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Chimeric RNAs are hybrid transcripts containing exons from two separate genes. Chimeric RNAs are traditionally considered to be transcribed from fusion genes caused by chromosomal rearrangement. These canonical chimeric RNAs are well characterized to be expressed in a cancer-unique pattern and/or act as oncogene products. However, benefited by the development of advanced deep sequencing technologies, novel types of non-canonical chimeric RNAs have been discovered to be generated from intergenic splicing without genomic aberrations. They can be formed through trans-splicing or cis-splicing between adjacent genes (cis-SAGe) mechanisms. Non-canonical chimeric RNAs are widely detected in normal physiology, although several have been shown to have a cancer-specific expression pattern. Further studies have indicated that some of them play fundamental roles in controlling cell growth and motility, and may have functions independent of the parental genes. These discoveries are unveiling a new layer of the functional transcriptome and are also raising the possibility of utilizing non-canonical chimeric RNAs as cancer diagnostic markers and therapeutic targets. In this chapter, we will overview different categories of chimeric RNAs and their expression in various types of cancerous and normal samples. Acknowledging that chimeric RNAs are not unique to cancer, we will discuss both bioinformatic and biological methods to identify credible cancer-specific chimeric RNAs. Furthermore, we will describe downstream methods to explore their molecular processing mechanisms and potential functions. A better understanding of the biogenesis mechanisms and functional products of cancer-specific chimeric RNAs will pave ways for the development of novel cancer biomarkers and therapeutic targets.

Robotic-assisted laparoscopic surgery (RALS) is evolving as an important surgical approach in the field of general surgery. We aimed to evaluate the learning curve for RALS procedures involving repair of hiatal hernias. A series of robotic-assisted hiatal hernia (HH) repairs were performed between 2013 and 2017 by a surgeon at a single institution. Data were entered into a retrospective database. Patient demographics and intraoperative parameters including console time (CT), surgery time (ST), and total operative time (OT) were examined and abstracted for learning curve analysis using the cumulative sum (CUSUM) method. Assessment of perioperative and post-operative outcomes were calculated using descriptive statistics. The average age of the patients was 57.4 years, average BMI was 29.9 kg/m2, median American Society of Anesthesiologists (ASA) classification was 2, and average Charlson Comorbidity Index (CCI) score was 2.8. The series had a mean CT of 132.6 min, mean ST of 145.1 min, and mean OT of 197.4 min. The CUSUM learning curve for CT was best approximated as a third-order polynomial consisting of three unique phases: the initial training phase (case 1–40), the improvement phase (case 41–85), and the mastery phase (case 86 onwards). There was no significant difference in perioperative complications between the phases. Short-term clinical outcomes were comparable with national standards and did not correlate significantly with operative experience. The three phases identified with CUSUM analysis represented characteristic stages of the learning curve for robotic hiatal hernia procedures. Our data suggest the training phase is achieved after 40 cases and a high level of mastery is achieved after approximately 85 cases. Thus, the CUSUM method serves as a useful tool for objectively evaluating practical skills for surgeons and can ultimately help establish milestones that assess surgical competency during robotic surgery training.

Chimeric RNAs are hybrid transcripts containing exons from two separate genes. Chimeric RNAs are traditionally considered to be transcribed from fusion genes caused by chromosomal rearrangement. These canonical chimeric RNAs are well characterized to be expressed in a cancer-unique pattern and/or act as oncogene products. However, benefited by the development of advanced deep sequencing technologies, novel types of non-canonical chimeric RNAs have been discovered to be generated from intergenic splicing without genomic aberrations. They can be formed through trans-splicing or cis-splicing between adjacent genes (cis-SAGe) mechanisms. Non-canonical chimeric RNAs are widely detected in normal physiology, although several have been shown to have a cancer-specific expression pattern. Further studies have indicated that some of them play fundamental roles in controlling cell growth and motility, and may have functions independent of the parental genes. These discoveries are unveiling a new layer of the functional transcriptome and are also raising the possibility of utilizing non-canonical chimeric RNAs as cancer diagnostic markers and therapeutic targets. In this chapter, we will overview different categories of chimeric RNAs and their expression in various types of cancerous and normal samples. Acknowledging that chimeric RNAs are not unique to cancer, we will discuss both bioinformatic and biological methods to identify credible cancer-specific chimeric RNAs. Furthermore, we will describe downstream methods to explore their molecular processing mechanisms and potential functions. A better understanding of the biogenesis mechanisms and functional products of cancer-specific chimeric RNAs will pave ways for the development of novel cancer biomarkers and therapeutic targets.

Fe–Ni alloy nanowires are widely used in high-density magnetic memories and catalysts due to their unique magnetic and electrochemical properties. Understanding the deformation mechanism and mechanical property of Fe–Ni alloy nanowires is of great importance for the development of devices. However, the detailed deformation mechanism of the alloy nanowires at different temperatures is unclear. Herein, the deformation mechanism of Fe–Ni alloy nanowires and their mechanical properties were investigated via the molecular dynamics simulation method. It was found that the local atomic pressure fluctuation of the Fe–Ni alloy nanowire surface became more prominent with an increase in the Ni content. At low temperature conditions (

To identify the incidence, location, etiology, and mortality of major vascular injuries in gynecologic laparoscopy for benign indications.A systematic review of PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and MEDLINE was conducted.One thousand ninety-seven studies were screened for inclusion with 147 full-text articles reviewed. Sixty-six studies published between 1978 and 2016 met inclusion criteria, representing 197,062 surgeries. Articles that were included reported the incidence of major vascular injuries during gynecologic laparoscopy for benign indications. Exclusion criteria included surgery for gynecologic malignancy, duplicated data, case series and reports, manuscripts not in English, and studies published only as abstracts.Injuries to the aorta, inferior vena cava, iliac (common, external, or internal), and inferior epigastric vessels were recorded, as were injuries denoted as major but not otherwise specified. A total of 179 major vascular injuries were reported with an incidence of 0.09% (95% CI 0.08-0.10). The inferior epigastric vessels were the most commonly injured vessel (0.04%, 95% CI 0.03-0.05), comprising 48% (95% CI 40-55) of all injuries. The majority of injuries occurred during abdominal entry (82%, 95% CI 76-89), and the remainder occurred during surgical dissection (18%, 95% CI 11-24). Most injuries were recognized intraoperatively (93%, 95% CI 87-100), and approximately half (55%, 95% CI 46-63) required laparotomy for repair. Only two of the 179 major vascular injuries resulted in death, for an overall mortality rate from vascular injuries of 0.001% (95% CI 0.000-0.004).The incidence of major vascular injury during gynecologic laparoscopy found in this review is very low, and the vast majority of injuries did not result in death. Laparoscopy remains a safe surgical technique in relation to vascular injuries when performed for benign gynecologic disease.

As a devastating complication of non-small cell lung cancer (NSCLC), the incidence of leptomeningeal metastasis (LM) is rising, largely due to overall longer survival of NSCLC, especially in patients with targetable molecular driver mutations. There is no clear consensus on the optimal management of LM. This review will cover recent advances in diagnosis, monitoring, and treatment of LM in NSCLC. In LM without oncogene drivers, systemic chemotherapy, intrathecal therapy, and radiation have modestly improved the clinical outcomes. Emerging data have also suggested encouraging activity of immunotherapy. At the same time, in LM with sensitizing EGFR mutations, osimertinib should be considered regardless of T790M status. Pulse erlotinib, afatinib, and newer agents with improved CNS penetration have also shown benefits. Moreover, accumulating evidences support potential benefits of molecularly targeted therapy in ALK-rearranged and other oncogene-driven NSCLC with LM. Future studies are warranted to better define the underlying mechanism, to optimize the clinical management, and to improve patient outcomes.

We evaluated the impact of diurnal variation on choroidal and retinal microvasculature and structural measurements using a swept-source optical coherence tomography angiography machine (SS-OCTA; PLEX Elite 9,000, Carl Zeiss Meditec, Inc., Dublin, USA). Fourteen participants who were without ocular diseases underwent SS-OCTA imaging using 3 × 3-mm2 macular scan pattern on two separate days at five time points. Choriocapillaris flow voids were generated to determine its density (percentage), size (μm) and numbers. Perfusion densities of the large superficial vessels, as well as capillaries on superficial and deep vascular plexuses were generated from retinal angiograms. Subfoveal choroidal and retinal thicknesses were manually measured. Repeated-measures ANOVA was used to investigate the impact of diurnal variation on choroidal and retinal measurements. There was no observable diurnal pattern for any of the flow void features, in terms of the density, size and numbers. There was a significant diurnal pattern observed in the choroidal thickness, where it decreased progressively during the day (P

Purpose To evaluate the change of retinal thickness and ocular microvasculature in a rat model of retinitis pigmentosa using swept source optical coherence tomography angiography (SS-OCTA). Methods Three-weeks-old Royal College of Surgeons (RCS) rats (n = 8) and age-matched control rats (n = 14) were imaged by a prototype SS-OCTA system. Follow-up measurements occurred every three weeks on six RCS rats until week 18, and cross-sectional measurements were conducted on control rats. Thicknesses of different retinal layers and the total retina were measured. The enface angiograms from superficial vascular plexiform (SVP) and deep capillary plexiform (DCP) were analyzed, and the image sharpness was also extracted from the choroidal angiograms. Immunohistochemical analysis was done in the RCS rats after week 18, as well as in three-week-old RCS rats and age-matched controls. Results In RCS rats, the thicknesses of the ganglion cell complex, the nuclear layer, the debris/photoreceptor layer and the total retina decreased over the weeks (P < 0.001). The SVP metrics remained unchanged whereas the DCP metrics decreased significantly over the weeks (P < 0.001). The immunohistochemical analysis confirmed our OCTA findings of capillary dropout in the DCP. The choroidal plexus appeared indistinct initially due to scattering of light at the intact retinal pigment epithelium (RPE) and became more visible after week nine probably due to RPE degeneration. Loss of choriocapillaris was visualized at week 18. In control rats, no vascular change was detected, but nuclear layers, photoreceptor layers and total retina showed slight thinning with age (P < 0.001). Conclusions Photoreceptor degeneration in RCS rats was associated with the loss of capillaries in DCP, but not in SVP. The OCTA imaging allows for the characterization of structural and angiographic changes in rodent models.

This study examines why most derivatives markets that settle on the day following expiration choose the opening rather than the closing price as the final settlement price (FSP), whereas most markets that settle on the expiration day select an average rather than a single price as the FSP. Four exogenous changes in the Taiwan Futures Exchange settlement procedures provide an experimental basis for studying the settlement procedures’ impact on underlying assets. Greatest market efficiency is observed when the FSP is determined by a single rather than an average price and hypothesize that manipulation is prevented at the expense of market quality.

Heterochromatin mainly comprises repeated DNA sequences that are prone to ectopic recombination. In Drosophila cells, ‘safe’ repair of heterochromatic double-strand breaks by homologous recombination relies on the relocalization of repair sites to the nuclear periphery before strand invasion. The mechanisms responsible for this movement were unknown. Here we show that relocalization occurs by directed motion along nuclear actin filaments assembled at repair sites by the Arp2/3 complex. Relocalization requires nuclear myosins associated with the heterochromatin repair complex Smc5/6 and the myosin activator Unc45, which is recruited to repair sites by Smc5/6. ARP2/3, actin nucleation and myosins also relocalize heterochromatic double-strand breaks in mouse cells. Defects in this pathway result in impaired heterochromatin repair and chromosome rearrangements. These findings identify de novo nuclear actin filaments and myosins as effectors of chromatin dynamics for heterochromatin repair and stability in multicellular eukaryotes. Relocalization of heterochromatic double-strand breaks to the nuclear periphery in Drosophila cells occurs via directed motions driven by nuclear actin filaments and myosins activated by the Smc5/6 complex.

Introduction: Lutetium-177(177Lu) DOTATATE is a form of peptide receptor radionuclide therapy (PRRT) targeting somatostatin receptor-2 (SSTR2), that is utilized in the treatment of neuroendocrine tumors. As various endocrine glands express SSTR2, 177Lu-DOTATATE can potentially disrupt endocrine function. The immediate post-treatment effects of 177Lu-DOTATATE on endocrine function are not known. Methods: We performed a retrospective analysis of data obtained from patients (≥18 years) enrolled under the 177Lu-DOTATATE trial (NCT03206060) for treatment of SSTR2 positive inoperable/metastatic pheochromocytoma/paraganglioma. 177Lu-DOTATATE (200 mCi) was administered intravenously every 8 weeks, for a total of 4 cycles. Endocrine evaluation was performed on blood samples obtained through an indwelling intravenous catheter during each cycle of PRRT on day 1 (pre-PRRT), day 2 (post-PRRT day 1), day 3 (post-PRRT day 2), day 30 (post-PRRT day 29), and day 60 (day 1 of the next cycle). Hormonal evaluation included ACTH, cortisol, TSH, free T4, GH, FSH, LH, testosterone, estradiol, and prolactin. Baseline abnormal hormonal values, and gonadotrophs in premenopausal women were excluded. Results: Data from 27 subjects (age: 54 ± 12.7 years; 13 female, 14 male) were analyzed. Three out of 27 patients (11.1%) developed clinically significant persistent endocrinopathies - secondary adrenal insufficiency (AI): (n=1 male), primary hypothyroidism: (n=1 male) and hypergonadotropic hypogonadism: (n=1 female). Compared to day 1, there were significant reductions in 1) ACTH (pg/mL) levels on day 2 (36.8 ± 34.1 vs. 23.1 ± 21; p

Our aim was to investigate the breathing patterns of children aged 5–9 years with asthma as they read aloud stories of increasingly difficulty. Eleven children with asthma were recruited from an ou...

Chronic alcohol consumption is linked to the development of alcohol-associated liver disease (ALD). This disease is characterized by a clinical spectrum ranging from steatosis to hepatocellular carcinoma. Several cell types are involved in ALD progression, including hepatic macrophages. Kupffer cells (KCs) are the resident macrophages of the liver involved in the progression of ALD by activating pathways that lead to the production of cytokines and chemokines. In addition, KCs are involved in the production of reactive oxygen species. Reactive oxygen species are linked to the induction of oxidative stress and inflammation in the liver. These events are activated by the bacterial endotoxin, lipopolysaccharide, that is released from the gastrointestinal tract through the portal vein to the liver. Lipopolysaccharide is recognized by receptors on KCs that are responsible for triggering several pathways that activate proinflammatory cytokines involved in alcohol-induced liver injury. In addition, KCs activate hepatic stellate cells that are involved in liver fibrosis. Novel strategies to treat ALD aim at targeting Kupffer cells. These interventions modulate Kupffer cell activation or macrophage polarization. Evidence from mouse models and early clinical studies in patients with ALD injury supports the notion that pathogenic macrophage subsets can be successfully translated into novel treatment options for patients with this disease.

Purpose To assess the repeatability of retinal vascular metrics using different postprocessing methods as obtained from the swept‐source optical coherence tomography angiography (SS‐OCTA). Methods Thirty‐two participants (63% males; mean [SD] age, 70 [7] years) underwent SS‐OCTA imaging (PLEX ® Elite 9000, Carl Zeiss Meditec, Inc., Dublin, USA). Each participant underwent 2 repeated scans of 2 scan protocols: a macular‐centred 3 × 3‐mm2 and a widefield 12 × 12‐mm2 for a total of 4 acquisitions. Images of superficial vascular plexuses (SVP) and deep vascular plexuses (DVP) were processed using different filters to generate the perfusion density (PD) and vessel density (VD). Vessel enhancement filters ranged from vessel targeted (Hessian and Gabor filters), classical denoising (Gaussian filter), to a scale‐selective adaption (modified Bayesian residual transform [MBRT]). Intra‐session repeatability of the different filters and their correlation with the original data set were calculated with the intraclass correlation coefficient (ICC) and Pearson's r. Results Of the 32 eyes, 17 and 15 were right and left eyes, respectively. For 3 × 3‐mm2 scans, both MBRT and Gabor filters yielded very good repeatable PD and VD (both ICCs > 0.87) values. Gabor filter was the most correlated with the original data set for the OCTA metrics (r = 0.95–0.97). For 12 × 12‐mm2 scans, MBRT filter produced good‐to‐moderate ICC values for SVP (ICC>0.89) and DVP (ICC>0.73) metrics. Both the MBRT and Gabor filters were highly correlated with the original 12 × 12‐mm2 scan data set (r = 0.96–0.98). The ICCs for the agreement between 3 × 3‐mm2 and cropped 12 × 12‐mm2 were high only for the PD values at the SVP layer and were poor for the VD at SVP and DVP measurements (ICC

A first example of radical hydroboration and hydrosilylation of

Pericentromeric heterochromatin largely comprises repeated DNA sequences prone to aberrant recombination during double-strand break (DSB) repair. Studies in Drosophila and mouse cells revealed that ‘safe’ homologous recombination (HR) repair of these sequences relies on the relocalization of repair sites to outside the heterochromatin domain before Rad51 recruitment. Relocalization requires a striking network of nuclear actin filaments (F-actin) and myosins generating directed motions. Understanding this pathway requires the ability to detect nuclear actin filaments that are significantly less abundant than cytoplasmic filaments, and to image and track repair sites for long time periods. Here we describe an optimized protocol for live cell imaging of nuclear F-actin in response to IR in Drosophila cells, and for repair focus tracking in mouse cells, including imaging setup, image processing approaches, and analytical methods. We emphasize approaches that can be applied to identify the most effective fluorescent markers for live cell imaging, strategies to minimize photobleaching and phototoxicity with a DeltaVision deconvolution microscope, and image processing and analysis methods using SoftWoRx and Imaris software. These approaches enable a deeper understanding of the spatial and temporal dynamics of heterochromatin repair and have broad applicability in the fields of nuclear architecture, nuclear dynamics, and DNA repair.

Intravascular large B-cell lymphoma (IVLBCL) is a rare entity, with a generally aggressive course that may vary based on geographic presentation. While a United States (US) registry study showed relatively good outcomes with IVLBCL, clinicopathological and treatment data were unavailable. We performed a detailed retrospective review of cases identified at 8 US medical centres, to improve understanding of IVLBCL and inform management. We compiled data retrieved via an Institutional Review Board-approved review of IVLBCL cases identified from 1999 to 2015 at nine academic institutions across the US. We characterized the cohort's clinical status at time of diagnosis, presenting diagnostic and clinical features of the disease, treatment modalities used and overall prognostic data. Our cohort consisted of 54 patients with varying degrees of clinical features. Adjusting for age, better performance status at presentation was associated with increased survival time for the patients diagnosed in vivo (hazard ratio: 2·12, 95% confidence interval 1·28, 3·53). Based on the data we have collected, it would appear that the time interval to diagnosis is a significant contributor to outcomes of patients with IVLBCL.

41 Background: TMPRSS2, a cell surface protease which is commonly upregulated in prostate cancer (PC) and regulated by androgens, is a necessary component for SARS-CoV2 cellular entry into respiratory epithelial cells. PC patients receiving ADT were reported to have a lower risk of SARS-CoV-2 infection. However, whether ADT may have an impact on the severity of COVID-19 illness in this population is poorly understood. Methods: In this study performed across 7 US medical centers, we retrospectively evaluated patients with active PC and SARS-COV-2 viral detection by PCR between 03/01/20 and 05/31/20. We collected information on demographics; medical comorbidities; medications; PC Gleason score at initial diagnosis; presence of active disease, metastases, and castration resistance; ADT use as defined by GnRH analog or antagonist within 3 months or castration levels of testosterone < 50 ng/dL within 6 months of COVID-19 diagnosis, or history of bilateral orchiectomy; active non-ADT systemic therapies including, but not limited to, androgen-receptor-targeted therapies and chemotherapy; and COVID-19-related outcomes including hospitalization, supplemental oxygen use, mechanical ventilation requirement, WHO COVID-19 ordinal scale for clinical improvement, follow-up duration, and vital status. Multivariable mixed-effect logistic regression was performed to evaluate any difference in COVID-19 clinical outcomes between patients on and not on ADT. Survival analysis was done using adjusted Cox proportion-hazards regression model. All tests were two-sided at 0.05 significance level. Results: We identified 465 evaluable patients with median age of 71 (61-81) years. Median duration of follow-up was 60 (12-114.2) days. In this follow up period, there were 195 (41.9%) hospitalizations and 111 (23.9%) deaths. When adjusted for age, BMI, and PC clinical disease state, overall survival (HR 1.28 [95%CI 0.79-2.08], P = 0.32), hospitalization status (HR 1.07 [0.61-1.87], P = 0.82), supplemental oxygen use (HR 1.29 [0.77-2.17], P = 0.34), and use of mechanical ventilation (HR 1.07 [0.51-2.23], P = 0.87) were not statistically different between ADT and non-ADT cohorts. Similarly, in subgroup analysis, no statistical difference in overall survival was found between ADT and non-ADT cohorts for hospitalized patients (HR 1.42 [0.82-2.47], P = 0.21) and those receiving supplemental oxygen (HR 1.10 [0.65-1.85], P = 0.73). Conclusions: In this retrospective cohort of PC patients, use of ADT prior to COVID-19 diagnosis does not protect against severe COVID-19 illness as defined by hospitalization, supplemental oxygen use, or death. Further preclinical work in understanding TMPRSS2 expression and androgen regulation in respiratory epithelial cells is needed. As well, longer clinical follow-up and additional clinical studies inclusive of prospective data are warranted to fully address this question.

Purpose To evaluate the focal structure–function associations among visual field (VF) loss, optical coherence tomography angiography (OCT-A) vascular measurements, and optical coherence tomography (OCT) structural measurements in glaucoma. Methods In this cross-sectional study, subjects underwent standard automated perimetry, OCT-based nerve fiber thickness measurements, and OCT-A imaging. Mappings of focal VF test locations with OCT and OCT-A measurements were defined using anatomically adjusted nerve fiber trajectories and were studied using multivariate mixed-effects analysis. Segmented regression analysis was used to determine the presence of breakpoints in the structure–function associations. Results The study included 119 eyes from 86 Chinese subjects with primary open-angle glaucoma (POAG). VF mean deviation was significantly associated with global capillary perfusion density (β = 0.13 ± 0.08) and global retinal nerve fiber layer thickness (β = 0.09 ± 0.02). Focal capillary density (FCD) was significantly associated with VF losses at 34 VF test locations (66.7% of 24-2 VF), with 24 of the 34 locations being within 20° of retinal eccentricity. Focal nerve layer (FNL) thickness was significantly associated with 16 VF test locations (31.4% of 24-2 VF; eight locations within 20° eccentricity). For VF test locations in the central 10° VF, VF losses below the breakpoint were significantly associated with FCD (slope, 0.89 ± 0.12, P < 0.001), but not with FNL thickness (slope, 0.57 ± 0.39, P = 0.15). Conclusions Focal capillary densities were significantly associated with a wider range of visual field losses and in a larger proportion of the visual field compared to nerve fiber thickness.

Reviewer Acknowledgements for Environment and Natural Resources Research, Vol. 10, No. 3, 2020

Reviewer Acknowledgements for Environment and Natural Resources Research, Vol. 10, No. 2, 2020

The choriocapillaris is a unique vascular plexus located posterior to the retinal pigment epithelium. In recent years, there is an increasing interest in the examination of the interrelationship between the choriocapillaris and eye diseases. We used several techniques to study choroidal perfusion, including laser Doppler flowmetry, laser speckle flowgraphy, and optical coherence tomography angiography (OCTA), but with the latter no standardized algorithm for quantitative analysis has been provided. We analyzed different algorithms to quantify flow voids in non-human primates that can be easily implemented into clinical research. In-vivo, high-resolution images of the non-human primate choriocapillaris were acquired with a swept-source OCTA (SS-OCTA) system with 100kHz A-scan/s rate, over regions of 3 × 3 mm2 and 12 × 12 mm2. The areas of non-perfusion, also called flow voids, were segmented with a structural, intensity adjusted, uneven illuminance-compensated algorithm and the new technique was compared to previously published methods. The new algorithm shows improved reproducibility and may have applications in a wide array of eye diseases including age-related macular degeneration (AMD). NMRC (Natl Medical Research Council, S’pore) Published version

Combined electric-acoustic stimulation (EAS) via hybrid cochlear implants is a relatively new treatment for severe-profound sloping high-frequency hearing loss. Residual acoustic hearing at low frequencies is a vital component of EAS, but it cannot be assumed that residual hearing will be normal; thresholds may be elevated, frequency selectivity may have decreased, or both. In this study, the effects of reduced frequency selectivity and elevated low-frequency thresholds on the intelligibility of speech in noise were simulated. Sentences mixed with a babble masker were processed by an eight-channel vocoder. Residual low-frequency hearing was simulated by replacing the first four channels with the unprocessed acoustic stimulus, with a spectrally smeared stimulus, or with a spectrally smeared and attenuated stimulus. These conditions simulated listening by cochlear implant users with no residual hearing, with normal residual hearing, or with various degrees of impaired residual hearing. Simulating no...

Cellular senescence is a state of irreversible cell cycle arrest that has been involved in many gastrointestinal diseases, including human cholestatic liver disorders. Senescence may play a role in biliary atresia, primary sclerosing cholangitis, cellular rejection, and primary biliary cirrhosis, four liver diseases affecting cholangiocytes and the biliary system. In this review, we examine proposed mechanisms of senescence-related biliary diseases, including hypotheses associated with the senescence-associated phenotype, induction of senescence in nearby cells, and the depletion of stem cell subpopulations. Current evidence for the molecular mechanisms of senescence in the previously mentioned diseases is discussed in detail, with attention to recent advances on the role of pathways associated with senescence-associated phenotype, stress-induced senescence, telomere dysfunction, and autophagy.

Cash-futures basis, a proxy for arbitrage opportunities, is examined, and the impact of informed trading and the changing roles of speculators and arbitrageurs are analyzed in both the non-expiration and near-expiration periods. While we observe that market frictions account to some extent for negative spreads, we also found that volatility and liquidity widen spread magnitude, suggesting that speculation dominates arbitrage in this market. Puzzlingly, we found that informed trading impacts spreads in the opposite manner, depending on whether the contract is near expiration, highlighting the importance of controlling for expiration in basis-spread tests. Finally, we construct a measure to proxy for market maturity and track these interactions throughout the course of the market's maturation.

Reviewer Acknowledgements for Environment and Natural Resources Research, Vol. 10, No. 1, 2020

This case-control study analyzes the results obtained from wide-field optical coherence tomographic angiography (OCTA) with and without removal of large vessels to assess the presence and severity of diabetic retinopathy among individuals with diabetes., Key Points Question What is the diagnostic performance of quantitative microvascular analysis using wide-field optical coherence tomographic angiography (OCTA) in eyes with diabetic retinopathy? Findings In this case-control study of 49 eyes in 27 control participants and 76 eyes in 47 participants with diabetes, microvascular metrics obtained from wide-field OCTA accurately classified severity of nonproliferative diabetic retinopathy with high sensitivity. Meaning The findings suggest that wide-field OCTA may be useful for assessment of microvascular status in eyes with diabetic retinopathy., Importance Wide-field optical coherence tomographic angiography (OCTA) may provide insights to peripheral capillary dropout in eyes with diabetic retinopathy (DR). Objective To describe the diagnostic performance of wide-field OCTA with and without large vessel removal for assessment of DR in persons with diabetes. Design, Setting, and Participants This case-control study was performed from April 26, 2018, to April 8, 2019, at a single tertiary eye center in Singapore. Case patients were those with type 2 diabetes for more than 5 years and bilateral DR diagnosed by fundus imaging; control participants included those with no self-reported history of diabetes, a fasting glucose level within the normal range in the past year, and no ocular pathologic findings. A wide-field (12 × 12-mm2) fovea-centered scan was performed using a prototype swept source OCTA system. Retinal microvasculature was examined by separating the angiograms into large vessels, capillaries, and capillary dropout regions. Main Outcomes and Measures Area under the receiver operating characteristic curve (AUC) for DR severity discrimination using wide-field vascular metrics. Retinal perfusion density (RPD), capillary perfusion density (CPD), large vessel density (LVD), and capillary dropout density (CDD) were calculated. Low-contrast regions were excluded from the calculation. Results A total of 49 eyes in 27 control participants (17 male [63.0%]; mean [SD] age, 59.96 [7.63] years; age range, 44-79 years) and 76 eyes in 47 patients with diabetes (29 male [61.7%]; mean [SD] age, 64.36 [8.08] years; range, 41-79 years) were included. Among eyes in patients with diabetes, 23 were in those with diabetes but no DR, 25 in those with mild nonproliferative DR, and 28 in those with moderate to severe nonproliferative DR. There was no difference in RPD, CPD, LVD, and CDD between the control group and the group with diabetes and no DR. There was a stepwise decrease in RPD, CPD, and CDD in the diabetes with no DR, mild nonproliferative DR, and moderate to severe nonproliferative DR groups, whereas LVD was not associated with DR staging. The nonproliferative DR group had decreased RPD, CPD, and CDD compared with the control group. The CPD had higher AUCs than RPD for discriminating diabetes with nonproliferative DR (combined mild and moderate to severe nonproliferative DR) vs no DM (AUC, 0.92 [95% CI, 0.87-0.98] vs 0.89 [95% CI, 0.83-0.95], P = .01), diabetes with no DR vs mild nonproliferative DR (AUC, 0.81 [95% CI, 0.68-0.94] vs 0.77 [95% CI, 0.64-0.91], P = .18), and mild nonproliferative DR vs moderate to severe nonproliferative DR (AUC, 0.82 [95% CI, 0.71-0.94] vs 0.78 [95% CI, 0.65-0.91], P = .01) but similar AUCs for no DM vs diabetes with no DR. The total perfusion density and CPD in wide-field OCTA had better discriminative power than the central 6 × 6-mm2 field (CPD, 0.89 [95% CI, 0.83-0.95] vs 0.84 [95% CI, 0.77-0.92], P = .06; total perfusion density, 0.93 [95% CI, 0.87-0.98] vs 0.90 [95% CI, 0.83-0.96], P = .06). Conclusions and Relevance The findings suggest that wide-field OCTA provides information on microvascular perfusion and may be useful for detecting predominant peripheral capillary dropout in eyes with nonproliferative DR. A vascular selectivity approach excluding the large vessels may improve the discriminative power for different stages of DR.

Drawing on large-scale international teachers’ data from Hungary, Korea, Norway, and Turkey in the Teaching and Learning International Survey in 2008 assessment, this study examined the relationships between new teachers’ beliefs about instruction (direct transmission and constructivist beliefs) and teaching practices (structured, student orientation, and enhanced activities) in the international contexts. The findings of this study showed that for new teachers from the four selected countries, their instructional practices were neither consistent nor aligned with their beliefs about instruction; thus, there were no consistent patterns of the relationship between teacher beliefs and their instructional practices in each country. The results were discussed from perspectives of two types of contexts: classroom and school contexts, and national and international contexts. This study adds to the understanding of relationships between teacher beliefs and instructional practices with international data sets.

Background: Needle trauma may cause neuropathy after nerve blockade. Even without injection, nerve injury can result from forceful needle–nerve contact (NNC). High opening injection pressures (OIPs) have been associated with intrafascicular needle tip placement and nerve damage; however, the relationship between OIP and NNC is unclear. The authors conducted a prospective, observational study to define this relationship. Methods: Sixteen patients scheduled for shoulder surgery under interscalene block were enrolled if they had clear ultrasound images of the brachial plexus roots. A 22-gauge stimulating needle was inserted within 1 mm of the root, and 1-ml D5W injected at 10 ml/min by using an automated pump. OIP was monitored using an in-line pressure manometer and injections aborted if 15 psi or greater. The needle was advanced to displace the nerve slightly (NNC), and the procedure repeated. Occurrence of evoked motor response and paresthesia were recorded. Results: Fifteen patients had at least one clearly visible root. OIP at 1 mm distance from the nerve was less than 15 psi (mean peak pressure 8.2 ± 2.4 psi) and the 1-ml injection could be completed in all but two cases (3%). In contrast, OIP during NNC was 15 psi or greater (mean peak pressure 20.9 ± 3.7 psi) in 35 of 36 injections. Aborting the injection when OIP reached 15 psi prevented commencement of injection in all cases of NNC except one. Conclusion: High OIP (≥15 psi) consistently detected NNC, suggesting that injection pressure monitoring may be useful in preventing injection against nerve roots during interscalene block.

Appropriate pain management after total shoulder arthroplasty (TSA) facilitates rehabilitation and may improve clinical outcomes.This prospective, observational study evaluated a multimodal analgesia clinical pathway for TSA.Ten TSA patients received an interscalene nerve block (25 cm(3) 0.375% ropivacaine) with intraoperative general anesthesia. Postoperative analgesia included regularly scheduled non-opioid analgesics (meloxicam, acetaminophen, and pregabalin) and opioids on demand (oral oxycodone and intravenous patient-controlled hydromorphone). Patients were evaluated twice daily to assess pain, anterior deltoid strength, handgrip strength, and sensory function.The nerve block lasted an average of 18 h. Patients had minimal pain after surgery; 0 (median score on a 0-10 scale) in the Post-Anesthesia Care Unit (PACU) but increased on postoperative day (POD) 1 to 2.3 (0.0, 3.8; median (25%, 75%)) at rest and 3.8 (2.1, 6.1) with movement. Half of the patients activated the patient-controlled analgesia four or fewer times in the first 24 h after surgery. Operative anterior deltoid strength was 0 in the PACU but returned to 68% by POD 1. Operative hand strength was 0 (median) in the PACU, but the third quartile (75%) had normalized strength 49% of preoperative value.Patients did well with this multimodal analgesic protocol. Pain scores were low, half of the patients used little or no intravenous opiate, and some patients had good handgrip strength. Future research can focus on increasing duration of analgesia from the nerve block, minimizing motor block, lowering pain scores, and avoiding intravenous opioids.

Reviewer Acknowledgements for Environment and Natural Resources Research, Vol. 9, No. 3, 2019

TPS4159 Background: Pheochromocytoma/paraganglioma (PHEO/PGL) is a rare malignancy that arises from chromaffin cells of typically the adrenal medulla but can also be of extra-adrenal origin. These tumors produce excessive catecholamines such as epinephrine and norepinephrine which causes labile hypertension, tachycardia, and flushing. Lu-177-DOTATATE (Lu-177-dodecanetetraacetic acid‐tyrosine-3-octreotate) is a radiolabeled somatostatin analog that is FDA approved for somatostatin receptor-positive neuroendocrine tumors. It is being being investigated in PHEO/PGL, which overexpress somatostatin receptors. Amino acid solutions containing lysine/arginine (L/A) are routinely co-administered with Lu-177-DOTATATE for renal radioprotection, although solutions containing other amino acids are also used. Methods: This is a prospective, single center, open label Phase 2 study evaluating the efficacy of Lu-177-DOTATATE in PHEO/PGL. Ninety patients will be enrolled, divided into two cohorts of 45 patients each ( SDHx mutation vs. apparent sporadic). Lu-177-DOTATATE is given at a fixed dose of 200 mCi with a co-administration of L/A amino acid solution q8 weeks for 4 cycles. The primary endpoint is the progression-free-survival (PFS) rate at 6 months. Secondary endpoints include response rate, overall survival, time to progression, quality of life measures, and examination of potential biomarkers such as biochemical profiles, Ga-68-DOTATATE PET, and F-18-FDG PET scans. Eligibility criteria include inoperable disease (including non-metastatic), histological confirmation of PHEO/PGL, evidence of disease progression by RECIST 1.1, ECOG performance status of 1 or better, and a positive Ga-68-DOTATATE PET scan. Exclusion criteria include prior treatment with systemic radionuclide therapy such as I-131-MIBG, brain parenchymal metastases, and standard organ dysfunction limitations. Interim analysis using a Simon two-stage optimal design will be performed separately for each cohort after enrollment of 18 patients. First patient accrual to this ongoing study was in the Fall of 2017, and as of February 2019, fourteen patients have been accrued. Preliminary results will be reported at the completion of stage 1 for each cohort. Clinical trial information: NCT03206060.

The function of microRNAs (miRNAs) during alcoholic liver disease (ALD) has recently become of great interest in biological research. Studies have shown that ALD associated miRNAs play a crucial role in the regulation of liver-inflammatory agents such as tumour necrosis factor-alpha (TNF-α), one of the key inflammatory agents responsible for liver fibrosis (liver scarring) and the critical contributor of alcoholic liver disease. Lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria, is responsible for TNF-α release by Kupffer cells. miRNAs are the critical mediators of LPS signalling in Kupffer cells, hepatocytes and hepatic stellate cells. Certain miRNAs, in particular miR-155 and miR-21, show a positive correlation in up-regulation of LPS signalling when they are exposed to ethanol. ALD is related to enhanced gut permeability that allows the levels of LPS to increase, leads to increased secretion of TNF-α by the Kupffer cells and subsequently promotes alcoholic liver injury through specific miRNAs. Meanwhile, two of the most frequently dysregulated miRNAs in steatohepatitis, miR-122 and miR-34a are the critical mediators in ethanol/LPS activated survival signalling during ALD. In this review, we summarize recent findings regarding the experimental and clinical aspects of functions of specific microRNAs, focusing mainly on inflammation and cell survival after ethanol/LPS treatment, and advances on the role of circulating miRNAs in human alcoholic disorders.

We performed this randomized trial to compare the recovery profile of patients receiving single injection (SISB) and continuous interscalene brachial plexus block (CISB) or general anesthesia (GA) for arthroscopic rotator cuff repair surgery through the first postoperative week. Our primary hypothesis was that the highest pain numeric rating scale (NRS) (worst pain score) at the end of the study week would be lower for patients in the CISB group than for patients in the SISB or GA groups.Seventy-one patients scheduled for elective outpatient arthroscopic rotator cuff repair were enrolled. CISB patients received 20 mL of 0.5% ropivacaine as a bolus through a catheter, whereas SISB patients received the same injection volume through a needle. CISB patients received an infusion of 0.2% ropivacaine at 5 mL/h with a patient-controlled bolus of 5 mL hourly for 48 hours. GA-only patients received a standardized general anesthetic. Postoperative highest NRS pain scores through the first postoperative week, time-to-first pain, analgesic consumption, fast-tracked postoperative anesthesia care unit (PACU) bypass rate, length of PACU stay, time-to-discharge home, total hours of sleep, and related adverse effects were recorded in the PACU and at home on postoperative days 1, 2, 3, and 7.No patient in the CISB or SISB groups reported a NRS ≥1 or required analgesics while in the PACU. While most patients in the CISB and SISB groups were fast-tracked to PACU discharge, no patient in the GA group was fast-tracked (Χ P = 0.003). Length of stay in the PACU was significantly shorter for the CISB and SISB groups than for the GA group (20 ± 31, 30 ± 42, and 165 ± 118 minutes, respectively (CISB vs GA, P0.001; SISB vs GA, P0.001), and time-to-discharge home was significantly shorter when compared with the GA group. Time to first pain report was longer in the CISB group. Mean NRS scores were lower for patients in the CISB group than in the SISB and GA groups on postoperative days 1 and 2, and use of narcotics (doses ≥1) was lower until postoperative day 3. Patients who received CISB slept significantly longer than patients who received SISB or GA (P0.01) during the first 48 hours postoperatively. By the end of the study week, 26% of patients in the CISB group, 83% in the SISB group, and 58% of GA patients reported NRS ≥4 (both P-values ≤ 0.05).The analgesic benefits of CISB found in the PACU and immediately after discharge extend through the intermediate recovery period ending on postoperative day 7.

This preliminary study investigated the acoustic differences between declarative questions and statements in two non-tonal languages (Arabic and English) and two tonal languages (Mandarin and Taiwanese). All participants read 28 English phrases in two sentence types: declarative question and statement. The non-native English speakers also read the phrases translated in their native languages. Acoustic measures derived from these sentences included measures of fundamental frequency (F0) and intensity. Results from multiple analysis of variance revealed that declarative questions, compared to statements, had significantly higher F0 and intensity regardless of language and speaker's nativeness. In addition, the F0 of a statement was found to be a strong predictor for that of the corresponding question in both non-tonal and tonal languages.

Purpose of review There has been an increasing use of peripheral nerve blocks (PNBs) in ambulatory surgery. Several recent reports have contributed to our understanding of the optimal PNB technique for specific surgical procedures in this setting. In this review, we have summarized the available literature on indications of PNBs for outpatient surgery of the upper extremity. Recent findings Although many of the recent studies focus on technical aspects of PNBs, few center on evidence-based indications or their utility in the ambulatory setting. The available literature suggests that although multiple techniques have been reported for outpatient shoulder surgery, interscalene brachial plexus block (ISBPB) is currently the most preferred technique. Supraclavicular, infraclavicular, and axillary brachial plexus blocks, however, are all commonly used and effective PNBs for outpatient surgery and analgesia of the arm, forearm, and hand. Summary ISBPB is currently the most beneficial PNB for outpatient shoulder surgery. Supraclavicular block functionally can be considered an alternative to the traditional ISBPB; however, additional studies are required before routine use can be recommended. Although the review identified several reports with benefits of one PNB technique over the others, the existing literature suggests that many of these techniques may be interchangeable with regards to procedures of the distal upper extremity. Future studies are indicated to help standardize the techniques, selection, and postoperative management of PNBs for specific surgical indications.

Questions remain about how to best prepare students to be environmentally literate. Although Canada and U.S. share similarities in education systems, diversity in student population, and historical roots in formalizing environmental education, Canada is one of the top performing countries in international science assessments while U.S. matches average performing countries. This study examined the relationship of individual and school-related factors to environmental literacy by comparing students’ performances in knowledge, awareness, attitudes, and behavior about environmental issues between U.S. and Canada using PISA 2006. Findings suggest that knowledge, awareness, attitudes, and behavior are inter-related, and development of certain domains of environmental literacy may be enhanced by classroom student investigations. Prior explanations for U.S. lower performance in environmental literacy cannot be attributed only to low socio-economic status and student diversity.

The aim of the research is to determine how the lifting of price restrictions on short sales and security-lending sales affects market efficiency, liquidity and arbitrage opportunities. The study examines trading behaviors of large and small traders separated by their transaction costs and shows the lifting of price restrictions strengthens the correlation between extreme order imbalance and extreme mispricing. Also, autocorrelations of the underpricing and overpricing persist longer, in particular for big traders, and so do those of buy-side and sell-side order imbalances. However, the outcomes for the post-lifting market efficiency are mixed. This paper provides evidence that lifting price restrictions enhances informed trading and the lead–lag relationship between mispricing and order imbalance in the cash and futures markets.