bluuebunny/crossref_metadata_2025 huggingface dataset:
Meta-Analysis of the Prevalence of HBV Infection Among Alcohol Users Worldwide
Authors: Magri Mariana Cavalheiro , Nunes Arielle Karen da Silva , Dantas Bianca Peixoto , Manchiero Caroline , Prata Thamiris Vaz Gago , Alves Grayce Mendes , Tengan Fátima Mitiko
Published: November 2019

Aims

To investigate the prevalence of hepatitis B virus (HBV) infection among alcohol users.

Methods

A systematic search of articles in the PubMed, Web of Science and EMBASE databases was conducted. The methodological quality of each study was scored, and a meta-analysis was performed taking into account the heterogeneity expected among the studies. Publication bias was assessed using Begg’s and Egger’s tests.

Results

The search identified 998 reports that yielded 18 eligible studies. The studies comprised 12,204 alcohol users, who were mostly men. The mean score on the quality evaluation was 6.9, and 11 studies were classified as having a low risk of bias. The estimated worldwide prevalence of HBV was 20.0% (95%CI: 19.0–20.0). The heterogeneity among the studies was substantial (I2 = 96.7%). In subgroup analyses, it was observed that among alcohol user dependents with no description of liver damage, alcohol users with different stages of chronic liver disease and alcohol users who all had cirrhosis, the estimated prevalence was 10.0% (95%CI: 8.0–14.0), 14.0% (95%CI: 13.0–15.0) and 32.0% (95%CI: 29.0–35.0), respectively. The meta-regression analysis showed that the study quality score had an influence on the investigated prevalence (P = 0.005). Nevertheless, the funnel plot showed asymmetry, and there was evidence of publication bias according to Egger’s test (P = 0.003) but not Begg’s test (P = 0.869).

Conclusions

The prevalence of HBV among alcohol users was high. HBV infection and alcohol consumption are factors affecting the development and worsening of liver disease; therefore, we suggest that adult alcohol users should be carefully monitored.
Amyloid and tau imaging biomarkers explain cognitive decline from late middle-age
Authors: Betthauser Tobey J , Koscik Rebecca L , Jonaitis Erin M , Allison Samantha L , Cody Karly A , Erickson Claire M , Rowley Howard A , Stone Charles K , Mueller Kimberly D , Clark Lindsay R , Carlsson Cynthia M , Chin Nathaniel A , Asthana Sanjay , Christian Bradley T , Johnson Sterling C
Published: November 2019

This study investigated differences in retrospective cognitive trajectories between amyloid and tau PET biomarker stratified groups in initially cognitively unimpaired participants sampled from the Wisconsin Registry for Alzheimer’s Prevention. One hundred and sixty-seven initially unimpaired individuals (baseline age 59 ± 6 years; 115 females) were stratified by elevated amyloid-β and tau status based on 11C-Pittsburgh compound B (PiB) and 18F-MK-6240 PET imaging. Mixed effects models were used to determine if longitudinal cognitive trajectories based on a composite of cognitive tests including memory and executive function differed between biomarker groups. Secondary analyses investigated group differences for a variety of cross-sectional health and cognitive tests, and associations between 18F-MK-6240, 11C-PiB, and age. A significant group × age interaction was observed with post hoc comparisons indicating that the group with both elevated amyloid and tau pathophysiology were declining approximately three times faster in retrospective cognition compared to those with just one or no elevated biomarkers. This result was robust against various thresholds and medial temporal lobe regions defining elevated tau. Participants were relatively healthy and mostly did not differ between biomarker groups in health factors at the beginning or end of study, or most cognitive measures at study entry. Analyses investigating association between age, MK-6240 and PiB indicated weak associations between age and 18F-MK-6240 in tangle-associated regions, which were negligible after adjusting for 11C-PiB. Strong associations, particularly in entorhinal cortex, hippocampus and amygdala, were observed between 18F-MK-6240 and global 11C-PiB in regions associated with Braak neurofibrillary tangle stages I–VI. These results suggest that the combination of pathological amyloid and tau is detrimental to cognitive decline in preclinical Alzheimer’s disease during late middle-age. Within the Alzheimer’s disease continuum, middle-age health factors likely do not greatly influence preclinical cognitive decline. Future studies in a larger preclinical sample are needed to determine if and to what extent individual contributions of amyloid and tau affect cognitive decline. 18F-MK-6240 shows promise as a sensitive biomarker for detecting neurofibrillary tangles in preclinical Alzheimer’s disease.
Recruitment of miR-8080 by luteolin inhibits androgen receptor splice variant 7 expression in castration-resistant prostate cancer
Authors: Naiki-Ito Aya , Naiki Taku , Kato Hiroyuki , Iida Keitaro , Etani Toshiki , Nagayasu Yuko , Suzuki Shugo , Yamashita Yoriko , Inaguma Shingo , Onishi Masaya , Tanaka Yasuhito , Yasui Takahiro , Takahashi Satoru
Published: November 2019

A need exists for seeking effective treatments for castration-resistant prostate cancer (CRPC) in response to its emergence following androgen deprivation therapy as a major clinical problem. In the present study, we investigated the chemopreventive and chemotherapeutic potential of luteolin, a flavonoid with antioxidative properties, on prostate cancer, including CRPC. Luteolin inhibited the progression of rat prostate carcinogenesis by induction of apoptosis in a transgenic rat for adenocarcinoma of prostate (TRAP) model. Luteolin decreased cell proliferation in a dose-dependent manner and induced apoptosis with the activation of caspases 3 and 7 in both rat (PCai1, established from a TRAP prostate tumor) and human (22Rv1) CRPC cells. Dietary luteolin also suppressed tumor growth via an increase in apoptosis and inhibition of angiogenesis in PCai1 and 22Rv1 xenografts implanted in castrated nude mice. We also focused on androgen receptor splice variant 7 (AR-V7), which contributes to cell proliferation and therapeutic resistance in CRPC. Luteolin dramatically suppressed AR-V7 protein expression in 22Rv1 cells in vitro and ex vivo. Microarray analysis identified MiR-8080, which contains a possible target sequence for AR-V7 3′-UTR, as a gene upregulated by luteolin. MiR-8080 transfection decreased the AR-V7 expression level and the induction of apoptosis in 22Rv1 cells. Furthermore, miR-8080 knockdown canceled luteolin decreasing AR-V7 and the cell growth of 22Rv1. MiR-8080 induced by luteolin intake enhanced the therapeutic effect of enzalutamide on 22Rv1 xenografts under castration conditions. These results indicate luteolin inhibits CRPC by AR-V7 suppression through miR-8080, highlighting luteolin and miR-8080 as promising therapeutic agents for this disease.
Frontal Beta Transcranial Alternating Current Stimulation Improves Reversal Learning
Authors: Wischnewski Miles , Joergensen Mie L , Compen Boukje , Schutter Dennis J L G
Published: November 2019

Electroencephalogram (EEG) studies suggest an association between beta (13–30 Hz) power and reversal learning performance. In search for direct evidence concerning the involvement of beta oscillations in reversal learning, transcranial alternating current stimulation (tACS) was applied in a double-blind, sham-controlled and between-subjects design. Exogenous oscillatory currents were administered bilaterally to the frontal cortex at 20 Hz with an intensity of 1 mA peak-to-peak and the effects on reward-punishment based reversal learning were evaluated in hundred-and-eight healthy volunteers. Pre- and post-tACS resting state EEG recordings were analyzed. Results showed that beta-tACS improved rule implementation during reversal learning and decreases left and right resting-state frontal theta/beta EEG ratios following tACS. Our findings provide the first behavioral and electrophysiological evidence for exogenous 20 Hz oscillatory electric field potentials administered over to the frontal cortex to improve reversal learning.
Parametric Characterization of a Taste Phenotype in Rats Selectively Bred for High Versus Low Saccharin Intake
Authors: Dess Nancy K , Chapman Clinton D
Published: November 2019

Taste signals food quality and reflects energy status and associated processes. Occidental high- and low-saccharin consuming rats (HiS, LoS) have been selectively bred for nearly 60 generations on intake of 0.1% saccharin in a 23-h two-bottle test, as a tool for studying individual differences in taste and its correlates in the domains of feeding, defensive, and social behavior. The saccharin phenotype itself has not been well characterized until now. The present series of parametric studies examined suprathreshold saccharin concentration-intake functions (Experiment 1), saccharin preference threshold (Experiments 2A and 2B), and intra- and inter-sweetener carryforward effects (Experiments 2B, 3A–3D). Results indicate high stability in line differences in behavior toward saccharin and also line-specific mutability of intake of saccharin and certain other sweeteners. Methodological and conceptual implications are discussed.
Invasive Mold Infections After Chimeric Antigen Receptor–Modified T-Cell Therapy: A Case Series, Review of the Literature, and Implications for Prophylaxis
Authors: Haidar Ghady , Dorritie Kathleen , Farah Rafic , Bogdanovich Tatiana , Nguyen M Hong , Samanta Palash
Published: November 2019

Data on invasive mold infections (IMIs) after chimeric antigen receptor-modified T-cell (CAR-T-cell) therapy are limited. We describe 2 patients with post–CAR-T-cell IMI (Fusarium, Mucorales) and review the published literature. We propose strategies to prevent IMIs in patients, based on the IMI rate and presence of neutropenia or steroid use.
O76 MICROANATOMY BASED STANDARDIZATION OF LEFT UPPER MEDIASTINAL LYMPH NODE DISSECTION IN THORACOSCOPIC ESOPHAGECTOMY IN THE PRONE POSITION
Authors: Shirakawa Yasuhiro , Maeda Naoaki , Tanabe Shunsuke , Noma Kazuhiro , Fujiwara Toshiyoshi
Published: November 2019

Aim

The purpose of this study is to establish and evaluate our new standardized procedure in left UMLND

Background & Methods

Although thoracoscopic esophagectomy in the prone position (TEPP) has become a standard surgery for esophageal cancer, upper mediastinal lymph node dissection (UMLND) in left side has been still an issue in TEPP. We have recently developed the standardization of left UMLND in TEPP based on the microanatomy of membranes and layers. Patients were divided into 1 of 2 groups: a pre-standardization group (n = 100) and a post-standardization group (n = 100). Eventually, 83 paired cases were matched using propensity score matching. We perform left UMLND while paying attention to the visceral sheath, vascular sheath and the fusion layer between them using magnified view.

Results

The thoracoscopic operative time was significantly shorter (P < 0.001) in the post-standardization group [n = 83; 209.0 (176.0 - 235.0) min] than in the pre-standardization group [n = 83; 235.5 (202.8 - 264.5) min]. No significant differences were found in the number of mediastinal lymph nodes dissected or intraoperative blood loss between the 2 groups. There was a tendency for the total postoperative morbidity to decrease in the post-standardization group. Furthermore, recurrent laryngeal nerve (RLN) palsy rate has significantly decreased in the post-standardization group (18.1% to 8.7%, P = 0.015).

Conclusion

The microanatomy-based standardization contributes the safe and efficient left UMLND.
Cost-effectiveness of a stepwise intervention to promote adherence to cervical cancer screening
Authors: Firmino-Machado João , Soeteman Djøra I , Lunet Nuno
Published: November 2019

Background

Cervical cancer screening is effective in reducing mortality, but adherence is generally low. We aimed to investigate the cost-effectiveness of a stepwise intervention to promote adherence to cervical cancer screening in Portugal.

Methods

We developed a decision tree model to compare the cost-effectiveness of four competing interventions to increase adherence to cervical cancer screening: (i) a written letter (standard-of-care); (ii) automated short message service text messages (SMS)/phone calls/reminders; (iii) automated SMS/phone calls/reminders + manual phone calls; (iv) automated SMS/phone calls/reminders + manual phone calls + face-to-face interviews. The main outcome measure was cost per quality-adjusted life year (QALY) measured over a 5-year time horizon. Costs were calculated from the societal and provider perspectives.

Results

From the societal perspective, the optimal strategy was automated SMS/phone calls/reminders, below a threshold of €8171 per QALY; above this and below €180 878 per QALY, the most cost-effective strategy was automated SMS/phone calls/reminders + manual phone calls and above this value automated SMS/phone calls/reminders + manual phone calls + face-to-face interviews. From the provider perspective, the ranking of the three strategies in terms of cost-effectiveness was the same, for thresholds of €2756 and €175 463 per QALY, respectively.

Conclusions

Assuming a willingness-to-pay threshold of one time the national gross domestic product (€22 398/QALY), automated SMS/phone calls/reminders + manual phone calls is a cost-effective strategy to promote adherence to cervical cancer screening, both from the societal and provider perspectives.
Inactivation of human norovirus and its surrogate by the disinfectant consisting of calcium hydrogen carbonate mesoscopic crystals
Authors: Shimakura Hidekatsu , Gen-Nagata Fumihiro , Haritani Makoto , Furusaki Koichi , Kato Yusei , Yamashita-Kawanishi Nanako , LE Dung T , Tsuzuki Masano , Tohya Yukinobu , Kyuwa Shigeru , Saito Hiroyuki , Horimoto Taisuke , Onodera Takashi , Haga Takeshi
Published: November 2019

Human norovirus is one of the major causes of foodborne gastroenteritis, and it can be easily transmitted from infected person, virus-contaminated foods and environmental surfaces. Effective disinfection method is needed to stop the transmission of human norovirus. CAC-717 is a new disinfectant consisting of calcium hydrogen carbonate mesoscopic crystals. We aimed to evaluate the efficacy of CAC-717 against human norovirus. This study used human norovirus derived from fecal specimens and cultured murine norovirus, which is one of the surrogate viruses for human norovirus. The disinfection effect against murine norovirus was estimated by infectivity assay and transmission electron microscopy. The inactivation effect against human norovirus was assessed by reverse transcription polymerase chain reaction. Disinfection effect of CAC-717 against the infectivity of murine norovirus was shown within 100 s after the CAC-717 treatment, presenting the destruction of viral capsids. The treatment of CAC-717 significantly reduced human norovirus genomic RNA (3.25-log reduction) by the presence of the mesoscopic structure of calcium hydrogen carbonate. CAC-717 stably inactivated human norovirus in stool suspensions. The inactivation effect of CAC-717 against human norovirus was less susceptible to organic substances than sodium hypochlorite. CAC-717 would be a useful alternative for disinfecting human norovirus in contaminated environmental surfaces.
Population structure and toxin gene profiles of Bacillus cereus sensu lato isolated from flour products
Authors: Kindle Patrick , Etter Danai , Stephan Roger , Johler Sophia
Published: November 2019

Data on the occurrence, population structure and toxinogenic potential of Bacillus cereus sensu lato isolated from flour is essential to enable improved risk assessment. We aimed to provide data on the occurrence of B. cereus sensu lato in flour products at retail level. In addition, we screened the isolates for Bacillus thuringiensis and Bacillus cytotoxicus and determined population structure and toxin gene profiles. We screened 89 flour products for presence of B. cereus sensu lato, resulting in 75 positive samples (84%). We were able to show that the population structure of members of the B. cereus group isolated from flour is highly diverse. Isolates were assigned to panC types II (4%), III (21%), IV (39%) and V (36%). Production of parasporal crystals characteristic for Bacillus thuringiensis was detected in seven isolates assigned to panC type III, IV and V. No B. cytotoxicus were detected. Two of the isolates harbored ces encoding cereulide, which causes the emetic syndrome. Various enterotoxin genes were found, with all isolates harboring nhe, 75% of isolates harboring hbl and 51% of the isolates harboring cytK-2. Our findings suggest that toxinogenic B. cereus sensu lato are common in flour products at retail level.
Recurrent pregnancy loss: diagnostic workup after two or three pregnancy losses? A systematic review of the literature and meta-analysis
Authors: van Dijk Myrthe M , Kolte Astrid M , Limpens Jacqueline , Kirk Emma , Quenby Siobhan , van Wely Madelon , Goddijn Mariëtte
Published: November 2019

BACKGROUND

Recurrent pregnancy loss (RPL) occurs in 1–3% of all couples trying to conceive. No consensus exists regarding when to perform testing for risk factors in couples with RPL. Some guidelines recommend testing if a patient has had two pregnancy losses whereas others advise to test after three losses.

OBJECTIVE AND RATIONALE

The aim of this systematic review was to evaluate the current evidence on the prevalence of abnormal test results for RPL amongst patients with two versus three or more pregnancy losses. We also aimed to contribute to the debate regarding whether the investigations for RPL should take place after two or three or more pregnancy losses.

SEARCH METHODS

Relevant studies were identified by a systematic search in OVID Medline and EMBASE from inception to March 2019. A search for RPL was combined with a broad search for terms indicative of number of pregnancy losses, screening/testing for pregnancy loss or the prevalence of known risk factors. Meta-analyses were performed in case of adequate clinical and statistical homogeneity. The quality of the studies was assessed using the Newcastle-Ottawa scale.

OUTCOMES

From a total of 1985 identified publications, 21 were included in this systematic review and 19 were suitable for meta-analyses. For uterine abnormalities (seven studies, odds ratio (OR) 1.00, 95% CI 0.79–1.27, I2 = 0%) and for antiphospholipid syndrome (three studies, OR 1.04, 95% CI 0.86–1.25, I2 = 0%) we found low quality evidence for a lack of a difference in prevalence of abnormal test results between couples with two versus three or more pregnancy losses. We found insufficient evidence of a difference in prevalence of abnormal test results between couples with two versus three or more pregnancy losses for chromosomal abnormalities (10 studies, OR 0.78, 95% CI 0.55–1.10), inherited thrombophilia (five studies) and thyroid disorders (two studies, OR 0.52, 95% CI: 0.06–4.56).

WIDER IMPLICATIONS

A difference in prevalence in uterine abnormalities and antiphospholipid syndrome is unlikely in women with two versus three pregnancy losses. We cannot exclude a difference in prevalence of chromosomal abnormalities, inherited thrombophilia and thyroid disorders following testing after two versus three pregnancy losses. The results of this systematic review may support investigations after two pregnancy losses in couples with RPL, but it should be stressed that additional studies of the prognostic value of test results used in the RPL population are urgently needed. An evidenced-based treatment is not currently available in the majority of cases when abnormal test results are present.
Relationship Between Census Tract–Level Poverty and Domestically Acquired Salmonella Incidence: Analysis of Foodborne Diseases Active Surveillance Network Data, 2010–2016
Authors: Hadler James L , Clogher Paula , Libby Tanya , Wilson Elisha , Oosmanally Nadine , Ryan Patricia , Magnuson Luke , Lathrop Sarah , Mcguire Suzanne , Cieslak Paul , Fankhauser Melissa , Ray Logan , Geissler Aimee , Hurd Sharon
Published: November 2019

Background

The relationships between socioeconomic status and domestically acquired salmonellosis and leading Salmonella serotypes are poorly understood.

Methods

We analyzed surveillance data from laboratory-confirmed cases of salmonellosis from 2010–2016 for all 10 Foodborne Disease Active Surveillance Network (FoodNet) sites, having a catchment population of 47.9 million. Case residential data were geocoded, linked to census tract poverty level, and then categorized into 4 groups according to census tract poverty level. After excluding those reporting international travel before illness onset, age-specific and age-adjusted salmonellosis incidence rates were calculated for each census tract poverty level, overall and for each of the 10 leading serotypes.

Results

Of 52 821geocodable Salmonella infections (>96%), 48 111 (91.1%) were domestically acquired. Higher age-adjusted incidence occurred with higher census tract poverty level (P < .001; relative risk for highest [≥20%] vs lowest [<5%] census tract poverty level, 1.37). Children <5 years old had the highest relative risk (2.07). Although this relationship was consistent by race/ethnicity and by serotype, it was not present in 5 FoodNet sites or among those aged 18–49 years.

Conclusion

Children and older adults living in higher-poverty census tracts have had a higher incidence of domestically acquired salmonellosis. There is a need to understand socioeconomic status differences for risk factors for domestically acquired salmonellosis by age group and FoodNet site to help focus prevention efforts.
Evaluation of phthalazinone phosphodiesterase inhibitors with improved activity and selectivity against Trypanosoma cruzi
Authors: De Araújo Julianna Siciliano , da Silva Patrícia Bernardino , Batista Marcos Meuser , Peres Raiza Brandão , Cardoso-Santos Camila , Kalejaiye Titilola D , Munday Jane C , De Heuvel Erik , Sterk Geert Jan , Augustyns Koen , Salado Irene G , Matheeussen An , De Esch Iwan , De Koning Harry P , Leurs Rob , Maes Louis , Soeiro Maria de Nazaré Correia
Published: November 2019

Background

Chagas’ disease, caused by the protozoan parasite Trypanosoma cruzi, needs urgent alternative therapeutic options as the treatments currently available display severe limitations, mainly related to efficacy and toxicity.

Objectives

As phosphodiesterases (PDEs) have been claimed as novel targets against T. cruzi, our aim was to evaluate the biological aspects of 12 new phthalazinone PDE inhibitors against different T. cruzi strains and parasite forms relevant for human infection.

Methods

In vitro trypanocidal activity of the inhibitors was assessed alone and in combination with benznidazole. Their effects on parasite ultrastructural and cAMP levels were determined. PDE mRNA levels from the different T. cruzi forms were measured by quantitative reverse transcription PCR.

Results

Five TcrPDEs were found to be expressed in all parasite stages. Four compounds displayed strong effects against intracellular amastigotes. Against bloodstream trypomastigotes (BTs), three were at least as potent as benznidazole. In vitro combination therapy with one of the most active inhibitors on both parasite forms (NPD-040) plus benznidazole demonstrated a quite synergistic profile (xΣ FICI = 0.58) against intracellular amastigotes but no interaction (xΣ FICI = 1.27) when BTs were assayed. BTs treated with NPD-040 presented disrupted Golgi apparatus, a swollen flagellar pocket and signs of autophagy. cAMP measurements of untreated parasites showed that amastigotes have higher ability to efflux this second messenger than BTs. NPD-001 and NPD-040 increase the intracellular cAMP content in both BTs and amastigotes, which is also released into the extracellular milieu.

Conclusions

The findings demonstrate the potential of PDE inhibitors as anti-T. cruzi drug candidates.
A preconditioned technique for SH- and Love-wave full-waveform inversion in time domain and crosstalk analysis
Authors: Yan Yingwei , Wang Zhejiang , Li Jing , Huai Nan , Zhang Yujia , Han Fei
Published: November 2019

For the problem of low horizontal resolution in the method of surface wave dispersion analysis, we apply the SH- and Love-wave full-waveforms to achieve 2D and 3D imaging of the subsurface. The gradient obtained by classical full-waveform inversion (FWI) is not scaled with increasing depth. The limited source frequency band, the non-uniform coverage between shot and geophone positions and double scattering are the main reasons for the phenomenon. The Hessian operator of the misfit function can clearly predict the inherent defocusing phenomenon and the artefacts generated by the double scattering in the gradient vector, and the inverse Hessian operator is used as a deconvolution operator to realise gradient preconditioning. We present an expression of the quasi-Hessian operator in SH- and Love-wave FWI based on inverse scattering theory in prestack depth migration, and apply a new preconditioned technique to the fault and large contrast (LC) model reconstruction test. The inverted results show that the new preconditioned technique can greatly improve the imaging accuracy compared with the gradient-based methods of FWI. From single-parameter tests, we can conclude that the quasi-Hessian operator plays roles in illumination compensation and parameter complement estimation in FWI. From the final reconstructed results of a dual-parameter model, we find that the inverted result of the density is slightly closer to the true model than S-wave velocity under the condition of the same comparative distance between the initial and true model, but parametric crosstalk of density is more serious.
Cutaneous leishmaniasis with secondary mucosal disease in a traveller due to Leishmania (Viannia) braziliensis
Authors: Crone Cornelia Geisler , Helleberg Marie
Published: November 2019

We describe the case of a Russian child with persistent mild eosinophilia in whom intestinal parasitism by Dibothriocephalus latus is finally diagnosed. This cestode is prevalent in circumpolar regions and, therefore, an uncommon finding in International Health units, where care for patients from tropical and subtropical areas is usually provided.
Efficient induction of haploid plants in wheat by editing of TaMTL using an optimized Agrobacterium-mediated CRISPR system
Authors: Liu Huiyun , Wang Ke , Jia Zimiao , Gong Qiang , Lin Zhishan , Du Lipu , Pei Xinwu , Ye Xingguo
Published: November 2019

The use of CRISPR/LbCpf1 and CRISPR/xCas9 systems in wheat have not yet been reported. In this study, we compared the efficiencies of three CRISPR editing systems (SpCas9, LbCpf1, and xCas9), and three different promoters (OsU6a, TaU3, and TaU6) that drive single-guide (sg)RNA, which were introduced into wheat via Agrobacterium-mediated transformation. The results indicated that TaU3 was a better choice than OsU6a or TaU6. The editing efficiency was higher using two sgRNAs than one sgRNA, and mutants with a large fragment deletion between the two sgRNAs were produced. The LbCpf1 and xCas9 systems could both be used successfully. Two endogenous genes, TaWaxy and TaMTL, were edited with high efficiency by the optimized SpCas9 system, with the highest efficiency (80.5%) being achieved when using TaU3 and two sgRNAs to target TaWaxy. Rates of seed set in the TaMTL-edited T0 transgenic plants were much lower than that of the wild-type. A haploid induction rate of 18.9% was found in the TaMTL-edited T1 plants using the CRISPR/SpCas9 system. Mutants with reverse insertion of the deleted sequences of TaMTL and TaWaxy between the two sgRNAs were identified in the edited T0 plants. In addition, wheat grains lacking embryos or endosperms were observed in the TaMTL-edited T1 generation.
Deciphering the nature of the pulsar wind nebula CTB 87 with XMM–Newton
Authors: Guest B , Safi-Harb S , MacMaster A , Kothes R , Olmi B , Amato E , Bucciantini N , Arzoumanian Z
Published: November 2019

CTB 87 (G74.9+1.2) is an evolved supernova remnant (SNR) which hosts a peculiar pulsar wind nebula (PWN). The X-ray peak is offset from that observed in radio and lies towards the edge of the radio nebula. The putative pulsar, CXOU J201609.2+371110, was first resolved with Chandra and is surrounded by a compact and a more extended X-ray nebula. Here, we use a deep XMM–Newton observation to examine the morphology and evolutionary stage of the PWN and to search for thermal emission expected from a supernova shell or reverse shock interaction with supernova ejecta. We do not find evidence of thermal X-ray emission from the SNR and place an upper limit on the electron density of 0.05 cm−3 for a plasma temperature kT ∼ 0.8 keV. The morphology and spectral properties are consistent with a ∼20-kyr-old relic PWN expanding into a stellar wind-blown bubble. We also present the first X-ray spectral index map from the PWN and show that we can reproduce its morphology by means of 2D axisymmetric relativistic hydrodynamical simulations.
PRMT1-mediated methylation of the microprocessor-associated proteins regulates microRNA biogenesis
Authors: Spadotto Valeria , Giambruno Roberto , Massignani Enrico , Mihailovich Marija , Maniaci Marianna , Patuzzo Francesca , Ghini Francesco , Nicassio Francesco , Bonaldi Tiziana
Published: November 2019

MicroRNA (miRNA) biogenesis is a tightly controlled multi-step process operated in the nucleus by the activity of the Microprocessor and its associated proteins. Through high resolution mass spectrometry (MS)- proteomics we discovered that this complex is extensively methylated, with 84 methylated sites associated to 19 out of its 24 subunits. The majority of the modifications occurs on arginine (R) residues (61), leading to 81 methylation events, while 30 lysine (K)-methylation events occurs on 23 sites of the complex. Interestingly, both depletion and pharmacological inhibition of the Type-I Protein Arginine Methyltransferases (PRMTs) lead to a widespread change in the methylation state of the complex and induce global decrease of miRNA expression, as a consequence of the impairment of the pri-to-pre-miRNA processing step. In particular, we show that the reduced methylation of the Microprocessor subunit ILF3 is linked to its diminished binding to the pri-miRNAs miR-15a/16, miR-17–92, miR-301a and miR-331. Our study uncovers a previously uncharacterized role of R-methylation in the regulation of miRNA biogenesis in mammalian cells.
ATIM-48 (LTBK-05). MULTIDIMENSIONAL PERSONALIZED RESPONSE ASSESSMENT TO MICROGLIA MODULATORS IN GLIOBLASTOMA BIOREACTORS
Authors: Shekarian Tala , Wachnowicz Anna Theresa , Flammer Julia , Paganetti Chiara , Martins Tomas , Muraro Manuele , Schürch Christian Martijn , Hutter Gregor
Published: November 2019

BACKGROUND

Recently, strategies harnessing the non-neoplastic immune tumor microenvironment (iTME), consisting of macrophages and microglia (TAMs), as well as adaptive immune cells have been employed to treat glioblastoma (GBM). To evaluate the effect of local TAM-modulating therapies in combination with T-cell checkpoint inhibitors, we generated 3D GBM perfusion bioreactor cultures from patient-derived samples. We report patient- and tumor region specific responses to microglia modulators and checkpoint inhibitors using multidimensional fluorescent microscopy techniques, and multiplexed cytokine measurements, Subsequently, we aime at identifying responders versus non-responders as well as predictive markers of treatment response.

METHODS

Fresh, neuronavigated GBM biopsies from tumor center and periphery were placed into perfusion bioreactors and cultured for 7 days. Explants were treated with combinations of TAM and T-cell modulating drugs including anti-PD1 and anti-CD47 antibodies and their combination. Tissue was harvested for histology, and supernatants were processed for multiplexed cytokine analysis. Multidimensional CODEX technology analysis using a customized TAM centric 54 marker panel was implemented, and a map of individualized response criteria to specific immunotherapies developed.

RESULTS

Multiplex cytokine analysis showed a dominance of proinflammatory cytokines (CCL2, CCL3, CCL4 and PAI-1) in the periphery of the tumor at baseline. We further observed that the tumor periphery was more responsive to treatments confirming the efficacy of the treatment after tumor resection. Using CODEX, we identified specific cell types responding to the treatment and undergoing phenotypic changes. Moreover, dynamic shifting of T-cell checkpoint expression levels under treatment pointed to potential resistance mechanisms in a subset of tumors. Further, we identified region-specific cytokine release as a response to the treatment in a series of 8 patient-specific explant cultures. In summary, we present an in-depth profiling of the GBM-region specific iTME at baseline and document its dynamic response under innate/adaptive immune modulators using CODEX.

CONCLUSION

The proposed approach serves as a patient-tailored ex vivo “Clinical Trial” by stratifying the individual patient’s iTME response.
Using Latent Class Analysis to Examine Susceptibility to Various Tobacco Products Among Adolescents
Authors: Bold Krysten W , Buta Eugenia , Simon Patricia , Kong Grace , Morean Meghan , Camenga Deepa , Krishnan-Sarin Suchitra
Published: November 2019

Introduction

Most tobacco use is initiated during adolescence and susceptibility is an important predictor of initiation. Research is needed to understand susceptibility across tobacco products among youth to inform prevention efforts.

Aims and Methods

We surveyed 2945 students from four Southeastern Connecticut high schools in 2017. We assessed susceptibility to future use of seven different tobacco products (ie, cigarettes, e-cigarettes, hookah, cigars, cigarillos, blunts, and smokeless tobacco) among youth who had never used a tobacco product. Susceptibility was coded as any response other than “definitely not” to three items assessing (1) curiosity, (2) willingness to experiment with the product in the future, and (3) willingness to try if offered by a friend. Latent class analysis was used to identify patterns of susceptibility across multiple tobacco products and sociodemographic predictors of these classes.

Results

Among n = 1246 youth who had never tried a tobacco product, 51.2% (n = 638) were susceptible to at least one product and 29.1% (n = 363) were susceptible to two or more products (average among susceptible youth: M = 2.4 products, SD = 1.7, range 1–7). Latent class analysis identified three classes: youth who were: (1) susceptible to all products (5.6%), (2) susceptible to e-cigarettes, hookah, and blunts (23.6%), and (3) mostly non-susceptible to all products (70.8%). In a multivariable model, demographic variables and peer tobacco use predicted class membership.

Conclusions

We observed high rates of susceptibility to non-traditional tobacco products among youth, and many youth were susceptible to more than one product. Targeting susceptibility across multiple tobacco products may be important for reducing youth tobacco use.

Implications

Patterns of polytobacco use susceptibility were identified among youth who had never previously used tobacco products. Many youth were susceptible to more than one product and we observed three distinct classes of susceptibility among youth: those who were mostly non-susceptible, those who were susceptible to alternative or non-traditional tobacco products (e-cigarettes, hookah, and blunts), and those who were susceptible to all tobacco products. These findings suggest the importance of addressing susceptibility across multiple tobacco products.
ESKAPE Pathogens in Bloodstream Infections Are Associated With Higher Cost and Mortality but Can Be Predicted Using Diagnoses Upon Admission
Authors: Marturano Joseph E , Lowery Thomas J
Published: November 2019

Background

ESKAPE bacteria are thought to be especially resistant to antibiotics, and their resistance and prevalence in bloodstream infections are rising. Large studies are needed to better characterize the clinical impact of these bacteria and to develop algorithms that alert clinicians when patients are at high risk of an ESKAPE infection.

Methods

From a US data set of >1.1 M patient encounters, we evaluated if ESKAPE pathogens produced worse outcomes than non-ESKAPE pathogens and if an ESKAPE infection could be predicted using simple word group algorithms built from decision trees.

Results

We found that ESKAPE pathogens represented 42.2% of species isolated from bloodstream infections and, compared with non-ESKAPE pathogens, were associated with a 3.3-day increase in length of stay, a $5500 increase in cost of care, and a 2.1% absolute increase in mortality (P < 1e-99). ESKAPE pathogens were not universally more resistant to antibiotics, but only to select antibiotics (P < 5e-6), particularly against common empiric therapies. In addition, simple word group algorithms predicted ESKAPE pathogens with a positive predictive value of 7.9% to 56.2%, exceeding 4.8% by random guessing (P < 1e-99).

Conclusions

Taken together, these data highlight the pathogenicity of ESKAPE bacteria, potential mechanisms of their pathogenicity, and the potential to predict ESKAPE infections upon admission. Implementing word group algorithms could enable earlier and targeted therapies against ESKAPE bacteria and thus reduce their burden on the health care system.
The Introduction of Duty into English Law and the Development of the Legal Subject
Authors: Dent Chris
Published: November 2019

‘Duty’ is a term that is used in several areas of the law—notably the ‘duty of care’ and ‘fiduciary duty’. This article considers the introduction of the term ‘duty’ itself to the law, before it became part of the compound terms. In order to do so, the article surveys a range of sub-disciplines, including trusts, negligence law, defamation and employment law, to identify the earliest uses of the term. To explore the potential motivations for its incorporation, additional material, such as early modern legal and, later, political treatises, is considered. The conclusion is that the introduction of the term, while reactionary, may still be seen in terms of the development of the legal subject in the English common law.
Effect of autologous NK cell immunotherapy on advanced lung adenocarcinoma with EGFR mutations
Authors: Hong Guodai , Chen Xuemei , Sun Xizhuo , Zhou Meiling , Liu Bing , Li Zhu , Yu Zhendong , Gao Wenbin , Liu Tao
Published: November 2019

This study investigated the efficiency of natural killer (NK) cell immunotherapy on non-small cell lung cancer with and without EGFR mutations in order to evaluate the response rate (RR) and progression-free survival (PFS). Among the 48 patients recruited, 24 were clinically confirmed to be EGFR mutation positive. The study group was treated with autologous NK cell immunotherapy. Comparisons of the lymphocyte number, serum tumour-related biomarkers, circulating tumour cells (CTC), Karnofsky Performance Status (KPS) and survival curves were carried out before and after NK cell immunotherapy. The safety and short-term effects were evaluated, followed by median PFS and RR assessments. The serum CEA and CA125 values were found lower in the NK cell therapy group than that of the non-NK treatment group (p < 0.05). The χ2 test showed a 75% RR of the study group A, significantly higher than that of the control group B (16.7%; p < 0.01). The RR of groups C (58.3%) and D (41.7%) were not statistically significant. The p values of the 4 groups were 0.012, 0.012, 0.166 and 1 from group A to group D, respectively. The median PFS was 9 months in EGFR mutation positive group undergoing NK cell infusion interference. By evaluating the changes in immune function, tumour biomarkers, CTC, KPS and PFS, we demonstrated that NK cell therapy had better clinical therapeutic effects on EGFR mutation-positive lung adenocarcinoma.
Value-Based Care for Musculoskeletal Pain: Are Physical Therapists Ready to Deliver?
Authors: Lentz Trevor A , Goode Adam P , Thigpen Charles A , George Steven Z
Published: November 2019

Early physical therapy models hold great promise for delivering high-value care for individuals with musculoskeletal pain. However, existing physical therapist practice and research standards are misaligned with value-based principles, which limits the potential for growth and sustainability of these models. This Perspective describes how the value proposition of early physical therapy can be improved by redefining harm, embracing a prognostic approach to clinical decision making, and advocating for system-wide guideline-adherent pain care. It also outlines the need to adopt a common language to describe these models and embrace new, rigorous study designs and analytical approaches to better understand where and how early physical therapy delivers value. The goal is to define a clear path forward to ensure physical therapists are aligned within health care systems to deliver on the American Physical Therapy Association’s vision of high-value care in a rapidly changing health care environment.
Development and validation of a deep-learning model for scoring of radiographic finger joint destruction in rheumatoid arthritis
Authors: Hirano Toru , Nishide Masayuki , Nonaka Naoki , Seita Jun , Ebina Kosuke , Sakurada Kazuhiro , Kumanogoh Atsushi
Published: November 2019

Objective

The purpose of this research was to develop a deep-learning model to assess radiographic finger joint destruction in RA.

Methods

The model comprises two steps: a joint-detection step and a joint-evaluation step. Among 216 radiographs of 108 patients with RA, 186 radiographs were assigned to the training/validation dataset and 30 to the test dataset. In the training/validation dataset, images of PIP joints, the IP joint of the thumb or MCP joints were manually clipped and scored for joint space narrowing (JSN) and bone erosion by clinicians, and then these images were augmented. As a result, 11 160 images were used to train and validate a deep convolutional neural network for joint evaluation. Three thousand seven hundred and twenty selected images were used to train machine learning for joint detection. These steps were combined as the assessment model for radiographic finger joint destruction. Performance of the model was examined using the test dataset, which was not included in the training/validation process, by comparing the scores assigned by the model and clinicians.

Results

The model detected PIP joints, the IP joint of the thumb and MCP joints with a sensitivity of 95.3% and assigned scores for JSN and erosion. Accuracy (percentage of exact agreement) reached 49.3–65.4% for JSN and 70.6–74.1% for erosion. The correlation coefficient between scores by the model and clinicians per image was 0.72–0.88 for JSN and 0.54–0.75 for erosion.

Conclusion

Image processing with the trained convolutional neural network model is promising to assess radiographs in RA.
Historical Returns of the Market Portfolio
Authors: Doeswijk Ronald , Lam Trevin , Swinkels Laurens
Published: November 2019

We create an annual return index for the invested global multiasset market portfolio. We use a newly constructed unique data set covering the entire market of financial investors. We analyze returns and risk from 1960 to 2017, a period during which the market portfolio realized a compounded real return in U.S. dollars of 4.45%, with a standard deviation of annual returns of 11.2%. The compounded excess return was 3.39%. We publish these data on returns of the market portfolio, so they can be used for future asset pricing and corporate finance studies.

Received March 4, 2019; editorial decision October 9, 2019 by Editor Jeffrey Pontiff. Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
BMSCs-assisted injectable Col I hydrogel-regenerated cartilage defect by reconstructing superficial and calcified cartilage
Authors: Cai Hanxu , Wang Peilei , Xu Yang , Yao Ya , Liu Jia , Li Tao , Sun Yong , Liang Jie , Fan Yujiang , Zhang Xingdong
Published: November 2019

The self-healing capacity of cartilage was limited due to absence of vascular, nervous and lymphatic systems. Although many clinical treatments have been used in cartilage defect repair and shown a promising repair result in short term, however, regeneration of complete zonal structure with physiological function, reconstruction cartilage homeostasis and maintaining long-term repair was still an unbridgeable chasm. Cartilage has complex zonal structure and multiple physiological functions, especially, superficial and calcified cartilage played an important role in keeping homeostasis. To address this hurdle of regenerating superficial and calcified cartilage, injectable tissue-induced type I collagen (Col I) hydrogel-encapsulated BMSCs was chosen to repair cartilage damage. After 1 month implantation, the results demonstrated that Col I gel was able to induce BMSCs differentiation into chondrocytes, and formed hyaline-like cartilage and the superficial layer with lubrication function. After 3 months post-surgery, chondrocytes at the bottom of the cartilage layer would undergo hypertrophy and promote the regeneration of calcified cartilage. Six months later, a continuous anatomical tidemark and complete calcified interface were restored. The regeneration of neo-hyaline cartilage was similar with adjacent normal tissue on the thickness of the cartilage, matrix secretion, collagen type and arrangement. Complete multilayer zonal structure with physiological function remodeling indicated that BMSCs-assisted injectable Col I hydrogel could reconstruct cartilage homeostasis and maintain long-term therapeutic effect.
Lack of effect of tart cherry concentrate dose on serum urate in people with gout
Authors: Stamp Lisa K , Chapman Peter , Frampton Christopher , Duffull Stephen B , Drake Jill , Zhang Yuqing , Neogi Tuhina
Published: November 2019

Objectives

Cherry concentrate has been suggested to reduce serum urate (SU) and gout flares. The aims of this study were to determine the magnitude of the effect of tart cherry concentrate on SU in people with gout, the most effective dose of tart cherry concentrate for lowering SU, and adverse effects.

Methods

Fifty people with gout and SU > 0.36 mmol/l were recruited. Half were on allopurinol and half were on no urate-lowering therapy. Participants were randomized to receive tart cherry juice concentrate: placebo, 7.5 ml, 15 ml, 22.5 ml or 30 ml twice daily for 28 days. Blood samples were taken at baseline, then at 1, 3 and 5 h post cherry and then on days 1, 3, 7, 14, 21 and 28. The area under the curve for SU was calculated over the 28-day study period.

Results

Cherry concentrate dose had no significant effect on reduction in SU area under the curve, urine urate excretion, change in urinary anthocyanin between day 0 and day 28, or frequency of gout flares over the 28-day study period (P = 0.76). There were 24 reported adverse events, with only one (hyperglycaemia) considered possibly to be related to cherry concentrate. Allopurinol use did not modify the effect of cherry on SU or urine urate excretion.

Conclusion

Tart cherry concentrate had no effect on SU or urine urate excretion. If there is an effect of cherry concentrate on gout flares over a longer time period, it is not likely to be mediated by reduction in SU.

Trial registration

Australian New Zealand Clinical Trials Registry (ANZCTR), https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368887, ANZCTR 12615000741583).