulators to treat cancer.
Bile acids and sphingolipids in non-alcoholic fatty liver disease
Authors: Jackson Kaitlyn G. , Way Grayson W. , Zhou Huiping
Published: July 2022

Non-alcoholic fatty liver disease (NAFLD) is one of the fastest-growing diseases, and its global prevalence is estimated to increase >50% by 2030. NAFLD is comorbid with metabolic syndrome, obesity, type 2 diabetes, and insulin resistance. Despite extensive research efforts, there are no pharmacologic or biological therapeutics for the treatment of NAFLD. Bile acids and sphingolipids are well-characterized signaling molecules. Over the last few decades, researchers have uncovered potential mechanisms by which bile acids and sphingolipids regulate hepatic lipid metabolism. Dysregulation of bile acid and sphingolipid metabolism has been linked to steatosis, inflammation, and fibrosis in patients with NAFLD. This clinical observation has been recapitulated in animal models, which are well-accepted by experts in the hepatology field. Recent transcriptomic and lipidomic studies also show that sphingolipids are important players in the pathogenesis of NAFLD. Moreover, the identification of bile acids as activators of sphingolipid-mediated signaling pathways established a novel theory for bile acid and sphingolipid biology. In this review, we summarize the recent advances in the understanding of bile acid and sphingolipid-mediated signaling pathways as potential contributors to NAFLD. A better understanding of the pathologic effects mediated by bile acids and sphingolipids will facilitate the development of new diagnostic and therapeutic strategies for NAFLD.
Prognostic significance of tumor budding in melanoma
Authors: Lino-Silva Leonardo S. , Zepeda-Najar César , Caro-Sánchez Claudia H. , Herrera-Gómez Ángel , Salcedo-Hernández Rosa A.
Published: July 2022

Cutaneous melanoma is an aggressive neoplasm with growing incidence and continuous research is undertaken for novel prognostic factors. This current research aims to determine if tumor budding is an independent factor that correlates with the survival of patients with melanoma. A total of 742 cases of melanoma were evaluated. A receiver operating curve (ROC) was performed to analyze tumor budding impact on survival, identifying a cutoff point associated with death. Subsequently, two groups of participants were created based on that result. Participants within the two groups were compared for clinicopathologic characteristics and survival analysis. Also, a multivariate analysis was performed. Of the total, 447 (60.2%) melanomas occurred in women and 295 in men. The mean age was 57.5 years + 15.75. The most common location was in acral areas (68.2%) followed by trunk (16.7%) and head and neck (15.1%). At presentation, 142 cases (19.1%) presented as stage I, 307 (41.4%) as stage II, 269 (36.3%) as stage III, and 24 (3, 2%) in stage IV. Regarding tumor budding, 586 (79%) cases showed tumor budding (at least one bud in 0.785 mm2), with a median of 5. From the ROC curve, 4.5 tumor buds/0.785 mm2 was the best cutoff point for correlation with death, grouping the series in low budding (0–4 buds/0.785 mm2) and high budding (>5 buds/0.785 mm2). Cases with high tumor budding were associated with older age, acral location, advanced clinical stages, ulceration, recurrence, and death. High tumor budding was associated with a significant decrease in 5-year overall survival (94.4% vs. 55.5%, P < 0.001). In the multivariate analysis, the factors remaining as independent predictors of survival were acral location, clinical stage IV, recurrence during clinical follow-up, and high tumor budding. High tumor budding (>5 buds in 0.785 mm2) independently correlates with 5-year overall survival rates and is associated with older age, acral location, advanced clinical stages, ulceration, recurrence, and death.
Febuxostat Protects Human Aortic Valve Endothelial Cells From Oxidized Low-density Lipoprotein–Induced Injury and Monocyte Attachment
Authors: Liang Xiangwen , Li Ping , Xie Wenchao , Lin Zhihai , Wang Zhengdong , Zeng Shuyi , Liu Ming
Published: July 2022

Atherosclerosis (AS) is a common cardiovascular disease with high morbidity and mortality. The pathogenesis of AS is closely related to endothelial dysfunction, which is mainly induced by oxidative stress, inflammation, and enhanced adhesion of monocytes to endothelial cells on the vessel wall. Febuxostat is a novel antigout agent recently reported to exert protective effects on endothelial dysfunction. This study aims to investigate the protective capacity of febuxostat against oxidized low-density lipoprotein (ox-LDL)-induced injury and monocyte attachment to endothelial cells. Human aortic valve endothelial cells (HAVECs) were stimulated with ox-LDL in the presence or absence of febuxostat (5 and 10 μM) for 6 hours. Mitochondrial reactive oxygen species were measured using MitoSox red staining, and the level of protein carbonyl was detected using enzyme-linked immunosorbent assay (ELISA). The expressions of IL-6, TNF-α, tissue factor (TF), VCAM-1, and ICAM-1 were evaluated with qRT-PCR assay and ELISA. Calcein-AM staining was used to determine the attachment of U937 monocytes to HAVECs. quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and Western blot were used to measure the expression level of early growth response 1 (Egr-1) in HAVECs. First, the elevated expression of LOX-1, activated oxidative stress, excessive secreted inflammatory factors, and promoted expression of TF induced by stimulation with ox-LDL were significantly reversed by febuxostat, indicating a protective effect of febuxostat against endothelial dysfunction. Second, the upregulated VCAM-1 and ICAM-1, as well as the increased proportion of adhered monocytes to HAVECs induced by ox-LDL, were significantly alleviated by febuxostat. Finally, the promoted expression level of Egr-1 induced by ox-LDL was pronouncedly suppressed by febuxostat. We conclude that febuxostat protected HAVECs from ox-LDL–induced injury and monocyte attachment.
Necrotizing Soft Tissue Infection of Abdominal Wall after Lipoabdominoplasty: Complication following Medical Tourism
Authors: Shrestha Sabi , Lue Melinda , Wang Howard T.
Published: July 2022

Necrotizing soft tissue infection (NSTI) is an acute life-threatening complication of cosmetic surgery. We present a case study of a 48-year-old woman diagnosed with NSTI of the abdominal wall following liposuction, abdominoplasty, and ventral hernia repair performed in Latin America. In the operating room, bowel perforation at the hepatic flexure was observed requiring emergent fascial debridement, bowel resection, and broad-spectrum antibiotics. She required multiple washouts and split-thickness skin grafts. Complications such as NSTI are possible after lipoabdominoplasty and are prevalent in cosmetic medical tourism, due, in part, to varying institutional standards and accreditations, and in some cases lack of consistent adherence to set standards. Complications after medical tourism contribute a significant burden to medical staff and the healthcare system in patients’ home countries. Patient education by their surgeons and plastic surgery societies should be prioritized. It is important for domestic emergency physicians, plastic surgeons, and other care providers to understand complications postcosmetic surgery to promote timely management.
Sex differences in ambulatory blood pressure levels, control and phenotypes of hypertension in hemodialysis patients
Authors: Theodorakopoulou Marieta P. , Karagiannidis Artemios G. , Alexandrou Maria-Eleni , Polychronidou Georgia , Karpetas Antonios , Giannakoulas George , Papagianni Aikaterini , Sarafidis Pantelis A.
Published: July 2022

Background and aims:

Ambulatory blood pressure (BP) control is worse in men than women with chronic kidney disease or kidney transplantation. So far, no study investigated possible sex differences in the prevalence, control, and phenotypes of BP according to predialysis and 48-h ambulatory blood pressure monitoring (ABPM) in hemodialysis patients. Further, no study has evaluated the diagnostic accuracy of predialysis BP in male and female hemodialysis patients.

Method:

One hundred and twenty-nine male and 91 female hemodialysis patients that underwent 48-h ABPM were included in this analysis. Hypertension was defined as: (1) predialysis SBP ≥140 or DBP ≥90 mmHg or use of antihypertensive agents, (2) 48-h SBP ≥130 or DBP ≥80 mmHg or use of antihypertensive agents.

Results:

Predialysis SBP did not differ between groups, while DBP was marginally higher in men. 48-h SBP (137.2 ± 17.4 vs. 132.2 ± 19.2 mmHg, P = 0.045), DBP (81.9 ± 12.1 vs. 75.9 ± 11.7 mmHg, P < 0.001) and daytime SBP/DBP were higher in men. The prevalence of hypertension was not different between groups with the use of predialysis BP or 48-h ABPM (92.2% vs. 89%, P = 0.411). However, concordant lack of control was more frequent in men than women (65.3% vs. 49.4%, P = 0.023). The prevalence of white-coat and masked hypertension did not differ between groups; the misclassification rate with the use of predialysis BP was marginally higher in women. In both sexes, predialysis BP showed low accuracy and poor agreement with ABPM for diagnosing ambulatory hypertension [area-under-the-curve in receiver-operating-curve analyses (SBP/DBP): men, 0.681/0.802, women: 0.586/0.707].

Conclusion:

Ambulatory BP levels are higher in male than female hemodialysis patients. Although hypertension prevalence is similar between sexes, men have worse rates of control. The diagnostic accuracy of predialysis BP was equally poor in men and women.
Update on the Corneal Dystrophies—Genetic Testing and Therapy
Authors: Weiss Jayne S. , Willoughby Colin E. , Abad–Morales Víctor , Turunen Joni A. , Lisch Walter
Published: July 2022

One major purpose of the IC3D Corneal Dystrophy Nomenclature Revision was to include genetic information with a goal of facilitating investigation into the pathogenesis, treatment, and perhaps even prevention of the corneal dystrophies, an ambitious goal. Over a decade has passed since the first publication of the IC3D Corneal Dystrophy Nomenclature Revision. Gene therapy is available for an early-onset form of inherited retinal degeneration called Leber congenital amaurosis, but not yet for corneal degenerations. We review the current state of affairs regarding our original ambitious goal. We discuss genetic testing, gene therapy [RNA interference (RNAi) and genome editing], and ocular delivery of corneal gene therapy for the corneal dystrophies. Why have gene therapy techniques not yet been introduced for the corneal dystrophies?
Mini-DMEK for the Treatment of Chronic Focal Corneal Endothelial Decompensation
Authors: Händel Alexander , Siebelmann Sebastian , Matthaei Mario , Cursiefen Claus , Bachmann Björn
Published: July 2022

Purpose:

The purpose of the study was to evaluate the feasibility of mini-descemet membrane endothelial keratoplasty (“Mini-DMEK,” graft diameter <5 mm) for the treatment of chronic focal corneal endothelial decompensation for reasons other than acute hydrops in patients with keratoconus.

Methods:

Of the 3010 patients registered in the prospective Cologne DMEK database, 16 patients with focal corneal endothelial decompensation treated with Mini-DMEK were identified. After exclusion of patients with acute hydrops in keratoconus (n = 9), indications for focal corneal endothelial decompensation were either defects in Descemet membrane after intraocular surgeries (n = 5) or corneal edema in the area of Haab striae in buphthalmus (n = 2). Best spectacle-corrected visual acuity, corneal thickness in the affected area, and rebubbling rates served as main outcome measures.

Results:

All patients showed a postoperative increase in the best spectacle-corrected visual acuity from preoperative logarithm of the minimum angle of resolution (logMAR) 1.1 (±0.7) to logMAR 0.3 (±0.2) after the first month (P = 0.046) and to logMAR 0.3 (±0.2) after half a year (5–7 months) (P = 0.025). The corneal thickness decreased from preoperative 757 μm (±125) to 603 μm (±121) after the first month (P = 0.031) and to 593 μm (±131) after half a year (5–7 months) (P = 0.031). Rebubbling was necessary in 43% of patients (3 of 7 eyes). In 2 patients, Mini-DMEK was performed as triple Mini-DMEK including cataract surgery.

Conclusions:

Mini-DMEK is an effective treatment option for focal chronic corneal endothelial decompensation caused by tears in Descemet membrane or other defects such as Haab striae. Mini-DMEK can also be performed as a triple procedure including cataract surgery (triple Mini-DMEK).
Pegylated Interferon Alpha 2a for the Treatment of Ocular Surface Squamous Neoplasia
Authors: Park Jongyeop , Han Jisang , Chung Tae-Young , Lim Dong Hui , Choi Chul Young
Published: July 2022

Purpose:

The purpose of this study was to introduce the initial experience in the use of topical pegylated interferon alpha 2a (PegIFN-α-2a) for ocular surface squamous neoplasia (OSSN).

Methods:

A retrospective medical record review of 8 eyes of 8 patients diagnosed with OSSN and treated with PegIFN-α-2a was performed. All cases were diagnosed of noninvasive OSSN both clinically and histologically. The pegIFN-α-2a was prescribed at a concentration of 20 μg/mL and applied 4 times a day for at least 3 months.

Results:

In all 8 cases, topical PegIFN-α-2a was well-tolerated and did not lead to discomfort or any adverse side effects. It resulted in reduction in lesion size and extent in all cases and complete resolution of the lesions.

Conclusions:

Topical PegIFN-α-2a might be an effective and safe treatment option for noninvasive OSSN.
Levator Palpebrae Superioris with Inferior Oblique Muscle Flaps for Total Ocular Surface Reconstruction
Authors: Maeng Michelle M. , Casella Alicia , Shoji Marissa K. , Amescua Guillermo , Rong Andrew J.
Published: July 2022

A healthy middle-aged man sustained extensive burns after a motor vehicle accident, including fourth-degree burns to the ocular adnexa. He had bilateral eyelid necrosis with complete tissue loss to the orbital rim. Progressive corneal thinning occurred bilaterally despite frequent lubrication, weekly amniotic membrane placement, and a Gunderson flap, ultimately requiring evisceration of his OS. In accordance with family wishes to perform all interventions for the OD, he underwent ocular surface reconstruction with levator palpebrae superioris (LPS) and inferior oblique (IO) muscle flaps, supplemented with an orbital fat transfer and bucket-handle muscle flap. These flaps were covered with porcine urinary bladder matrix and remained viable with complete globe coverage postoperatively. Although local eyelid flaps traditionally involve tissue supplied by branches of the external carotid artery, this case suggests that orbital-internal carotid artery based flaps utilizing the LPS and IO muscles may achieve ocular surface coverage after complete periocular and facial soft tissue loss.
Ocular–Oral Synkinesis Without Facial Palsy After Trauma: A Case Report
Authors: Gu Tianyi , Zhao Minghao , Zhang Chao
Published: July 2022

Ocular–oral synkinesis refers to the unintended contraction of the perioral muscles during voluntary eye closure. This phenomenon can either be congenital or occasionally develop during recovery from facial palsy. In this study, we report a case of ocular–oral synkinesis without facial palsy after trauma.
Long Term Effect of Canaloplasty on IOP and use of IOP-Lowering Medications in Patients with Open Angle Glaucoma
Authors: Ondrejka Simon , Körber Norbert , Dhamdhere Kavita
Published: July 2022

Purpose:

To assess the long-term safety and effectiveness of canaloplasty in reducing intraocular pressure (IOP) and use of IOP-lowering medications in eyes with open-angle glaucoma (OAG).

Setting:

Surgical center (Augencentrum Köln, Köln, Germany).

Design:

Retrospective study of 206 eyes from 130 patients.

Methods:

Canaloplasty was performed using the VISCO360® or OMNI® surgical system as a stand-alone procedure in 22 eyes and concomitantly with cataract extraction (CE) in 185 eyes with chronic OAG insufficiently controlled or intolerant to IOP-lowering medications. The number of hypotensive medications and IOP were recorded at baseline, Day 1, Week 1, Month 1, Month 3, and every three months thereafter, with the last follow-up visit at 36±6 months post-surgery. Patients were stratified by baseline IOP (Group 1, IOP >18 mmHg; Group 2, IOP ≤18 mmHg). Treatment success in Group 1 was defined as a reduction in IOP and the use of IOP-lowering medications; Group 2 success was defined as maintenance of a lower IOP and a reduction in medication use.

Results:

Preoperative mean IOP of both Groups was 21.1±8.8 mmHg, with an average 2.0±0.9 hypotensive medications. The primary success endpoint was met by 73% of patients, with a mean IOP reduction in Group 1 (131 eyes; 21.8 to 15.6 mmHg, p < 0.0001), and a maintenance of IOP control in Group 2 (76 eyes; 15.4 to 13.9 mmHg, p = 0.24). Medications decreased from 2.2±0.9 to 0.9±1.1 in Group 1 (P = 0.024) and from 1.8±0.8 to 0.7±1.0 in Group 2 (P = 0.003).

Conclusions:

Canaloplasty alone or in conjunction with CE with the VISCO360 or OMNI surgical system is a safe, tissue-sparing and effective MIGS, using a clear corneal incision in phakic or pseudophakic eyes. Canaloplasty performed with both evaluated devices achieved statistically significant, consistent and clinically meaningful reductions in IOP and use of IOP-lowering medications in adult patients with OAG. In the consistent cohort (n=42), the IOP lowering effect lasted up to 42 months, with ongoing data collection expected to describe long-term effectiveness of this intervention.