bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of a Claims-Based Frailty Index Against Physical Performance and Adverse Health Outcomes in the Health and Retirement Study
Authors: Kim Dae Hyun , Glynn Robert J , Avorn Jerry , Lipsitz Lewis A , Rockwood Kenneth , Pawar Ajinkya , Schneeweiss Sebastian 
Published: August 2018

Abstract

Background
A claims-based frailty index (CFI) was developed based on a deficit-accumulation approach using self-reported health information. This study aimed to independently validate the CFI against physical performance and adverse health outcomes.

Methods
This retrospective cohort study included 3,642 community-dwelling older adults who had at least 1 health care encounter in the year prior to assessments of physical performance in the 2008 Health and Retirement Study wave. A CFI was estimated from Medicare claims data in the past year. Gait speed, grip strength, and the 2-year risk of death, institutionalization, disability, hospitalization, and prolonged (>30 days) skilled nursing facility (SNF) stay were evaluated for CFI categories (robust: <0.15, prefrail: 0.15–0.24, mildly frail: 0.25–0.34, moderate-to-severely frail: ≥0.35).

Results
The prevalence of robust, prefrail, mildly frail, and moderate-to-severely frail state was 52.7%, 38.0%, 7.1%, and 2.2%, respectively. Individuals with higher CFI had lower mean gait speed (moderate-to-severely frail vs robust: 0.39 vs 0.78 m/s) and weaker grip strength (19.8 vs 28.5 kg). Higher CFI was associated with death (moderate-to-severely frail vs robust: 46% vs 7%), institutionalization (21% vs 5%), activity of daily living disability (33% vs 9%), instrumental activity of daily living disability (100% vs 22%), hospitalization (79% vs 23%), and prolonged SNF stay (17% vs 2%). The odds ratios per 1-SD (=0.07) difference in CFI were 1.46–2.06 for these outcomes, which remained statistically significant after adjustment for age, sex, and a comorbidity index.

Conclusion
The CFI is useful to identify individuals with poor physical function and at greater risks of adverse health outcomes in Medicare data.
Population genomics of wild Chinese rhesus macaques reveals a dynamic demographic history and local adaptation, with implications for biomedical research
Authors: Liu Zhijin , Tan Xinxin , Orozco-terWengel Pablo , Zhou Xuming , Zhang Liye , Tian Shilin , Yan Zhongze , Xu Huailiang , Ren Baoping , Zhang Peng , Xiang Zuofu , Sun Binghua , Roos Christian , Bruford Michael W , Li Ming 
Published: August 2018

Abstract

Background
The rhesus macaque (RM, Macaca mulatta) is the most important nonhuman primate model in biomedical research. We present the first genomic survey of wild RMs, sequencing 81 geo-referenced individuals of five subspecies from 17 locations in China, a large fraction of the species' natural distribution.

Results
Populations were structured into five genetic lineages on the mainland and Hainan Island, recapitulating current subspecies designations. These subspecies are estimated to have diverged 125.8 to 51.3 thousand years ago, but feature recent gene flow. Consistent with the expectation of a larger body size in colder climates and smaller body size in warmer climates (Bergman's rule), the northernmost RM lineage (M. m. tcheliensis), possessing the largest body size of all Chinese RMs, and the southernmost lineage (M. m. brevicaudus), with the smallest body size of all Chinese RMs, feature positively selected genes responsible for skeletal development. Further, two candidate selected genes (Fbp1, Fbp2) found in M. m. tcheliensis are involved in gluconeogenesis, potentially maintaining stable blood glucose levels during starvation when food resources are scarce in winter. The tropical subspecies M. m. brevicaudus showed positively selected genes related to cardiovascular function and response to temperature stimuli, potentially involved in tropical adaptation. We found 118 single-nucleotide polymorphisms matching human disease-causing variants with 82 being subspecies specific.

Conclusions
These data provide a resource for selection of RMs in biomedical experiments. The demographic history of Chinese RMs and their history of local adaption offer new insights into their evolution and provide valuable baseline information for biomedical investigation.
Resisting austerity measures to social policies: multiple explanatory case studies
Authors: O’Campo Patricia , Freiler Alix , Muntaner Carles , Gelormino Elena , Huegaerts Kelly , Puig-Barrachina Vanessa , Mitchell Christiane 
Published: August 2018

Abstract
Since Margaret Thatcher reached power in the United Kingdom, European governments have increasingly turned to neoliberal forms of policy-making, focusing, especially after the 2008 Great Recession on ‘austerity policies’ rather than investing in social protection policies. We applied a multiple explanatory case studies methodology to examine how and why challenges and resistance to these austerity measures are successful or not in four settings for three different social policy issues: using a gender lens in state budgeting in Andalusia (Spain), maintaining unemployment benefits in Italy and cuts to fuel poverty reduction programs in Northern Ireland and England. In particular, we intended to learn about whether resistance strategies are shared across disparate cases or whether there are unique activities that lead to successful resistance to austerity policies. As our approach drew from realist philosophy of science, we started with initial theories concerning collective action, political ideology and political power of affected populations. Our findings suggest that there are similarities between the cases we studied despite differences in political and policy contexts. We found that joint action between advocacy groups was effective in resisting cuts to social spending. Evidence also indicates that the social construction of target populations is important in resisting changes to social programmes. This was observed in both England and Northern Ireland where pensioners held significant political clout.
Characterization of a clinical Clostridioides difficile isolate with markedly reduced fidaxomicin susceptibility and a V1143D mutation in rpoB
Authors: Schwanbeck Julian , Riedel Thomas , Laukien Friederike , Schober Isabel , Oehmig Ines , Zimmermann Ortrud , Overmann Jörg , Groß Uwe , Zautner Andreas E , Bohne Wolfgang 
Published: August 2018

Abstract

Objectives
The identification and characterization of clinical Clostridioides difficile isolates with reduced fidaxomicin susceptibility.

Methods
Agar dilution assays were used to determine fidaxomicin MICs. Genome sequence data were obtained by single-molecule real-time (SMRT) sequencing in addition to amplicon sequencing of rpoB and rpoC alleles. Allelic exchange was used to introduce the identified mutation into C. difficile 630Δerm. Replication rates, toxin A/B production and spore formation were determined from the strain with reduced fidaxomicin susceptibility.

Results
Out of 50 clinical C. difficile isolates, isolate Goe-91 revealed markedly reduced fidaxomicin susceptibility (MIC >64 mg/L). A V1143D mutation was identified in rpoB of Goe-91. When introduced into C. difficile 630Δerm, this mutation decreased fidaxomicin susceptibility (MIC >64 mg/L), but was also associated with a reduced replication rate, low toxin A/B production and markedly reduced spore formation. In contrast, Goe-91, although also reduced in toxin production, showed normal growth rates and only moderately reduced spore formation capacities. This indicates that the rpoBV1143D allele-associated fitness defect is less pronounced in the clinical isolate.

Conclusions
To the best of our knowledge, this is the first description of a pathogenic clinical C. difficile isolate with markedly reduced fidaxomicin susceptibility. The lower-than-expected fitness burden of the resistance-mediating rpoBV1143D allele might be an indication for compensatory mechanisms that take place during in vivo selection of mutants.
RETRACTED: Long noncoding RNA NSCLCAT1 increases non–small cell lung cancer cell invasion and migration through the Hippo signaling pathway by interacting with CDH1
Authors: Zhao Wei , Zhang Le-Ning , Wang Xiao-Long , Zhang Ji , Yu Hai-Xiang 
Published: August 2018

ABSTRACTMetastatic growth is the leading cause of cancer‐related death in non–small cell lung cancer (NSCLC). Metastasis is believed to be initiated by an increase in cell motility mediated by the loss of cell–cell adhesion because of the suppression of E‐cadherin [encoded by Cadherin 1 (CDH1)]. However, very little is known about the molecular mechanism of CDH1 regulation. Therefore, we hypothesized that non–small cell lung cancer—associated transcript‐1 (NSCLCAT1) suppresses functional CDH1 and mediates the Hippo signaling pathway, resulting in increased cell migration and invasion, and reduced apoptosis. Initially, microarray profiling and target prediction programs were employed to identify whether NSCLCAT1 targets CDH1. Next, quantitative PCR was used to determine the expression pattern of NSCLCAT1 in 114 specimens. The biologic functions of NSCLCAT1 in NSCLC were assessed through the up‐regulation and down‐regulation of the levels of endogenous NSCLCAT1 with the use of NSCLCAT1 vector or small interfering RNA against NSCLCAT1 in NSCLC cells. Furthermore, the Hippo signaling pathway in NSCLC cells was blocked by applying the verteporfin treatment to have a better understanding on the pivotal role of the Hippo signaling pathway in NSCLC. Microarray expression profiles of long noncoding RNAs, GSE19804 and GSE27262), revealed that NSCLCAT1 was up‐regulated in NSCLC. Among patients with NSCLC, we determined that the NSCLCAT1 was robustly induced, whereas CDH1 was suppressed. The luciferase activity determination identified CDH1 as a NSCLCAT1 target. NSCLCAT1 was found to increase cell viability, migration, and invasion and to reduce apoptosis in NSCLC cells. The results from the quantitative PCR and Western blot analysis revealed that NSCLCAT1 modulated the Hippo signaling pathway. Furthermore, the inhibition of the Hippo signaling pathway by verteporfin treatment led to the loss of the effect of NSCLCAT1 on NSCLC cells. In summary, our findings suggested that NSCLCAT1 potentially has a role in NSCLC and NSCLCAT1‐mediated regulation of the Hippo signaling pathway through the transcriptional repression of CDH1; therefore, the functional suppression or inhibition of NSCLCAT1 could be used as a novel therapeutic pathway in the control of aggressive and metastatic NSCLC.—Zhao, W., Zhang, L.‐N., Wang, X.‐L., Zhang, J., Yu, H.‐X.Long noncoding RNA NSCLCAT1 increases non‐small cell lung cancer cell invasion and migration through the Hippo signaling pathway by interacting with CDH1. FASEB J. 33, 1151–1166 (2019). www.fasebj.org
Facilitation of MrgprD by TRP‐A1 promotes neuropathic pain
Authors: Wang Changming , Gu Leying , Ruan Yonglan , Geng Xiao , Xu Miao , Yang Niuniu , Yu Lei , Jiang Yucui , Zhu Chan , Yang Yan , Zhou Yuan , Guan Xiaowei , Luo Wenqin , Liu Qin , Dong Xinzhong , Yu Guang , Lan Lei , Tang Zongxiang 
Published: August 2018

ABSTRACTNeuropathic pain remains a therapeutic challenge because of its complicated mechanisms. Mas‐related GPCR D (MrgprD) is specifically expressed in small‐diameter, nociceptive neurons of dorsal root ganglia (DRGs) and is implicated in pain modulation. However, the underlying mechanism of MrgprD involved in neuropathic pain remains elusive. In this study, we used behavioral experiments and physiologic examination methods to investigate the role of MrgprD in chronic constriction injury (CCI)–induced neuropathic pain. We found that MrgprD is necessary for the initiation of mechanical hypersensitivity and cold allodynia, but not for heat allodynia. Moreover, we demonstrated that transient receptor potential cation channel (TRP)‐A1 was the ion channel downstream of MrgprD, and the β‐alanine–induced calcium signal was attributed mostly to TRP‐A1 function. We further showed that PKA serves as a downstream mediator of β‐alanine–activated MrgprD signaling to activate TRP‐A1 in DRG neurons and in human embryonic kidney 293 cells, to coexpress MrgprD and TRP‐A1 plasmids. Finally, we found that the β‐alanine–induced pain behavior was increased, whereas the itching behavior was unchanged in CCI models compared with sham‐injured animals. Knockout of TRPA1 also attenuated the β‐alanine–induced pain behavior in CCI models. In conclusion, MrgprD is essential in cold allodynia in CCI‐induced neuropathic pain through the PKA–TRP‐A1 pathway. TRP‐A1 facilitates MrgprD to development of neuropathic pain. Our findings reveal a novel mechanism of neuropathic pain formation and highlight MrgprD as a promising drug target for the treatment of neuropathic pain.—Wang, C., Gu, L., Ruan, Y., Geng, X., Xu, M., Yang, N., Yu, L., Jiang, Y., Zhu, C., Yang, Y., Zhou, Y., Guan, X., Luo, W., Liu, Q., Dong, X., Yu, G., Lan, L., Tang, Z. Facilitation of MrgprD by TRP‐A1 promotes neuropathic pain. FASEB J. 33, 1360–1373 (2019). www.fasebj.org
Generation and analysis of a mouse model of pseudohypoaldosteronism type II caused by KLHL3 mutation in BTB domain
Authors: Lin Chien-Ming , Cheng Chih-Jen , Yang Sung-Sen , Tseng Min-Hua , Yen Ming-Tso , Sung Chih-Chien , Lin Shih-Hua 
Published: August 2018

ABSTRACTThe Kelch‐like 3 (KLHL3) mutations contributed to the most common causative genes in patients with pseudohypoaldosteronism type II (PHAII); however, the molecular mechanisms of PHAII‐causing mutations in BTB domain of KLHL3 in vivo have not been investigated. We generated and analyzed Klhl3 knock‐in (KI) mice carrying a missense M131V mutation in the BTB domain (corresponding to human KLHL3 M78V mutation). Klhl3M131V/+ KI mice exhibited typical PHAII phenotype with an exaggerated diuretic response to hydrochlorothiazide. Their kidney tissues showed an unchanged KLHL3, decreased cullin 3 (Cul3), and increased with‐no‐lysine kinases (WNKs) WNK1 and WNK4 along with an enhanced downstream ste20‐related proline/alanine‐rich kinase/oxidative stress response kinase 1‐N(K)CC phosphorylation. Their Cul3 protein in the cytosol of distal convoluted tubule cells was also significantly attenuated on immunogold‐labeling electron microscopy. In micro‐dissected renal tubules, Klhl3M131V/+ KI mice expressed high levels of Wnk4 mRNA in the distal nephron. In vitro coimmunoprecipitation showed the KLHL3 BTB domain mutation retained intact interaction with WNKs but reduced binding to Cul3, thus leading to the increased abundance of total WNKs. In summary, Klhl3M131V/+ KI mice feature typical PHAII with a simultaneous increase of WNK1 and WNK4 through the impaired KLHL3 BTB domain binding to Cul3.—Lin, C.‐M., Cheng, C.‐J., Yang, S.‐S., Tseng, M.‐H., Yen, M.‐T., Sung, C.‐C., Lin, S.‐H. Generation and analysis of a mouse model of pseudohypoaldosteronism type II caused by KLHL3 mutation in BTB domain. FASEB J. 33, 1051–1061 (2019). www.fasebj.org
Allergen immunotherapy as add-on to biologic agents
Authors: Lombardi Carlo , Canonica Giorgio W. , Passalacqua Giovanni 
Published: August 2018

Purpose of review
In this review, we sought to outline many of the recent evidences about the available clinical trials in which biologic agents [i.e. omalizumab (OMA)] were associated as add-on to allergen-specific immunotherapy (AIT).

Recent findings
The available literature shows that OMA may be a valuable option as add-on to AIT for respiratory allergy, or food desensitization, especially in the escalation or build-up phases, in which adverse events are more commonly expected. The encouraging data for hymenoptera venom allergy remain limited to case reports, and no structured clinical trial is available.

Summary
Over the past decade, studies of OMA used with AIT have shown promising results. Today, big randomized, double-blind, placebo-controlled trials are needed to better select those patients who would benefit from the addition of OMA (or other biologic agents) to AIT, as well as optimal dosing schedules, optimal duration of treatments and, finally, adequate evaluation about pharmacoeconomic aspects.
Mortality and survival in systemic sclerosis: a review of recent literature
Authors: Poudel Dilli R. , Derk Chris T. 
Published: August 2018

Purpose of review
Systemic sclerosis is a debilitating rheumatic disease with high morbidity and mortality. This review attempts to provide the most recent update on mortality and survival and their determinants in systemic sclerosis (SSc).

Recent findings
SSc remains an uncommon rheumatic disease with high mortality. There have been attempts to devise more comprehensive but simpler scoring systems to prognosticate survival in SSc, which will influence triaging of patients and guide the utilization of aggressive treatment strategies.

Summary
Updated literature review on mortality and survival in SSc has confirmed its high-case fatality but a slowly improving survival profile over time. It identifies some gaps in knowledge, especially in regards to ethnic differences.
A Prospective Cohort Study of the Association Between Body Mass Index and Incident Bacterial Vaginosis
Authors: Lokken Erica M. , Richardson Barbra A. , Kinuthia John , Mwinyikai Khamis , Abdalla Amina , Jaoko Walter , Mandaliya Kishorchandra , Shafi Juma , Scott McClelland R. 
Published: August 2018

Background
Some studies suggest that higher body mass index is associated with increased susceptibility to bacterial vaginosis (BV), but results are conflicting.

Methods
Female sex workers aged 16 to 45 years and participating in an open, prospective cohort study in Mombasa, Kenya between 2000 and 2014 were included in this analysis. Up to 2 years of follow-up were included per woman. Body mass index (BMI) was categorized as underweight (≤18.5), normal (18.5–24.9), overweight (25–29.9), and obese (≥30). Bacterial vaginosis was assessed using Nugent scores. Generalized estimating equations were used to estimate relative risks of the association between BMI and BV.

Results
At baseline, 32.1% (n = 625) of 1946 women had BV. Half of women were overweight (31.1%, n = 606) or obese (20.1%, n = 391). Participants contributed 14,319 follow-up visits. Adjusting for age, compared to women with normal BMI, overweight (adjusted relative risk, 0.91; 95% confidence interval, 0.81–1.02) and obese (adjusted relative risk, 0.82; 95% confidence interval, 0.71–0.94) women were at lower risk for BV (joint P = 0.03).

Conclusions
Obese women had a nearly 20% lower risk of BV compared with women with normal BMI. Potential mechanisms for this effect, including possible effects of diet, obesity-associated changes in the gut microbiome, and systemic estrogen levels, should be explored.
Toll Like Receptor 4 Mediated Lymphocyte Imbalance Induces Nec-Induced Lung Injury
Authors: Jia Hongpeng , Sodhi Chhinder P. , Yamaguchi Yukihiro , Lu Peng , Ladd Mitchell R. , Werts Adam , Fulton William B. , Wang Sanxia , Prindle Thomas , Hackam David J. 
Published: August 2018

ABSTRACT
Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in premature infants, and is associated with the development of severe lung inflammation. The pathogenesis of NEC-induced lung injury remains unknown, yet infiltrating immune cells may play a role. In support of this possibility, we now show that NEC in mice and humans was associated with the development of profound lung injury that was characterized by an influx of Th17 cells and a reduction in T regulatory lymphocytes (Tregs). Importantly, the adoptive transfer of CD4+ T cells isolated from lungs of mice with NEC into the lungs of immune incompetent mice (Rag1−/− mice) induced profound inflammation in the lung, while the depletion of Tregs exacerbated NEC induced lung injury, demonstrating that imbalance of Th17/Treg in the lung is required for the induction of injury. In seeking to define the mechanisms involved, the selective deletion of toll-like receptor 4 (TLR4) from the Sftpc1 pulmonary epithelial cells reversed lung injury, while TLR4 activation induced the Th17 recruiting chemokine (C-C motif) ligand 25 (CCL25) in the lungs of mice with NEC. Strikingly, the aerosolized inhibition of both CCL25 and TLR4 and the administration of all trans retinoic acid restored Tregs attenuated NEC-induced lung injury. In summary, we show that TLR4 activation in Surfactant protein C-1 (Sftpc1) cells disrupts the Treg/Th17 balance in the lung via CCL25 leading to lung injury after NEC and reveal that inhibition of TLR4 and stabilization of Th17/Treg balance in the neonatal lung may prevent this devastating complication of NEC.
Efficacy and Safety of Complete Mesocolic Excision in Patients With Colon Cancer
Authors: Gao Zhidong , Wang Chao , Cui Yancheng , Shen Zhanlong , Jiang Kewei , Shen Danhua , Wang Yi , Zhan Siyan , Guo Peng , Yang Xiaodong , Liu Fangfang , Shen Kai , Liang Bin , Yin Mujun , Xie Qiwei , Wang Youli , Wang Shan , Ye Yingjiang 
Published: August 2018

Objective:
The aim of the study was to evaluate the oncological outcomes of complete mesocolic excision (CME) in colon cancer patients.

Summary Background Data:
CME is considered a standard procedure for colon cancer patients. However, previous evidence regarding the effect of CME on prognosis has fundamental limitations that prevent it from being fully accepted.

Methods:
Patients who underwent radical resection for colon cancer were enrolled between November 2012 and March 2016. According to the principles of CME, patients were stratified into 2 groups based on intraoperative surgical fields and specimen photographs. The primary outcome was local recurrence-free survival (LRFS). The clinicopathological data and follow-up information were collected and recorded. The final follow-up date was April 2016. The trial was registered in ClinicalTrials.gov (identifier: NCT01724775).

Results:
There were 220 patients in the CME group and 110 patients in the noncomplete mesocolic excision (NCME) group. Baseline characteristics were well balanced. Compared with NCME, CME was associated with a greater number of total lymph nodes (24 vs 20, P = 0.002). Postoperative complications did not differ between the 2 groups. CME had a positive effect on LRFS compared with NCME (100.0% vs 90.2%, log-rank P < 0.001). Mesocolic dissection (100.0% vs 87.9%, log-rank P < 0.001) and nontumor deposits (97.2% vs 91.6%, log-rank P < 0.022) were also associated with improved LRFS.

Conclusions:
Our findings demonstrate that, compared with NCME, CME improves 3-year LRFS without increasing surgical risks.
Local adaptation and the evolution of inversions on sex chromosomes and autosomes
Authors: Connallon Tim , Olito Colin , Dutoit Ludovic , Papoli Homa , Ruzicka Filip , Yong Lengxob 
Published: August 2018

Spatially varying selection with gene flow can favour the evolution of inversions that bind locally adapted alleles together, facilitate local adaptation and ultimately drive genomic divergence between species. Several studies have shown that the rates of spread and establishment of new inversions capturing locally adaptive alleles depend on a suite of evolutionary factors, including the strength of selection for local adaptation, rates of gene flow and recombination, and the deleterious mutation load carried by inversions. Because the balance of these factors is expected to differ between X (or Z) chromosomes and autosomes, opportunities for inversion evolution are likely to systematically differ between these genomic regions, though such scenarios have not been formally modelled. Here, we consider the evolutionary dynamics of X-linked and autosomal inversions in populations evolving at a balance between migration and local selection. We identify three factors that lead to asymmetric rates of X-linked and autosome inversion establishment: (1) sex-biased migration, (2) dominance of locally adapted alleles and (3) chromosome-specific deleterious mutation loads. This theory predicts an elevated rate of fixation, and depressed opportunities for polymorphism, for X-linked inversions. Our survey of data on the genomic distribution of polymorphic and fixed inversions supports both theoretical predictions.This article is part of the theme issue ‘Linking local adaptation with the evolution of sex differences'.