bluuebunny/crossref_metadata_2025_split huggingface dataset:
Botox injection into the lower esophageal sphincter induces hiatal paralysis and gastroesophageal reflux
Authors: Kumar Dushyant , Zifan Ali , Mittal Ravinder K. 
Published: October 2019

Background: Endoscopic intrasphincteric injection of Botox (ISIB) is used routinely for the treatment of achalasia esophagus and other spastic motor disorders. Studies show that the ISIB reduces the smooth muscle lower esophageal sphincter (LES) pressure. The esophageal hiatus, formed by the right crus of diaphragm, surrounds the cranial half of the LES and works like an external LES. We studied the effects of ISIB on the LES and hiatal contraction and gastroesophageal reflux (GER). Fourteen patients treated with ISIB were studied. Esophageal manometry-impedance recordings were performed before and after the ISIB. Hiatal contraction was assessed during tidal inspiration, forced inspiration, Müller’s maneuver, and straight leg raise. In 6 subjects, the manometry were repeated 6–12 mo after the ISIB. The esophagogastric junction (EGJ) pressure was measured at end expiration (LES pressure) and at the peak of maneuvers (hiatal contraction). Transdiaphragmatic pressure (pdi; force of diaphragmatic contraction) was measured at the peak of forced inspiration. GER was measured from the impedance recordings. The EGJ pressure at end expiration (LES pressure) decreased significantly after the Botox injection. The peak EGJ pressure at tidal inspiration, forced inspiration, Müller’s maneuver, and straight leg raise was also dramatically reduced by the ISIB. There was no effect of Botox on the pdi during forced inspiration. Seven of 10 subjects demonstrated GER during maneuvers following the ISIB. Six to 12 mo after ISIB, the LES and hiatal contraction pressure returned to the pre-ISIB levels. ISIB, in addition to decreasing LES pressure, paralyzes the esophageal hiatus (crural diaphragm) and induces GER. NEW & NOTEWORTHY The sphincter mechanism at the lower end of the esophagus comprises smooth muscle lower esophageal sphincter (LES) and skeletal muscle crural diaphragm (hiatus). Current thinking is that the endoscopic intrasphincteric injection of Botox (ISIB), used routinely for the treatment of achalasia esophagus, reduces LES pressure. Our study shows that ISIB, even though injected into the LES, diffuses into the hiatus and causes its paralysis. These findings emphasize the importance of esophageal hiatus as an important component of the antireflux barrier and that the ISIB is refluxogenic.
Inactivating NF1 Mutations Are Enriched in Advanced Breast Cancer and Contribute to Endocrine Therapy Resistance
Authors: Pearson Alex , Proszek Paula , Pascual Javier , Fribbens Charlotte , Shamsher Monee K. , Kingston Belinda , O'Leary Ben , Herrera-Abreu Maria T. , Cutts Rosalind J. , Garcia-Murillas Isaac , Bye Hannah , Walker Brian A. , Gonzalez De Castro David , Yuan Lina , Jamal Sabri , Hubank Mike , Lopez-Knowles Elena , Schuster Eugene F. , Dowsett Mitch , Osin Peter , Nerurkar Ashutosh , Parton Marina , Okines Alicia F.C. , Johnston Stephen R.D. , Ring Alistair , Turner Nicholas C. 
Published: October 2019

Abstract

Purpose:
Advanced breast cancer (ABC) has not been subjected to the same degree of molecular scrutiny as early primary cancer. Breast cancer evolves with time and under the selective pressure of treatment, with the potential to acquire mutations with resistance to treatment and disease progression. To identify potentially targetable mutations in advanced breast cancer, we performed prospective molecular characterization of a cohort of patients with ABC.

Experimental Design:
Biopsies from patients with advanced breast cancer were sequenced with a 41 genes targeted panel in the ABC Biopsy (ABC-Bio) study. Blood samples were collected at disease progression for circulating tumor DNA (ctDNA) analysis, along with matched primary tumor to assess for acquisition in ABC in a subset of patients.

Results:
We sequenced 210 ABC samples, demonstrating enrichment compared with primary disease for potentially targetable mutations in HER2 (in 6.19% of samples), AKT1 (7.14%), and NF1 (8.10%). Of these enriched mutations, we show that NF1 mutations were frequently acquired in ABC, not present in the original primary disease. In ER-positive cancer cell line models, loss of NF1 resulted in endocrine therapy resistance, through both ER-dependent and -independent mechanisms. NF1 loss promoted ER-independent cyclin D1 expression, which could be therapeutically targeted with CDK4/6 inhibitors in vitro. Patients with NF1 mutations detected in baseline circulating tumor DNA had a good outcome on the CDK4/6 inhibitor palbociclib and fulvestrant.

Conclusions:
Our research identifies multiple therapeutic opportunities for advanced breast cancer and identifies the previously underappreciated acquisition of NF1 mutations.
Hemodynamics and Prognostic Impact of Concomitant Mitral Stenosis in Patients Undergoing Surgical or Transcatheter Aortic Valve Replacement for Aortic Stenosis
Authors: Kato Nahoko , Padang Ratnasari , Pislaru Cristina , Miranda William R. , Hoshina Mizuho , Shibayama Kentaro , Watanabe Hiroyuki , Scott Christopher G. , Greason Kevin L. , Pislaru Sorin V. , Nkomo Vuyisile T. , Pellikka Patricia A. 
Published: October 2019

Background:
Mitral stenosis frequently coexists in patients with severe aortic stenosis. Mitral stenosis severity evaluation is challenging in the setting of combined aortic stenosis and mitral stenosis because of hemodynamic interactions between the 2 valve lesions. The impact of aortic valve replacement (AVR) for severe aortic stenosis on mitral stenosis is unknown. This study aimed to assess the effect of AVR on mitral stenosis hemodynamics and the clinical outcomes of patients with severe aortic stenosis with and without mitral stenosis.

Methods:

We retrospectively investigated patients who underwent surgical AVR or transcatheter AVR for severe aortic stenosis from 2008 to 2015. Mean transmitral gradient by Doppler echocardiography ≥4 mm Hg was identified as mitral stenosis; patients were then stratified according to mitral valve area (MVA, by continuity equation) as >2.0 cm
2
or ≤2.0 cm
2
. MVA before and after AVR in patients with mitral stenosis were evaluated. Clinical outcomes of patients with and without mitral stenosis were compared using 1:2 matching for age, sex, left ventricular ejection fraction, method of AVR (surgical AVR versus transcatheter AVR) and year of AVR.

Results:

Of 190 patients with severe aortic stenosis and mitral stenosis (age 76±9 years, 42% men), 184 were matched with 362 with severe aortic stenosis without mitral stenosis. Among all mitral stenosis patients, the mean MVA increased after AVR by 0.26±0.59 cm
2
(from 2.00±0.50 to 2.26±0.62 cm
2
,
P
<0.01). MVA increased in 105 (55%) and remained unchanged in 34 (18%). Indexed stroke volume ≤45 mL/m
2
(odds ratio [OR] 2.40; 95% CI, 1.15–5.01;
P
=0.020) and transcatheter AVR (OR, 2.36; 95% CI, 1.17–4.77;
P
=0.017) were independently associated with increase in MVA. Of 107 with significant mitral stenosis (MVA ≤2.0 cm
2
), MVA increased to >2.0 cm
2
after AVR in 52 (49%, pseudo mitral stenosis) and remained ≤2.0 cm
2
in 55 (51%, true mitral stenosis). During follow-up of median 2.9 (0.7–4.9) years, true mitral stenosis was an independent predictor of all-cause mortality (adjusted hazard ratio, 1.88; 95% CI, 1.20–2.94;
P
<0.01).

Conclusions:

MVA improved after AVR in nearly half of patients with severe aortic stenosis and mitral stenosis. MVA remained ≤2.0 cm
2
(true mitral stenosis) in nearly half of patients with severe aortic stenosis and significant mitral stenosis; this was associated with worse survival among patients undergoing AVR for severe aortic stenosis.
Flood and Inundation Forecasting in the Sparsely Gauged Transboundary Chenab River Basin Using Satellite Rain and Coupling Meteorological and Hydrological Models
Authors: Asghar Malik Rizwan , Ushiyama Tomoki , Riaz Muhammad , Miyamoto Mamoru 
Published: October 2019

Abstract
Flood forecasting in a transboundary river basin is challenging due to insufficient data sharing between countries in the upper and lower reaches of a basin. A solution is the use of satellite-observed rainfall and numerical weather prediction (NWP) for hydrological forecasting. We applied this method to the transboundary sparsely gauged Chenab River basin in Pakistan and India to reproduce the exceptionally high flood in 2014. We employed global NWPs by three weather centers to consider forecast uncertainty and downscaled them using the Weather Research and Forecasting (WRF) Model to prepare precipitation inputs. For hydrological simulations, we used a kinematic wave model, the Integrated Flood Analysis System (IFAS), for the upper-reach basin with high mountains and steep slopes, and we used a diffusive-wave rainfall–runoff–inundation (RRI) model for low altitudes and mild slopes. In our forecasting experiment, the precipitation by the global NWP was not able to predict flood peaks consistently. However, the downscaled rainfall by regional NWP showed good performance in predicting flood waves quantitatively, and a multimodel approach provided added value in issuing reliable warning as early as 6 days in advance. A confident streamflow forecasting near the border of the countries also led to reliable inundation forecasting by the RRI model in the lower-reach basin.
Single-plant GWAS coupled with bulk segregant analysis allows rapid identification and corroboration of plant-height candidate SNPs
Authors: Gyawali Abiskar , Shrestha Vivek , Guill Katherine E. , Flint-Garcia Sherry , Beissinger Timothy M. 
Published: October 2019

AbstractBackgroundGenome wide association studies (GWAS) are a powerful tool for identifying quantitative trait loci (QTL) and causal single nucleotide polymorphisms (SNPs)/genes associated with various important traits in crop species. Typically, GWAS in crops are performed using a panel of inbred lines, where multiple replicates of the same inbred are measured and the average phenotype is taken as the response variable. Here we describe and evaluate single plant GWAS (sp-GWAS) for performing a GWAS on individual plants, which does not require an association panel of inbreds. Instead sp-GWAS relies on the phenotypes and genotypes from individual plants sampled from a randomly mating population. Importantly, we demonstrate how sp-GWAS can be efficiently combined with a bulk segregant analysis (BSA) experiment to rapidly corroborate evidence for significant SNPs.ResultsIn this study we used the Shoepeg maize landrace, collected as an open pollinating variety from a farm in Southern Missouri in the 1960’s, to evaluate whether sp-GWAS coupled with BSA can efficiently and powerfully used to detect significant association of SNPs for plant height (PH). Plant were grown in 8 locations across two years and in total 768 individuals were genotyped and phenotyped for sp-GWAS. A total of 306 k polymorphic markers in 768 individuals evaluated via association analysis detected 25 significant SNPs (P ≤ 0.00001) for PH. The results from our single-plant GWAS were further validated by bulk segregant analysis (BSA) for PH. BSA sequencing was performed on the same population by selecting tall and short plants as separate bulks. This approach identified 37 genomic regions for plant height. Of the 25 significant SNPs from GWAS, the three most significant SNPs co-localize with regions identified by BSA.ConclusionOverall, this study demonstrates that sp-GWAS coupled with BSA can be a useful tool for detecting significant SNPs and identifying candidate genes. This result is particularly useful for species/populations where association panels are not readily available.
New different origins and evolutionary processes of AP2/EREBP transcription factors in Taxus chinensis
Authors: Zhang Meng , Chen Ying , Jin Xiaofei , Cai Yuxin , Yuan Yuanyuan , Fu Chunhua , Yu Longjiang 
Published: October 2019

AbstractBackgroundTaxusspp. produces the anticancer drug, taxol, and hence is planted as an industrial crop in China. APETALA2/ethylene response element binding proteins (AP2/EREBPs) are the key regulators of plant development, growth, and stress responses. Several homologues control taxol biosynthesis. Identifying the AP2/EREBP proteins fromTaxusis important to increase breeding and production and clarify their evolutionary processes.ResultsAmong the 90 genes from multiTaxus chinensistranscriptome datasets, 81 encoded full-length AP2-containing proteins. A domain structure highly similar to that of angiosperm AP2/EREBPs was found in 2 AP2, 2 ANT, 1 RAV, 28 dehydration-responsive element-binding proteins, and 47 ethylene-responsive factors contained, indicating that they have extremely conservative evolution processes. A new subgroup protein, TcA3Bz1, contains three conserved AP2 domains and, a new domain structure of AP2/EREBPs that is different from that of known proteins. The new subtype AP2 proteins were also present in several gymnosperms (Gingko biloba) and bryophytes (Marchantia polymorpha). However, no homologue was found inSelaginella moellendorffii, indicating unknown evolutionary processes accompanying this plant’s evolution. Moreover, the structures of the new subgroup AP2/EREBPs have different conserved domains, such as B3, zf-C3Hc3H, and agent domains, indicating their divergent evolution in bryophytes and gymnosperms. Interestingly, three repeats of AP2 domains have separately evolved from mosses to gymnosperms for most of the new proteins, but the AP2 domain of Gb_11937 has been replicated.ConclusionThe new subtype AP2/EREBPs have different origins and would enrich our knowledge of the molecular structure, origin, and evolutionary processes of AP2/EREBP transcription factors in plants.
Cognitive impairments in patients with persistent symptoms attributed to Lyme disease
Authors: Berende Anneleen , Agelink van Rentergem Joost , Evers Andrea W. M. , ter Hofstede Hadewych J. M. , Vos Fidel J. , Kullberg Bart Jan , Kessels Roy P. C. 
Published: October 2019

Abstract

Background
Persistent symptoms attributed to Lyme borreliosis often include self-reported cognitive impairment. However, it remains unclear whether these symptoms can be substantiated by objective cognitive testing.

Methods
For this observational study, cognitive performance was assessed in 280 adults with persistent symptoms attributed to Lyme borreliosis (as part of baseline data collected for the Dutch PLEASE study). Cognitive testing covered the five major domains: episodic memory, working memory / attention, verbal fluency, information-processing speed and executive function. Patients’ profiles of test scores were compared to a large age-, education- and sex-adjusted normative sample using multivariate normative comparison. Performance validity was assessed to detect suboptimal effort, and questionnaires were administered to measure self-reported cognitive complaints, fatigue, anxiety, depressive symptoms and several other psychological factors.

Results
Of 280 patients, one was excluded as the test battery could not be completed. Of the remaining 279 patients, 239 (85.4%) displayed sufficient performance validity. Patients with insufficient performance validity felt significantly more helpless and physically fatigued, and less orientated. Furthermore, they had a lower education level and less often paid work. Of the total study cohort 5.7% (n = 16) performed in the impaired range. Among the 239 patients who displayed sufficient performance validity, 2.9% (n = 7) were classified as cognitively impaired. No association between subjective cognitive symptoms and objective impairment was found.

Conclusions
Only a small percentage of patients with borreliosis-attributed persistent symptoms have objective cognitive impairment. Performance validity should be taken into account in neuropsychological examinations of these patients. Self-report questionnaires are insufficiently valid to diagnose cognitive impairment.

Trial registration
ClinicalTrials.gov NCT01207739. Registered 23 September 2010.
Forecasting incidence of hand, foot and mouth disease using BP neural networks in Jiangsu province, China
Authors: Liu Wendong , Bao Changjun , Zhou Yuping , Ji Hong , Wu Ying , Shi Yingying , Shen Wenqi , Bao Jing , Li Juan , Hu Jianli , Huo Xiang 
Published: October 2019

AbstractBackgroundHand, foot and mouth disease (HFMD) is a rising public health problem and has attracted considerable attention worldwide. The purpose of this study was to develop an optimal model with meteorological factors to predict the epidemic of HFMD.MethodsTwo types of methods, back propagation neural networks (BP) and auto-regressive integrated moving average (ARIMA), were employed to develop forecasting models, based on the monthly HFMD incidences and meteorological factors during 2009–2016 in Jiangsu province, China. Root mean square error (RMSE) and mean absolute percentage error (MAPE) were employed to select model and evaluate the performance of the models.ResultsFour models were constructed. The multivariate BP model was constructed using the HFMD incidences lagged from 1 to 4 months, mean temperature, rainfall and their one order lagged terms as inputs. The other BP model was fitted just using the lagged HFMD incidences as inputs. The univariate ARIMA model was specified as ARIMA (1,0,1)(1,1,0)12(AIC = 1132.12, BIC = 1440.43). And the multivariate ARIMAX with one order lagged temperature as external predictor was fitted based on this ARIMA model (AIC = 1132.37, BIC = 1142.76). The multivariate BP model performed the best in both model fitting stage and prospective forecasting stage, with a MAPE no more than 20%. The performance of the multivariate ARIMAX model was similar to that of the univariate ARIMA model. Both performed much worse than the two BP models, with a high MAPE near to 40%.ConclusionThe multivariate BP model effectively integrated the autocorrelation of the HFMD incidence series. Meanwhile, it also comprehensively combined the climatic variables and their hysteresis effects. The introduction of the climate terms significantly improved the prediction accuracy of the BP model. This model could be an ideal method to predict the epidemic level of HFMD, which is of great importance for the public health authorities.
Risk factors and survival of patients infected with carbapenem-resistant Klebsiella pneumoniae in a KPC endemic setting: a case-control and cohort study
Authors: Cienfuegos-Gallet Astrid V. , Ocampo de Los Ríos Ana M. , Sierra Viana Patricia , Ramirez Brinez Faiver , Restrepo Castro Carlos , Roncancio Villamil Gustavo , del Corral Londoño Helena , Jiménez J. Natalia 
Published: October 2019

AbstractBackgroundMany gaps in the burden of resistant pathogens exist in endemic areas of low- and middle-income economies, especially those endemic for carbapenem resistance. The aim of this study is to evaluate risk factors for carbapenem-resistance, to estimate the association between carbapenem-resistance and all-cause 30-day mortality and to examine whether mortality is mediated by inappropriate therapy.MethodsA case-control and a cohort study were conducted in one tertiary-care hospital in Medellín, Colombia from 2014 to 2015. Phenotypic and genotypic characterization of isolates was performed. In the case-control study, cases were defined as patients infected with carbapenem-resistantK. pneumoniae(CRKP) and controls as patients infected with carbapenem-susceptibleK. pneumoniae(CSKP). A risk factor analysis was conducted using logistic regression models. In the cohort study, the exposed group was defined as patients infected with CRKP and the non-exposed group as patients infected with CSKP. A survival analysis using an accelerated failure time model with a lognormal distribution was performed to estimate the association between carbapenem resistance and all-cause 30-day-mortality and to examine whether mortality is mediated by inappropriate therapy.ResultsA total of 338 patients were enrolled; 49 were infected with CRKP and 289 with CSKP. Among CRKP isolates CG258 (n = 29), ST25 (n = 5) and ST307 (n = 4) were detected. Of importance, every day of meropenem (OR 1.18, 95%CI 1.10–1.28) and cefepime (OR 1.22, 95%CI 1.03–1.49) use increase the risk of carbapenem resistance. Additional risk factors were previous use of ciprofloxacin (OR 2.37, 95%CI 1.00–5.35) and urinary catheter (OR 2.60, 95%CI 1.25–5.37). Furthermore, a significant lower survival time was estimated for patients infected with CRKP compared to CSKP (Relative Times 0.44, 95%CI 0.24–0.82). The strength of association was reduced when appropriate therapy was included in the model (RT = 0.81 95%CI 0.48–1.37).ConclusionShort antibiotic courses had the potential to reduce the selection and transmission of CRKP. A high burden in mortality occurred in patients infected with CRKP in a KPC endemic setting and CRKP leads to increased mortality via inappropriate antibiotic treatment. Furthermore, dissemination of recognized hypervirulent clones could add to the list of challenges for antibiotic resistance control.
Prognostic value of estrogen receptor-α and progesterone receptor in curatively resected colorectal cancer: a retrospective analysis with independent validations
Authors: Ye Shu-Biao , Cheng Yi-Kan , Zhang Lin , Wang Xue-Ping , Wang Lei , Lan Ping 
Published: October 2019

Abstract

Background
Prognostic assessment is crucial for optimal treatment. The aim of our study was to investigate the potential impact of estrogen receptor-α (ER-α) and progesterone receptor (PR) on the prognosis of colorectal cancer (CRC) patients who received curative resection.

Methods
Retrospective evaluation of two independent cohorts of CRC patients maintained prospectively in 2009–2010 (training set) (n = 148) and 2007–2009 (internal validation set) (n = 485). Furthermore, we used an external independent CRC cohort from The Cancer Genome Atlas (TCGA) (n = 511) for further validation. ER-α and PR expression as well as other potential prognostic factors were retrospectively evaluated in training set with respect to overall survival (OS), local relapse free survival (LRFS) and distant metastasis free survival (DMFS). The prognostic factors found in training set will be validated in two validation cohorts.

Results
On univariate analysis for the training set, OS, LRFS and DMFS were not associated with PR expression. While patients with ER-αexpression were found to have poor prognosis. In addition, multivariate analysis showed that ER-αexpression maintained significance with respect to OS (HR, 5.06; p = 0.002), LRFS (HR, 8.81; p = 0.002) and DMFS (HR, 8.07; p = 0.004). Similarly, ER-α expression showed prognostic significance with respect to OS with hazard ratios (HRs) of 1.572 (95% CI: 1.001–2.467, p = 0.049) and 1.624 (95% CI: 1.047–2.520, p = 0.031) for the internal and external validation cohort, respectively.

Conclusion
ER-α expression was a biomarker of poor prognosis and it might inform treatment decision for high risk CRC patients. However, PR expression was not associated with survival outcomes.