bluuebunny/crossref_metadata_2025 huggingface dataset:
Temporal Description of Annual Temperature and Rainfall in the Bawku Area of Ghana
Authors: Asamoah Yaw , Ansah-Mensah Kow
Published: April 2020

With varied implications, Ghana’s temperature and rainfall are projected to rise and decline, respectively. A study exposing specific areas of concern for appropriate responses in this regard is a welcome one. This study sought to describe the temporal variations in temperature and rainfall in the Bawku Area of Ghana. A forty-year (1976–2015) daily climate data was collected on three meteorological stations from the Ghana Meteorological Agency. Normality test, homogeneity test, Standardised Precipitation Index (SPI) analysis, Mann–Kendall trend test, and One-way post hoc ANOVA were performed using XLSTAT and DrinC. Over the period under study, the mean annual rainfall pattern was generally erratic, fluctuating between 669.8 mm and 1339.4.6 mm with an annual average of 935.3 mm. The long-term (40-year period) average temperature of the three stations, on the other hand, was 28.7°C, varying between 26.9°C and 29.9°C annually. Whereas the SPI value of 2006 was ≥2.0, indicating extremely wet year with 2.3% probability of recurring once every 50 years, 1988 was the hottest year with temperature anomaly value of 1.2°C, while coolest years were 1979 (−1.8°C) and 1976 (−1.0°C). The Mann–Kendall trend test showed a rise in rainfall in Binduri, Garu-Tempane, and Manga, yet none of the rainfall changes were statistically significant (P>0.05). Mean temperature on the other hand experienced a significant rise (P<0.05). With an R-square of 34.7%, the rise in temperature in Manga witnessed the most significant change in annual temperature changes. There were statistically significant (P<0.05) differences in the interdecadal temperature over the 40-year period. Generally, it can be stated that both temperature and rainfall vary in the study area with various degrees of disparities, but temperature assumes an upward trend at a faster rate. We therefore recommend that stakeholders resort to the construction of dams and boreholes to ensure regular availability of water for both domestic and agricultural uses.
The Modulation of Laser Refractive Surgery on Sensory Eye Dominance of Anisometropia
Authors: Liu Hongting , Chen Qi , Lan Fangfang , Luo Yan , Lin Enwei , Luo Wuqiang , Kong Ming , Wang Jiangxia , Zhang Fengju
Published: April 2020

Purpose. To evaluate the effect of laser refractive surgery on sensory eye dominance of anisometropia. Methods. A total of 156 subjects with nonanisometropic myopia and 70 subjects with anisometropic myopia were enrolled in the first part of the study. The dichoptic motion coherence threshold technique was applied to collect the normal dataset and distribution of sensory eye dominance. The second part of the study included 40 subjects with nonanisometropic myopia and 40 subjects with anisometropic myopia who received the femtosecond laser-assisted in situ keratomileusis (Fs-LASIK). A comprehensive ophthalmologic evaluation was performed with particular attention to sensory eye dominance preoperatively and one-week and one-month postoperatively. The ocular dominance index (ODI) was applied to evaluate the subject’s overall degree of sensory ocular dominance. Visual acuity, sighting eye dominance, and stereo acuity were also accessed. Results. In experiment one, the mean ODI in the nonanisometropic group and the anisometropic group was 1.48 ± 0.63 and 1.95 ± 1.07, respectively. The ODI values of the anisometropic group were significantly higher than those of the nonanisometropic group (Mann–Whitney U test, P<0.001). The demographics information and the distribution of ODI values in both groups are summarized in tables and figures. In experiment two, all LASIK procedures were uneventful and no postoperative complications were observed during the postoperative follow-up. Preoperatively, the ODI values of the anisometropic LASIK group were significantly higher than those of the nonanisometropic LASIK group, which was consistent with the results of part 1. However, one week after operation, the mean ODI values of the anisometropic LASIK group had significantly decreased from 1.89 ± 1.09 to 1.39 ± 0.44. And, the mean ODI values slightly increased to 1.65 ± 0.61 one-month postoperatively. In the nonanisometropic LASIK group, there were no statistically significant differences of ODI changes among preoperative, post-one-week and post-one-month visits. The demographics information and the changes of ODI of both LASIK groups are summarized in tables and figures. Conclusion. Stronger sensory eye dominance is seen in the subjects with anisometropic myopia compared to subjects with nonanisometropic myopia. The strong sensory dominance of anisometropia becomes more balanced at one week of postoperation but returns to the preoperative level after one month. Laser refractive surgery had a short-term modulation of sensory eye dominance.
Nail Biting as a Cause of Appendicitis
Authors: Pagacz Michael , Bao Philip , Moreno Juan Carlos Alvarez , Howard Lydia
Published: April 2020

Ingestion of a foreign body is commonly encountered in clinical practice, but most cause no complications, passing spontaneously through the gastrointestinal tract. However, they can cause obstructive signs and symptoms, and surgical intervention for extraction of the foreign body may be required after identifying its location. We present here the case of a 49-year-old woman who presented to our emergency room with abdominal pain localizing to the right lower quadrant. Evaluation was most consistent with acute appendicitis, and she underwent uncomplicated appendectomy. A keratin nail with Actinomyces was identified in her appendix. Foreign bodies in the appendix can cause simple appendicitis, perforation, periappendiceal abscess, and peritonitis. Regardless of etiology, an appendectomy often ends up the primary treatment, but unusual and rare causes are worth noting if only for the clinician to be aware of when evaluating the next patient with abdominal pain and considering treatment options or future prevention. Our case is an example of a rare scenario in which an Actinomyces-contaminated human nail lodged in the appendix of a woman eventually resulting in acute appendicitis.
Outcomes of Refractive Surgery Consultations at an Academic Center: Characteristics Associated with Proceeding (or Not Proceeding) with Surgery
Authors: Kuo Irene C. , Lee Benjamin , Wang Jiangxia
Published: April 2020

Objective. Refractive surgery volume has not rebounded despite economic recovery and literature describing safety, efficacy, and high patient satisfaction. We sought to examine characteristics of consultation seekers and status after consultation. Methods. Charts of patients seeking refractive surgery at Johns Hopkins University from 2013 through 2016 were retrospectively reviewed for age, gender, refractive characteristics, and outcome: surgery (photorefractive keratectomy, laser in-situ keratomileusis, implantable collamer lens, or refractive lens exchange); no surgery—“lost candidate” (good candidates who were lost after consultation); noncandidates based on technological limitations or contraindications; or no surgery—possessing expectations that surgery would not meet. Associations between characteristics and status after consultation were examined. Results. Twenty percent (142/712) of all patients were “lost candidates”; 57% (408/712) completed surgery. More women (56% or 401/712) sought consultation, but a greater percentage (63% or 195/311) of men completed surgery than women did (53% or 213/401) p=0.02. Of consultation seekers, 60% were low myopes, 29% were high myopes (>6 diopters of myopic spherical equivalent), and 11% were hyperopes. Surgical patients’ mean age was 34.2 ± 10.2 (standard deviation) years; for each additional year of age, patients were less likely to have surgery p<0.001. Hyperopes were ≥3 times more likely than myopes to have expectations not met by surgery or to be noncandidates than to have surgery p<0.005. Conclusions. Most patients seeking refractive surgery had 6 diopters or less of myopia. About 20% of patients were lost after consultation; better counseling and follow-up of candidates may be warranted. Expectations and technology limit eligibility for many, especially hyperopes. Low surgery volume may affect training of future refractive surgeons.
Electrophysiological and Structural Changes in Chinese Patients with LHON
Authors: Wang Min , Guo Hong , Li Shiying , Wang Gang , Long Yanling , Meng Xiaohong , Liu Bo , Liu Yong , Robson Anthony G. , Yin Zheng Qin
Published: April 2020

Objective. To review retrospectively the electrophysiological and structural changes in 13 Chinese patients with Leber hereditary optic neuropathy (LHON). Methods. 26 eyes of 13 patients with a genetically confirmed diagnosis of LHON were categorized into two groups according to the duration of the disease: group 1 (duration less than 3 months) and group 2 (duration between 3 months and 18 years). Clinical history, comprehensive visual electrophysiology, optical coherence tomography (OCT), and color fundus photography were performed. Results. Fundoscopy showed optic disc hyperemia in group 1 and optic atrophy in group 2. OCT measures of retinal nerve fiber layer (RNFL) thickness around the optic disc and surrounding macula were normal in group 1 but reduced in group 2 (10 of 10 eyes). The thickness of the retinal ganglion cell layer (GCL) plus inner plexiform layer (IPL) surrounding the macula reduced significantly in group 1 and group 2 compared with a healthy control group. Pattern ERG (PERG) P50 amplitude was normal, but the N95/P50 ratio reduced in most of group 1 (4 of 5 eyes) and in all of group 2 (11 eyes). PERG P50 peak time was abnormally short in group 2. Multifocal electroretinography (mfERG) showed subnormal responses associated with ring 1 (the central area) and ring 2 in group 1 and reductions in rings 1, 2, and 3 in group 2. Conclusion. The study highlights differences in retinal structure and function between the acute and chronic stages of LHON in a group of Chinese patients. There is PERG evidence of retinal ganglion cell dysfunction and OCT evidence of GCL + IPL thinning in both groups, but there is additional peripapillary RNFL loss in the chronic stage, associated with more severe RGC dysfunction. There is multifocal ERG evidence of localized macular dysfunction in both acute and chronic groups. The study highlights the importance of comprehensive electrophysiological and structural assessments of the retina in LHON and is pertinent to studies that aim to monitor disease progression or the effects of future therapeutic interventions.
To Probe Full and Partial Activation of Human Peroxisome Proliferator-Activated Receptors by Pan-Agonist Chiglitazar Using Molecular Dynamics Simulations
Authors: Sullivan Holli-Joi , Wang Xiaoyan , Nogle Shaina , Liao Siyan , Wu Chun
Published: April 2020

Chiglitazar is a promising new-generation insulin sensitizer with low reverse effects for the treatment of type II diabetes mellitus (T2DM) and has shown activity as a nonselective pan-agonist to the human peroxisome proliferator-activated receptors (PPARs) (i.e., full activation of PPARγ and a partial activation of PPARα and PPARβ/δ). Yet, it has no high-resolution complex structure with PPARs and its detailed interactions and activation mechanism remain unclear. In this study, we docked chiglitazar into three experimentally resolved crystal structures of hPPAR subtypes, PPARα, PPARβ/δ, and PPARγ, followed by 3 μs molecular dynamics simulations for each system. Our MM-GBSA binding energy calculation revealed that chiglitazar most favorably bound to hPPARγ (-144.6 kcal/mol), followed by hPPARα (-138.0 kcal/mol) and hPPARβ (-135.9 kcal/mol), and the order is consistent with the experimental data. Through the decomposition of the MM-GBSA binding energy by residue and the use of two-dimensional interaction diagrams, key residues involved in the binding of chiglitazar were identified and characterized for each complex system. Additionally, our detailed dynamics analyses support that the conformation and dynamics of helix 12 play a critical role in determining the activities of the different types of ligands (e.g., full agonist vs. partial agonist). Rather than being bent fully in the direction of the agonist versus antagonist conformation, a partial agonist can adopt a more linear conformation and have a lower degree of flexibility. Our finding may aid in further development of this new generation of medication.
Magnitude and Predictors of Antenatal Depression among Pregnant Women Attending Antenatal Care in Sodo Town, Southern Ethiopia: Facility-Based Cross-Sectional Study
Authors: Chuma Bekalu Thomas , Sagaro Getu Gamo , Astawesegn Feleke Hailemichael
Published: April 2020

Background. Depression affects approximately 10 to 20% of pregnant women globally, and one in ten and two in five women in developed and developing countries develop depression during pregnancy, respectively. However, evidence regarding its magnitude and predictors in Southern Ethiopia is limited. The present study is aimed at assessing the magnitude and predictors of antenatal depression among pregnant women attending antenatal care in Sodo town. Methods. A facility-based cross-sectional study was conducted among 403 antenatal care attendants in Sodo town from November 2 to January 30, 2017. Systematic random sampling was used to select the study population, and data were collected by using a pretested and structured questionnaire. Data were entered using Epi-data 4.2 and then exported and analyzed using SPSS version 20. Bivariate and multivariable logistic regression analyses were used to assess the association between the dependent variable and independent variables. Variables with P value less than 0.05 were considered as statistically significant. Results. A total of 400 pregnant women were interviewed. The magnitude of antenatal depression was 16.3% (95% CI (12.8%, 19.9%)). Husband’s educational status, at the college and above (AOR: 0.09; 95% CI (0.03, 0.34), regular exercise (AOR: 0.16; 95% CI (0.07, 0.36)), planned pregnancy (AOR: 0.16; 95% CI (0.06, 0.44)), use of family planning (AOR: 0.31; 95% CI (0.14, 0.66)), previous history of anxiety (AOR: 2.96; 95% CI (1.30, 6.74)), previous history of obstetric complications (AOR: 19.03; 95% CI (5.89, 61.47)), and current obstetric complications (AOR: 30.38; 95% CI (3.14, 294.19)) were significant predictors of antenatal depression. Conclusion. Nearly one in six pregnant women had antenatal depression. The husband’s educational status, regular exercise, planned pregnancy, use of family planning, previous history of anxiety, previous history of obstetric complications, and current history of obstetric complications were significant predictors of antenatal depression. Screening for depression during routine antenatal care could be essential and recommended to identify early and prevent further morbidities and mortalities due to antenatal depression.
Detection of Epstein-Barr Virus in 130 Cases of Eyelid Sebaceous Gland Carcinoma Using In Situ Hybridization
Authors: Gao Huanhuan , Tang Lijuan , Lin Jianxian , Zhang Wenxin , Li Yongping , Zhang Ping
Published: April 2020

Purpose. In this study, we aimed to investigate the presence of Epstein–Barr virus (EBV) in the eyelid sebaceous gland carcinoma (SGC) and its association with the clinicopathologic features. Methods. One hundred and thirty paraffin-embedded SGC specimens were retrieved from the Clinical Pathology Department of Zhongshan Ophthalmic Center. Epstein–Barr virus-encoded RNA (EBER) was detected with in situ hybridization (ISH) using the Leica BOND system autostainer. The age and gender distributions of all patients were analyzed and compared with earlier reports. Pearson’s χ2 and Fisher’s exact tests were used to determine the association between clinicopathological features such as age, gender, laterality eye, tumor basal dimension, degree of tumor differentiation, and EBER positivity. Likewise, the relationship between the grade and tumor basal dimension in EBER-positive SGC of the eyelid was analyzed. Results. Thirty-four out of one hundred and thirty (26.2%) eyelid SGC specimens were positively stained for EBER. The age range of highest incidence was 46–75 years, and the female to male ratio was 1 : 0.9. No significant correlation was found between EBER-positivity and age (p=0.5370), gender (p=0.4758), and degree of tumor differentiation (p=0.7787). However, EBV positivity was strongly correlated with the right eye (p=0.0287), the tumor basal dimension (p=0.0001). EBV positivity grade presented statistically associated with tumor size (p=0.0329). Conclusion. We conclude that ISH is a sensitive method to identify EBV in SGC of the eyelid. A possible causal association of EBV in SGC patients is suggested by high frequency of EBER-ISH positivity and its association with the clinicopathologic features.
Bifocal and Multifocal Contact Lenses for Presbyopia and Myopia Control
Authors: Remón Laura , Pérez-Merino Pablo , Macedo-de-Araújo Rute J. , Amorim-de-Sousa Ana I. , González-Méijome José M.
Published: April 2020

Bifocal and multifocal optical devices are intended to get images into focus from objects placed at different distances from the observer. Spectacles, contact lenses, and intraocular lenses can meet the requirements to provide such a solution. Contact lenses provide unique characteristics as a platform for implementing bifocality and multifocality. Compared to spectacles, they are closer to the eye, providing a wider field of view, less distortion, and their use is more consistent as they are not so easily removed along the day. In addition, contact lenses are also minimally invasive, can be easily exchangeable, and, therefore, suitable for conditions in which surgical procedures are not indicated. Contact lenses can remain centered with the eye despite eye movements, providing the possibility for simultaneous imaging from different object distances. The main current indications for bifocal and multifocal contact lenses include presbyopia correction in adult population and myopia control in children. Considering the large numbers of potential candidates for optical correction of presbyopia and the demographic trends in myopia, the potential impact of contact lenses for presbyopia and myopia applications is undoubtedly tremendous. However, the ocular characteristics and expectations vary significantly between young and older candidates and impose different challenges in fitting bifocal and multifocal contact lenses for the correction of presbyopia and myopia control. This review presents the recent developments in material platforms, optical designs, simulated visual performance, and the clinical performance assessment of bifocal and multifocal contact lenses for presbyopia correction and/or myopia progression control.
Pharmacokinetic Comparisons of Naringenin and Naringenin-Nicotinamide Cocrystal in Rats by LC-MS/MS
Authors: Xu Dan , Zhang Gui-Qiu , Zhang Ting-Ting , Jin Bo , Ma Chen
Published: April 2020

Naringenin (NAR), 4′,5,7-trihydroxydihydroflavone, has a wide range of pharmacological activities but shows poor water solubility and low bioavailability. The pharmacokinetics and bioavailability of naringenin-nicotinamide cocrystal (NAR-NCT), which offers improved solubility, were evaluated in this study. Rats were orally administered NAR, a physical mixture of naringenin and nicotinamide (NAR + NCT), and NAR-NCT. The relative bioavailability of NAR-NCT was 175.09% of NAR, Cmax was 8.43 and 2.06 times of NAR and NAR + NCT, respectively, Tmax was advanced from 0.49 h to 0.09 h, CL was decreased from 91.1 L/h/kg to 49.1 L/h/kg, and t1/2 was increased from 5.37 h to 8.24 h, highlighting its rapid absorption and slow elimination. This study showed that NAR-NCT could improve the bioavailability of NAR.
Clinicopathological and Prognostic Characteristics of Malaysian Triple Negative Breast Cancer Patients Undergoing TAC Chemotherapy Regimen
Authors: Abdul Aziz Ahmad Aizat , Md Salleh Md Salzihan , Ankathil Ravindran
Published: April 2020

Triple negative breast cancer (TNBC) is associated with aggressive tumour phenotype and early tumour relapse following diagnosis. Generally, clinicopathological features such as tumour size, patient’s age at diagnosis, tumour histology subtypes, grade and stage, involvement of lymph nodes, and menopausal status are commonly used for predicting disease progression, prospects of recurrence, and treatment response. Prognostic value of clinicopathological features on Malaysian TNBC patients is limited. Thus, this study is aimed at investigating the association of clinicopathological features on disease-free survival (DFS) and overall survival (OS) of Malaysian TNBC patients undergoing TAC chemotherapy. Seventy-six (76) immunohistochemistry-confirmed TNBC patients were recruited. The clinicopathological features of TNBC patients were collected and recorded. Kaplan-Meier and log-rank followed by a Cox proportional hazard regression model were performed to evaluate the TNBC patients’ survival. Out of 76 TNBC patients, 25 were chemoresistant and 51 were chemoresponders to the TAC chemotherapy regimen. The overall 5-year cumulative DFS and OS of TNBC patients were 63.5% and 76.3%, respectively. Multivariate Cox analysis demonstrated that medullary and metaplastic histology subtypes and positive axillary lymph node metastasis were significant prognostic factors associated with relapse with adjusted HR: 5.76, 95% CI: 2.35, 14.08 and adjusted HR: 3.55, 95% CI: 1.44, 8.74, respectively. Moreover, TNBC patients with medullary and metaplastic histology subtypes and positive axillary lymph node metastases had a higher risk to death than patients who had infiltrating ductal carcinoma and negative axillary lymph node metastasis (adjusted HR: 8.30, 95% CI: 2.38, 28.96 and adjusted HR: 6.12, 95% CI: 1.32, 28.42, respectively). Our results demonstrate the potential use of medullary and metaplastic histology subtype and positive axillary lymph node metastasis as a potential biomarker in predicting relapse and survival of the TNBC patients. This warrants further studies on intensification of chemotherapy and also identification and development of targeted therapy to reduce relapses and improve survival of TNBC patients.
Long-Term Gemcitabine Treatment Reshapes the Pancreatic Tumor Microenvironment and Sensitizes Murine Carcinoma to Combination Immunotherapy
Authors: Principe Daniel R. , Narbutis Matthew , Kumar Sandeep , Park Alex , Viswakarma Navin , Dorman Matthew J. , Kamath Suneel D. , Grippo Paul J. , Fishel Melissa L. , Hwang Rosa F. , Thummuri Dinesh , Underwood Patrick W. , Munshi Hidayatullah G. , Trevino Jose G. , Rana Ajay
Published: April 2020

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death with a median survival time of 6–12 months. Most patients present with disseminated disease and the majority are offered palliative chemotherapy. With no approved treatment modalities for patients who progress on chemotherapy, we explored the effects of long-term gemcitabine administration on the tumor microenvironment to identify potential therapeutic options for chemorefractory PDAC. Using a combination of mouse models, primary cell line–derived xenografts, and established tumor cell lines, we first evaluated chemotherapy-induced alterations in the tumor secretome and immune surface proteins by high throughput proteomic arrays. In addition to enhancing antigen presentation and immune checkpoint expression, gemcitabine consistently increased the synthesis of CCL/CXCL chemokines and TGFβ-associated signals. These secreted factors altered the composition of the tumor stroma, conferring gemcitabine resistance to cancer-associated fibroblasts in vitro and further enhancing TGFβ1 biosynthesis. Combined gemcitabine and anti-PD-1 treatment in transgenic models of murine PDAC failed to alter disease course unless mice also underwent genetic or pharmacologic ablation of TGFβ signaling. In the setting of TGFβ signaling deficiency, gemcitabine and anti-PD-1 led to a robust CD8+ T-cell response and decrease in tumor burden, markedly enhancing overall survival. These results suggest that gemcitabine successfully primes PDAC tumors for immune checkpoint inhibition by enhancing antigen presentation only following disruption of the immunosuppressive cytokine barrier. Given the current lack of third-line treatment options, this approach warrants consideration in the clinical management of gemcitabine-refractory PDAC.

Significance:

These data suggest that long-term treatment with gemcitabine leads to extensive reprogramming of the pancreatic tumor microenvironment and that patients who progress on gemcitabine-based regimens may benefit from multidrug immunotherapy.

See related commentary by Carpenter et al., p. 3070
APOBGenotypes andCDH13Haplotypes in the Cholesterol-Related Pathway Genes Predict Non–Small Cell Lung Cancer Survival
Authors: Deng Wei , Liu Hongliang , Luo Sheng , Clarke Jeffrey , Glass Carolyn , Su Li , Lin Lijuan , Christiani David C. , Wei Qingyi
Published: April 2020

Background:

Several oncogenic signals are involved in the synthesis, metabolism, transportation, and modulation of cholesterol. However, the roles of genetic variants of the cholesterol pathway genes in cancer survival remain unclear.

Methods:

We investigated associations between 26,781 common SNPs in 209 genes of the cholesterol pathway and non–small cell lung cancer (NSCLC) survival by utilizing genotyping data from two published genome-wide association studies. We used multivariate Cox proportional hazards regression and expression quantitative trait loci analyses to identify survival-associated SNPs and their correlations with the corresponding mRNA expression, respectively. We also used the Kaplan–Meier survival analysis and bioinformatics functional prediction to further evaluate the identified independent SNPs.

Results:

We found five independent SNPs (APOB rs1801701C>T; CDH13 rs35859010 C>T, rs1833970 T>A, rs254315 T>C, and rs425904 T>C) to be significantly associated with NSCLC survival in both discovery and replication datasets. When the unfavorable genotype (APOB rs1801701CC) and haplotypes (CDH13 rs35859010-rs1833970-rs254315-rs425904 C-A-T-C and T-T-T-T) were combined into a genetic score as the number of unfavorable genotypes/haplotypes (NUGH) in the multivariate analysis, an increased NUGH was associated with worse survival (Ptrend < 0.0001). In addition, both APOB rs1801701T<C and CDH13 rs425904C<T were correlated with mRNA expression of the genes in normal lung tissues from the genotype-tissue expression project.

Conclusions:

Genetic variants of APOB and CDH13 in the cholesterol pathway were associated with NSCLC survival, possibly by affecting their gene expression.

Impact:

Genetic variants of APOB and CDH13 in the cholesterol pathway may provide new scientific insights into NSCLC prognosis.
Letting the GENIE Out of Its Bottle: Examining the Potential of Real-World Clinicogenomic Data
Authors: Castellanos Emily , Baxi Shrujal S.
Published: April 2020

In this issue, Smyth and colleagues investigate the natural history of AKT1-mutant metastatic breast cancer using the AACR Project GENIE, a novel research platform comprised of real-world, clinicogenomic data. A rare subset of tumors, AKT1-mutant breast cancers demonstrated similar clinical and demographic characteristics and overall survival as AKT1–wild-type tumors, but a longer duration of therapy on mTOR inhibitors.

See related article by Smyth et al., p. 526.
Anti-VEGF Treatment Enhances CD8+ T-cell Antitumor Activity by Amplifying Hypoxia
Authors: de Almeida Patricia E. , Mak Judy , Hernandez Genevive , Jesudason Rajiv , Herault Aurelie , Javinal Vincent , Borneo Jovencio , Kim Jeong M. , Walsh Kevin B.
Published: April 2020

Antiangiogenic therapies that target the VEGF pathway have been used clinically to combat cancer for over a decade. Beyond having a direct impact on blood vessel development and tumor perfusion, accumulating evidence indicates that these agents also affect antitumor immune responses. Numerous clinical trials combining antiangiogenic drugs with immunotherapies for the treatment of cancer are ongoing, but a mechanistic understanding of how disruption of tumor angiogenesis may impact immunity is not fully discerned. Here, we reveal that blockade of VEGF-A with a mAb to VEGF augments activation of CD8+ T cells within tumors and potentiates their capacity to produce cytokines. We demonstrate that this phenomenon relies on the disruption of VEGFR2 signaling in the tumor microenvironment but does not affect CD8+ T cells directly. Instead, the augmented functional capacity of CD8+ T cells stems from increased tumor hypoxia that initiates a hypoxia-inducible factor-1α program within CD8+ T cells that directly enhances cytokine production. Finally, combinatorial administration of anti-VEGF with an immunotherapeutic antibody, anti-OX40, improved antitumor activity over single-agent treatments. Our findings illustrate that anti-VEGF treatment enhances CD8+ T-cell effector function and provides a mechanistic rationale for combining antiangiogenic and immunotherapeutic drugs for cancer treatment.
Predictors of Outcomes in Hypoxic-Ischemic Encephalopathy following Hypothermia: A Meta-Analysis
Authors: Ouwehand Sabine , Smidt Lisanne C.A. , Dudink Jeroen , Benders Manon J.N.L. , de Vries Linda S. , Groenendaal Floris , van der Aa Niek E.
Published: April 2020

Introduction: Prediction of neurodevelopmental outcome in infants with hypoxic-ischemic encephalopathy remains an important challenge. Various studies have shown that the predictive ability of different modalities changed after the introduction of therapeutic hypothermia. This paper reviews the diagnostic test accuracy of the different modalities that are being used to predict neurodevelopmental outcomes following therapeutic hypothermia. Methods: A systematic literature search was performed using Embase and PubMed. Two reviewers independently included eligible studies and extracted data. The quality of the studies was assessed using the Quality in Prognosis Studies Tool. Meta-analyses were performed where possible. Results: Forty-seven articles and 3 conference abstracts were included, reporting on 3,072infants of whom 39% died or had an adverse neurodevelopmental outcome. A meta-analysis could be performed using 37 articles on (amplitude-integrated) electroencephalography (EEG), conventional magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and proton magnetic resonance spectroscopy (1H-MRS). Amplitude-integrated EEG (aEEG) at 24 and 72 h showed similar high diagnostic OR, while aEEG at 6 h and EEG performed less, both due to a low specificity. For MRI, most studies reported scoring systems in which early (<8 days) MRI performed better than late (≥8 days) MRI. Injury to the posterior limb of the internal capsule on MRI or to the thalami on DWI were strong individual predictors, as was an increased lactate/N-acetylaspartate peak on 1H-MRS. Conclusions: In the era of therapeutic hypothermia, the different modalities remain good predictors of neurodevelopmental outcome. However, timing should be taken into account. aEEG may initially be false positive and gets more reliable after 24 h. In contrast, MRI should be used during the first week, as its predictive value decreases afterwards.
Identification of Some Errors in the Genome Assembly of Bovidae by FISH
Authors: De Lorenzi Lisa , Parma Pietro
Published: April 2020

From an economic point of view, Bovidae represent the most important family of the Ruminantia suborder. Thus, the mitochondrial and nuclear genomes of Bos taurus were among the first genomes to be sequenced after the sequencing of the human genomes. Over the millennia, the evolution of the genomes of the 3 main species belonging to the Bovidae family - B. taurus (BTA), Ovis aries (OAR), and Capra hircus (CHI) - has led to few chromosome rearrangements. Certainly, the availability and free access to the animal genomes significantly contributed to the improvement of animal genetics; however, some errors may exist due to the high automation in the genomic assembly construction process. In this work, some differences between the genomes of cattle, goat, and sheep highlighted by bioinformatics analysis have been verified by FISH, confirming that some errors persist even in the most recent genome assemblies. This type of approach has allowed us to detect a misassembly of a region belonging to BTA16 and to the homologues OAR12 and CHI16, a misassembly of a short tract in BTA22, OAR19, and CHI22, an incorrect mapping of a region of BTA21 and of CHI27 and OAR26, a discrepancy in the BTA26, OAR22, and CHI26 assemblies, a missed inversion in CHI1 compared to BTA1 and OAR1, and the exact assembly of a region of about 7 Mb in OAR10 and CHI12. Incorrect positioning of genomic tracts can cause unintended consequences in genetic analyses, especially when the data represent a starting point for the construction of genetic tools. In the new genomic assemblies published after the conclusion of our experiments, however, the accuracy in the construction of animal assemblies has been much improved, even if the new assemblies present more extended unmapped portions than the previous versions. The gap could be filled by comparative analyses between similar species or FISH.
The Effect of Body Position on Measures of Arterial Stiffness in Humans
Authors: Cohen Jeremy , Pignanelli Christopher , Burr Jamie
Published: April 2020

Background: The dynamics ofpulsatile waveforms travelling the central aorta are governed by pressures and arterial compliance. Arterial stiffness, the inverse of compliance, is an independent risk factor for cardiovascular disease and has been suggested as a superior risk index compared to brachial blood pressure (BP). Arterial stiffness is typically measured via carotid-femoral pulse wave velocity (cfPWV) in the supine position; however, different body positions alter orthostatic column height, impacting heart rate and BP. The purpose of this investigation was to examine different body positions and associated measures of cfPWV. Methods: Measures of resting cfPWV were acquired simultaneously with BP during supine, head-up tilt (HUT), head-down tilt (HDT), and Fowler’s position, all at 45 degrees from vertical. Results: Relative to supine, cfPWV was increased 1.1 ± 1.0 and 1.5 ± 1.1 m/s (both p ≤ 0.001) in HUT and Fowler’s positions, respectively. Supine to HDT cfPWV was unaltered (p = 0.1), despite an increase in mean arterial pressure (MAP) (10 ± 9 mm Hg). When cfPWV was normalized to MAP, the same effects persisted (p ≤ 0.001). Conclusion: Increasing orthostatic column height by changing posture independently increases resting cfPWV, concurrent with increases in BP. This data demonstrates the impact of body position on measures of central artery stiffness, which may have clinical relevance.
New Compound Heterozygous Splice Site Mutations of the Skeletal Muscle Ryanodine Receptor (RYR1) Gene Manifest Fetal Akinesia: A Linkage with Congenital Myopathies
Authors: Zecevic Nebojsa , Arsenijevic Vladimir , Manolakos Emmanouil , Papoulidis Ioannis , Theocharis Georgios , Sartsidis Anastasios , Tsagas Tryfon , Tziotis Ioannis , Dagklis Themistoklis , Kalogeros Georgios , Tsakiridis Ioannis , Filipovic Stankovic Milica , Eleftheriades Makarios
Published: April 2020

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been linked to malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. RYR1 is an intracellular calcium release channel and plays a crucial role in the sarcoplasmic reticulum and transverse tubule connection. Here, we report 2 fetuses from the same parents with compound heterozygous mutations in the RYR1 gene (c.10347+1G>A and c.10456-2Α>G) who presented with fetal akinesia and polyhydramnios at 27 and 19 weeks of gestation with intrauterine growth restriction in the third pregnancy. The prospective parents of the fetuses were heterozygous carriers for c.10456-2Α>G (mother) and c.10347+1G>A (father). Both mutations affect splice sites resulting in dysfunctional protein forms probably missing crucial domains of the C-terminus. Our findings reveal a new RYR1 splice site mutation (c.10456-2Α>G) that may be associated with the clinical features of myopathies, expanding the RYR1 spectrum related to these pathologies.
Is the Affordable Care Act Medicaid Expansion Linked to Change in Rate of Ventricular Assist Device Implantation for Blacks and Whites?
Authors: Breathett Khadijah K. , Knapp Shannon M. , Wightman Patrick , Desai Archita , Mazimba Sula , Calhoun Elizabeth , Sweitzer Nancy K.
Published: April 2020

Background:

The Affordable Care Act (ACA) has been associated with increased heart transplant listings among blacks, who are disproportionately uninsured. It is unclear whether the ACA is also associated with increased ventricular assist device implantation in blacks.

Methods:

Using Healthcare Cost and Utilization Project Data State Inpatient Databases from 19 states and Washington DC, we analyzed 1157 patients from early-adopter states (ACA Medicaid expansion by January 2014) and 785 patients from nonadopter states (no implementation from 2013 to 2014). Piecewise Poisson regression with a discontinuity was used to estimate change in census-adjusted rates of ventricular assist device implants by race and ACA adopter status 1 year before and after January 2014.

Results:

Following the ACA Medicaid expansion, the proportional change in rate increased significantly among blacks from early adopter (1.40 [95% CI, 1.12–1.75], pre 0.57/100 000 to post-ACA 0.80/100 000) but not nonadopter states (1.25 [95% CI, 0.98–1.58], pre 0.40/100 000 to post-ACA 0.50/100 000). However, the early and nonadopter changes in implantation rates were not statistically different from each other (
P
=0.50). There were no immediate changes in whites in either state group following the ACA Medicaid expansion (early adopter, 1.12 [95% CI, 0.98–1.29], pre 0.27/100 000 to post-ACA 0.30/100 000; nonadopter, 0.98 [95% CI, 0.82–1.16], pre 0.27/100 000 to post-ACA 0.26/100 000).

Conclusions:

Among eligible states participating in Healthcare Cost and Utilization Project Data State Inpatient Databases, the ACA was not associated with immediate changes in ventricular assist device implantation rates by race. Although a significant increase in implantation rate was observed among blacks from early-adopter states, the change was not statistically different from the change seen in nonadopter states.
Changes in Nut Consumption and Subsequent Cardiovascular Disease Risk Among US Men and Women: 3 Large Prospective Cohort Studies
Authors: Liu Xiaoran , Guasch‐Ferré Marta , Drouin‐Chartier Jean‐Philippe , Tobias Deirdre K. , Bhupathiraju Shilpa N. , Rexrode Kathryn M. , Willett Walter C. , Sun Qi , Li Yanping
Published: April 2020

Background

We aim to evaluate the association of within‐individual changes in consumption of total and specific types of nuts and the subsequent risk of incident cardiovascular disease (
CVD
) in
US
men and women.

Methods and Results

We included 34 103 men from the HPFS (Health Professionals Follow‐Up Study) (1986–2012), 77 815 women from the NHS (Nurses’ Health Study) (1986–2012), and 80 737 women from the NHS
II
(1991–2013). We assessed nut consumption every 4 years using validated food frequency questionnaires. We used multivariable Cox proportional hazards regression models to examine the association between 4‐year changes in nut consumption and risk of confirmed
CVD
end points in the subsequent 4 years. Per 0.5 serving/day increase in total nut consumption was associated with lower risk of
CVD
(relative risk [RR], 0.92; 95%
CI
, 0.86–0.98), coronary heart disease (RR, 0.94; 95% CI, 0.89–0.99), and stroke (RR, 0.89; 95% CI, 0.83–0.95). Compared with individuals who remained nonconsumers in a 4‐year interval, those who had higher consumption of total nuts (≥0.5 servings/day) had a lower risk of
CVD
(RR, 0.75; 95% CI, 0.67–0.84), coronary heart disease (RR, 0.80; 95% CI, 0.69–0.93), and stroke (RR, 0.68; 95% CI, 0.57–0.82) in next 4 years. Individuals who decreased nut consumption by ≥0.50 servings/day had a higher risk of developing
CVD
(RR, 1.14; 95% CI, 0.99–1.32), coronary heart disease (RR, 1.06; 95% CI, 0.88–1.28), and stroke (RR, 1.28; 95% CI, 1.02–1.60) when compared with those who maintained their nut consumption.

Conclusions

Increasing total consumption of nuts and intake of individual types of nuts (eg, walnuts, other tree nuts, and peanuts) was associated with a subsequent lower risk of
CVD
. These data support the role of nut intake in the primary prevention of
CVD
.

Registration

URL
:
http://www.clini​caltr​ials.gov
. Unique identifiers:
NCT
00005152 and
NCT
00005182.
Characteristic Histopathological Findings and Cardiac Arrest Rhythm in Isolated Mitral Valve Prolapse and Sudden Cardiac Death
Authors: Han Hui‐Chen , Parsons Sarah A. , Teh Andrew W. , Sanders Prashanthan , Neil Christopher , Leong Trishe , Koshy Anoop N. , Vohra Jitendra K. , Kalman Jonathan M. , Smith Karen , O'Donnell David , Hare David L. , Farouque Omar , Lim Han S.
Published: April 2020

Background

The association between mitral valve prolapse (MVP) and sudden death remains controversial. We aimed to describe histopathological changes in individuals with autopsy‐determined isolated
MVP
(
iMVP
) and sudden death and document cardiac arrest rhythm.

Methods and Results

The Australian National Coronial Information System database was used to identify cases of
iMVP
between 2000 and 2018. Histopathological changes in
iMVP
and sudden death were compared with 2 control cohorts matched for age, sex, height, and weight (1 group with noncardiac death and 1 group with cardiac death). Data linkage with ambulance services provided cardiac arrest rhythm for
iMVP
cases. From 77 221 cardiovascular deaths in the National Coronial Information System database, there were 376 cases with
MVP
. Individual case review yielded 71 cases of
iMVP
. Mean age was 49±18 years, and 51% were women. Individuals with
iMVP
had higher cardiac mass (447 g versus 355 g;
P
<0.001) compared with noncardiac death, but similar cardiac mass (447 g versus 438 g;
P
=0.64) compared with cardiac death. Individuals with
iMVP
had larger mitral valve annulus compared with noncardiac death (121 versus 108 mm;
P
<0.001) and cardiac death (121 versus 110 mm;
P
=0.002), and more left ventricular fibrosis (79% versus 38%;
P
<0.001) compared with noncardiac death controls. In those with
iMVP
and witnessed cardiac arrest, 94% had ventricular fibrillation.

Conclusions

Individuals with
iMVP
and sudden death have increased cardiac mass, mitral annulus size, and left ventricular fibrosis compared with a matched cohort, with cardiac arrest caused by ventricular fibrillation. The histopathological changes in
iMVP
may provide the substrate necessary for development of malignant ventricular arrhythmias.
White Matter Hyperintensity, Immediate Antihypertensive Treatment, and Functional Outcome After Acute Ischemic Stroke
Authors: Zhu Shiguang , Qian Sifan , Xu Tan , Peng Hao , Dong Ruiguo , Wang Dunjing , Yuan Xiaodong , Guo Libin , Zhang Yonghong , Geng Deqin , Zhong Chongke
Published: April 2020

Background and Purpose—

It remains unknown that whether white matter hyperintensity (WMH) severity influences the effect of antihypertensive treatment in acute ischemic stroke. We aimed to investigate the effects of early antihypertensive treatment on death and disability among patients with acute ischemic stroke according to WMH severities.

Methods—

This study was a secondary analysis of the data from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). Severity of WMH was evaluated using Fazekas rating scale score among 303 participants with available magnetic resonance imaging data and was categorized into none-mild WMH (Fazekas score 0–2) and moderate-severe WMH (Fazekas score 3–6). Functional outcome was death or major disability (modified Rankin Scale score of ≥3) at 14 days or hospital discharge and within 3 months.

Results—

WMH severity was significantly associated with an increased risk of death or major disability. Each 1 score increase in Fazekas score was associated with an adjusted odds ratio (95% CI) of 1.25 (1.03–1.51) for 14 days or hospital discharge and 1.39 (1.12–1.72) for 3-month functional outcome. There were no significant interactions between antihypertensive treatment and WMH severity (both
P
>0.1) on functional outcome at 14 days or hospital discharge and within 3 months. The neutral effects of immediate antihypertensive treatment were observed both in patients with moderate-severe WMH and none-mild WMH.

Conclusions—

Participants with higher WMH burden had increased risk of death or major disability after acute ischemic stroke. Early antihypertensive treatment had a neutral effect on clinical outcomes among acute ischemic stroke patients with a variety of WMH severities.

Registration—

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01840072.
Halakhic Truth and Erroneous Ruling: a Study of the Philosophy of Halakhah in the School of R. Nissim of Gerona—R. Isaac Bar Sheshet and R. Ḥasdai Crescas
Authors: Ravitsky Aviram
Published: April 2020

This study analyzes the attitude toward the conflict between halakhah and science in the thought of two halakhic authorities of fifteenth-century Spain who developed the ideas of their master, R. Nissim of Gerona, in different directions. R. Isaac bar Sheshet Perfet (Rivash) privileged halakhah over science for epistemological reasons because of its basis in revelation and tradition, but it appears that R. Ḥasdai Crescas stressed faith in the halakhic authority of the sages, even in cases of an erroneous ruling, as a way to increase the believing Jew’s motivation to serve God.
Sharīʿah-compliant or Sharīʿah-based? The Changing Ethical Discourse of Islamic Finance
Authors: Calder Ryan
Published: April 2020

Observers call upon Islamic financial institutions to move beyond offering merely Sharīʿah-compliant instruments toward offering more Sharīʿah-based ones. But when did these terms come into usage, and why? What precisely do people mean by ‘Sharīʿah-based’? In this article we argue that the term ‘Sharīʿah-compliant’ emerged in the 1990s and allowed Islamic finance institutions to leave behind scandals of the 1980s, presenting Islamic finance anew as a technically rational project grounded in Sharīʿah expertise. In contrast, the call for Sharīʿah-based finance became popular in the 2000s, and especially after the 2008 global financial crisis, which made systemic stability and product transparency pressing concerns. Usages of ‘Sharīʿah-based’ fall into three categories: those that stress separation from conventional finance, those that stress authenticity, and those that stress welfare. This definitional multiplicity is not a problem but rather a starting point for debate and a sign of Islamic finance’s growing maturity as an ethical project.
A Revised Inner-Qurʾanic Chronology Based on Mean Verse Lengths and the Medina I Counting System
Authors: Farrin Raymond K.
Published: April 2020

This article uses mean verse length data to propose a relative timeline for the Qurʾan, proceeding from the work of Nicolai Sinai and others. The timeline is based on the general observation that the verses become longer over the course of revelation. The study uses the Medina I verse count, which research has indicated is more likely to be an original or stem system than the Kufan one printed in the Qurʾans of today. From the data, three periods emerge: Early Meccan, Later Meccan, and Medinan. Besides contributing to a specific timeline for receiving the suras, the data supports the formation of a Qurʾanic nucleus at an early stage in Mecca.