bluuebunny/crossref_metadata_2025 huggingface dataset:
Intratumoral Immunotherapy for Early-stage Solid Tumors
Authors: Hong Wan Xing , Haebe Sarah , Lee Andrew S. , Westphalen C. Benedikt , Norton Jeffrey A. , Jiang Wen , Levy Ronald
Published: February 2020

The unprecedented benefits of immunotherapy in advanced malignancies have resulted in increased interests in exploiting immune stimulatory agents in earlier-stage solid tumors in the neoadjuvant setting. However, systemic delivery of immunotherapies may cause severe immune-related side-effects and hamper the development of combination treatments. Intratumoral delivery of neoadjuvant immunotherapy provides a promising strategy in harnessing the power of immunotherapy while minimizing off-target toxicities. The direct injection of immune stimulating agents into the tumor primes the local tumor-specific immunity to generate a systemic, durable clinical response. Intratumoral immunotherapy is a highly active area of investigation resulting in a plethora of agents, for example, immune receptor agonists, non-oncolytic and oncolytic viral therapies, being tested in preclinical and clinical settings. Currently, more than 20 neoadjuvant clinical trials exploring distinct intratumoral immune stimulatory agents and their combinations are ongoing. Practical considerations, including appropriate timing and optimal local delivery of immune stimulatory agents play an important role in safety and efficacy of this approach. Here, we discuss promising approaches in drug delivery technologies and opportunity for combining intratumoral immunotherapy with other cancer treatments and summarize the recent preclinical and clinical evidences that highlighted its promise as a part of routine oncologic care.
Pathologically Complete Response after Triple Therapy in Locally Advanced Esophageal Cancer in a Hereditary Hemorrhagic Telangiectasia Patient
Authors: Park Robin , Philp Alisdair , Nagji Alykhan S. , Kasi Anup
Published: February 2020

Hereditary hemorrhagic telangiectasia (HHT) is a disorder characterized by vascular manifestations including mucocutaneous and visceral telangiectasias and arteriovenous malformations. Herein we present the case of a relatively young patient with HHT with an incidentally discovered locally advanced esophageal cancer on endoscopic screening and pathologically complete response after neoadjuvant chemoradiation. This case highlights an unusual tumor response to chemoradiation in locally advanced esophageal cancer, and the surveillance care of HHT patients.
Compact wide stopband microstrip lowpass filter using polygon patches and meandered lines
Authors: Musavy Adel , Sheikhi Akram
Published: February 2020

In this paper, a low pass ﬁlter based on T-Shaped resonator is presented. The T-Shaped resonator consists of meandered lines and rectangular patches. Also, the LC model and transfer function of the proposed resonator is presented. For suppression of spurious harmonics, a bandstop structure consists of hexangular patches and open stubs has been utilized. Finally, the wide stopband microstrip lowpass filter with cutoff frequency 2.72 GHz has been simulated, fabricated and measured. The LPF has good characteristics such as wide stopband and insertion loss lower than 0.18 dB in the passband region. The rejection level is less than -20 dB from 2.98 up to 21.3 GHz. The filter size is 10.5 mm×12.7 mm, or 0.131 λg× 0.158 λg, where λg is the guided wavelength. The measured and simulated results of the filter is in good agreement with each other, which show the merits of low insertion loss and wide stopband.
Optimal Multivariate Tuning with Neuron-Level and Population-Level Energy Constraints
Authors: Harel Yuval , Meir Ron
Published: February 2020

Optimality principles have been useful in explaining many aspects of biological systems. In the context of neural encoding in sensory areas, optimality is naturally formulated in a Bayesian setting as neural tuning which minimizes mean decoding error. Many works optimize Fisher information, which approximates the minimum mean square error (MMSE) of the optimal decoder for long encoding time but may be misleading for short encoding times. We study MMSE-optimal neural encoding of a multivariate stimulus by uniform populations of spiking neurons, under firing rate constraints for each neuron as well as for the entire population. We show that the population-level constraint is essential for the formulation of a well-posed problem having finite optimal tuning widths and optimal tuning aligns with the principal components of the prior distribution. Numerical evaluation of the two-dimensional case shows that encoding only the dimension with higher variance is optimal for short encoding times. We also compare direct MMSE optimization to optimization of several proxies to MMSE: Fisher information, maximum likelihood estimation error, and the Bayesian Cramér-Rao bound. We find that optimization of these measures yields qualitatively misleading results regarding MMSE-optimal tuning and its dependence on encoding time and energy constraints.
Neural Model of Coding Stimulus Orientation and Adaptation
Authors: Vaitkevičius Henrikas , Švegžda Algimantas , Stanikūnas Rytis , Bliumas Remigijus , Šoliūnas Alvydas , Kulikowski Janus J.
Published: February 2020

The coding of line orientation in the visual system has been investigated extensively. During the prolonged viewing of a stimulus, the perceived orientation continuously changes (normalization effect). Also, the orientation of the adapting stimulus and the background stimuli influence the perceived orientation of the subsequently displayed stimulus: tilt after-effect (TAE) or tilt illusion (TI). The neural mechanisms of these effects are not fully understood. The proposed model includes many local analyzers, each consisting of two sets of neurons. The first set has two independent cardinal detectors (CDs), whose responses depend on stimulus orientation. The second set has many orientation detectors (OD) tuned to different orientations of the stimulus. The ODs sum up the responses of the two CDs with respective weightings and output a preferred orientation depending on the ratio of CD responses. It is suggested that during prolonged viewing, the responses of the CDs decrease: the greater the excitation of the detector, the more rapid the decrease in its response. Thereby, the ratio of CD responses changes during the adaptation, causing the normalization effect and the TAE. The CDs of the different local analyzers laterally inhibit each other and cause the TI. We show that the properties of this model are consistent with both psychophysical and neurophysiological findings related to the properties of orientation perception, and we investigate how these mechanisms can affect the orientation's sensitivity.
Galgos and Podencos in Spain: A Rescue’s Perspective
Authors: Robinson Lisa , Watkinson Julie
Published: February 2020

This article introduces readers to the status of sighthounds in Spain, the abuse they endure at the hands of humans, and the work being carried out to help them by Galgos Del Sol, a local rescue with international partners. This paper is not based on empirical data or on scientific methods; it is, however, sourced directly from the experiences of an established Spanish sighthound rescue organisation, and affords the reader a unique and informed insight into this area.
Social Mobility and Promotion of Officers to Senior Ranks in the Royal Navy: Meritocracy or Class Ceiling?
Authors: Clark Stephen M. , Hack-Polay Dieu , Bal P. Matthijs
Published: February 2020

This article examines the extent to which socioeconomic background affects the chances of promotion to senior ranks within the Royal Navy and how the upwardly mobile often face a “class ceiling.” The researchers collected quantitative data within the Royal Navy. The research found a disproportionate overrepresentation of officers from socioeconomically advantaged backgrounds, creating a homogenous upper echelon and self-selecting elite hierarchy. The authors argue for the systematic collection of socioeconomic background data and longitudinal analysis to focus efforts toward engendering the conditions for social mobility and the ability to quantitatively assess the impact of policy changes on future social mobility outcomes. The research contributes to understand contemporary social mobility issues and is the first quantitative analysis of Royal Navy officers’ socioeconomic backgrounds. The research provides perspectives on which other Armed Forces (including the United States) that face diversity issues could reflect. The article repositions military issues in mainstream academic discourse.
Implications of Tumor Size, Subsite, and Adjuvant Therapy on Outcomes in pT4aN0 Oral Cavity Carcinoma
Authors: Namin Arya W. , Bollig Craig A. , Harding Brette C. , Dooley Laura M.
Published: February 2020

Objective

To determine if tumor size, subsite, and adjuvant radiation therapy (AXRT) are associated with overall survival (OS) in patients with pT4aN0 oral cavity squamous cell carcinoma (OSCC) who underwent mandibulectomy with negative surgical margins (NSMs).

Study Design

Retrospective cohort study.

Setting

National Cancer Database (NCDB).

Subjects and Methods

Retrospective analysis of the NCDB that included patients diagnosed with pT4aN0 OSCC who underwent mandibulectomy with NSMs between 2004 and 2015. The association of age, Charlson‐Deyo score (CDS), tumor size, subsite, and AXRT with OS was analyzed. The cases were divided into 3 subgroups based on maximal tumor dimension for subgroup analysis; tumors ≤2.0 cm, tumors 2.1 to 4.0 cm, and tumors >4.0 cm.

Results

For the entire cohort; age (P <. 001; hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.02‐1.03), CDS (P =. 013; HR, 0.57; 95% CI, 0.37‐0.89), tongue subsite (P =. 003; HR, 2.01; 95% CI, 1.27‐3.40), floor of mouth subsite (P =. 001; HR, 1.76; 95% CI, 1.28‐2.42), tumor size (P <. 001; HR, 0.57; 95% CI, 0.45‐0.72), and AXRT (P <. 001; HR, 1.46; 95% CI, 1.24‐1.72) were associated with OS on multivariate analysis. On subgroup analysis, AXRT not significantly associated with OS in patients with gingival, hard palate, retromolar trigone, and not specified tumors ≤2.0 cm (P =. 323; HR, 1.29; 95% CI, 0.78‐2.15).

Conclusions

In patients with pT4aN0 OSCC who underwent mandibulectomy with NSMs, age, CDS, tongue subsite, floor of mouth subsite, tumor size, and AXRT are associated with OS. AXRT was not significantly associated with overall survival in patients with gingival, hard palate, retromolar trigone, and not specified tumors ≤2.0 cm.
Willingness to Discuss and Screen for Pre-Exposure Prophylaxis in Pharmacies Among Men Who Have Sex With Men
Authors: Crawford Natalie D. , Albarran Taynel , Chamberlain Allison , Hopkins Roderick , Josma Dorie , Morris Joseph , Onwubiko Udodirim N.
Published: February 2020

Objective:

To determine the willingness to discuss and be screened for pre-exposure prophylaxis (PrEP) in pharmacies among MSM.

Methods:

Led by Georgia’s Fulton County Board of Health, this study surveyed individuals who attended 2 Atlanta-based Gay Pride events in 2018. This analysis was limited to those who identified as men who have sex with men (MSM) who were not HIV positive and reported never using PrEP. Multivariable regression was used to determine the correlates of willingness to discuss and be screened for PrEP in-pharmacy.

Results:

Most (69%) were willing to discuss PrEP with pharmacy staff and 61.35% were willing to be screened for PrEP in-pharmacy. Those who were interested in PrEP were significantly more willing to discuss PrEP in-pharmacy compared to those not interested in PrEP (prevalence ratio [PR]: 1.65; 95% confidence interval [95% CI]: 1.11-2.48). Race was not associated with willingness to discuss PrEP with pharmacy staff. However, black MSM (BMSM) were less willing to be screened in pharmacies than white MSM, until we accounted for interest in PrEP (PR: 1.27; 95% CI: 1.09-1.48).

Discussion:

Pharmacies may be an optimal setting to expand PrEP access to reach racial minorities who have the highest need but are not being reached. Pharmacy-based PrEP discussions and screening could improve awareness of HIV status and increase PrEP knowledge and uptake. Future studies should determine optimal pharmacy conditions under which PrEP screening and uptake are acceptable for BMSM.
Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL after ibrutinib failure
Authors: Gauthier Jordan , Hirayama Alexandre V. , Purushe Janaki , Hay Kevin A. , Lymp James , Li Daniel H. , Yeung Cecilia C. S. , Sheih Alyssa , Pender Barbara S. , Hawkins Reed M. , Vakil Aesha , Phi Tinh-Doan , Steinmetz Rachel N. , Shadman Mazyar , Riddell Stanley R. , Maloney David G. , Turtle Cameron J.
Published: February 2020

We previously reported durable responses in relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) patients treated with CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell immunotherapy after ibrutinib failure. Because preclinical studies showed that ibrutinib could improve CAR T cell-antitumor efficacy and reduce cytokine release syndrome (CRS), we conducted a pilot study to evaluate the safety and feasibility of administering ibrutinib concurrently with CD19 CAR T-cell immunotherapy. Nineteen CLL patients were included. The median number of prior therapies was 5, and 17 patients (89%) had high-risk cytogenetics (17p deletion and/or complex karyotype). Ibrutinib was scheduled to begin ≥2 weeks before leukapheresis and continue for ≥3 months after CAR T-cell infusion. CD19 CAR T-cell therapy with concurrent ibrutinib was well tolerated; 13 patients (68%) received ibrutinib as planned without dose reduction. The 4-week overall response rate using 2018 International Workshop on CLL (iwCLL) criteria was 83%, and 61% achieved a minimal residual disease (MRD)-negative marrow response by IGH sequencing. In this subset, the 1-year overall survival and progression-free survival (PFS) probabilities were 86% and 59%, respectively. Compared with CLL patients treated with CAR T cells without ibrutinib, CAR T cells with concurrent ibrutinib were associated with lower CRS severity and lower serum concentrations of CRS-associated cytokines, despite equivalent in vivo CAR T-cell expansion. The 1-year PFS probabilities in all evaluable patients were 38% and 50% after CD19 CAR T-cell therapy, with and without concurrent ibrutinib, respectively (P = .91). CD19 CAR T cells with concurrent ibrutinib for R/R CLL were well tolerated, with low CRS severity, and led to high rates of MRD-negative response by IGH sequencing.
A [60]fullerene nanoconjugate with gemcitabine: synthesis, biophysical properties and biological evaluation for treating pancreatic cancer
Authors: Nalepa Paweł , Gawecki Robert , Szewczyk Grzegorz , Balin Katarzyna , Dulski Mateusz , Sajewicz Mieczysław , Mrozek-Wilczkiewicz Anna , Musioł Robert , Polanski Jaroslaw , Serda Maciej
Published: February 2020

Background

The first-line chemotherapy drug that is used to treat pancreatic ductal adenocarcinoma is gemcitabine. Unfortunately, its effectiveness is hampered by its chemo-resistance, low vascularization and drug biodistribution limitations in the tumor microenvironment. Novel nanotherapeutics must be developed in order to improve the prognosis for patients with pancreatic cancer.

Results

We developed a synthetic methodology for obtaining a water-soluble nanoconjugate of a [60]fullerene-glycine derivative with the FDA-approved drug gemcitabine (nanoC60GEM). The proposed synthetic protocol enables a highly water-soluble [60]fullerene-glycine derivative (6) to be obtained, which was next successfully conjugated with gemcitabine using the EDCI/NHS carbodiimide protocol. The desired nanoconjugate was characterized using mass spectrometry and DLS, IR and XPS techniques. The photogeneration of singlet oxygen and the superoxide anion radical were studied by measuring 1O2 near-infrared luminescence at 1270 nm, followed by spin trapping of the DMPO adducts by EPR spectroscopy. The biological assays that were performed indicate that there is an inhibition of the cell cycle in the S phase and the induction of apoptosis by nanoC60GEM.

Conclusion

In this paper, we present a robust approach for synthesizing a highly water-soluble [60]fullerene nanoconjugate with gemcitabine. The performed biological assays on pancreatic cancer cell lines demonstrated cytotoxic effects of nanoC60GEM, which were enhanced by the generation of reactive oxygen species after blue LED irradiation of synthesized fullerene nanomaterial.
Graph regularized L2,1-nonnegative matrix factorization for miRNA-disease association prediction
Authors: Gao Zhen , Wang Yu-Tian , Wu Qing-Wen , Ni Jian-Cheng , Zheng Chun-Hou
Published: February 2020

Background

The aberrant expression of microRNAs is closely connected to the occurrence and development of a great deal of human diseases. To study human diseases, numerous effective computational models that are valuable and meaningful have been presented by researchers.

Results

Here, we present a computational framework based on graph Laplacian regularizedL2,1-nonnegative matrix factorization (GRL2,1-NMF) for inferring possible human disease-connected miRNAs. First, manually validated disease-connected microRNAs were integrated, and microRNA functional similarity information along with two kinds of disease semantic similarities were calculated. Next, we measured Gaussian interaction profile (GIP) kernel similarities for both diseases and microRNAs. Then, we adopted a preprocessing step, namely, weighted K nearest known neighbours (WKNKN), to decrease the sparsity of the miRNA-disease association matrix network. Finally, theGRL2,1-NMF framework was used to predict links between microRNAs and diseases.

Conclusions

The new method (GRL2, 1-NMF) achieved AUC values of 0.9280 and 0.9276 in global leave-one-out cross validation (global LOOCV) and five-fold cross validation (5-CV), respectively, showing that GRL2, 1-NMF can powerfully discover potential disease-related miRNAs, even if there is no known associated disease.
Association of neuromuscular reversal by sugammadex and neostigmine with 90-day mortality after non-cardiac surgery
Authors: Oh Tak Kyu , Ryu Jung-Hee , Nam Sunwoo , Oh Ah-Young
Published: February 2020

Background

Reversing a neuromuscular blockade agent with sugammadex is known to lessen postoperative complications by reducing postoperative residual curarization. However, its effects on 90-day mortality are unknown. Therefore, this study aimed to compare the effects of sugammadex and neostigmine in terms of 90-day mortality after non-cardiac surgery.

Methods

This retrospective cohort study analyzed the medical records of adult patients aged 18 years or older who underwent non-cardiac surgery at a single tertiary care hospital between 2011 and 2016. Propensity score matching and Cox regression analysis were used to investigate the effectiveness of sugammadex and neostigmine in lowering 90-day mortality after non-cardiac surgery.

Results

A total of 65,702 patients were included in the analysis (mean age: 52.3 years, standard deviation: 15.7), and 23,532 of these patients (35.8%) received general surgery. After propensity score matching, 14,179 patients (3906 patients from the sugammadex group and 10,273 patients from the neostigmine group) were included in the final analysis. Cox regression analysis in the propensity score-matched cohort showed that the risk of 90-day mortality was 40% lower in the sugammadex group than in the neostigmine group (hazard ratio: 0.60, 95% confidence interval: 0.37, 0.98; P = 0.042). These results were similar in the multivariable Cox regression analysis of the entire cohort (hazard ratio: 0.62, 95% confidence interval: 0.39, 0.96; P = 0.036).

Conclusions

This retrospective cohort study suggested that reversing rocuronium with sugammadex might be associated with lower 90-day mortality after non-cardiac surgery compared to neostigmine. However, since this study did not evaluate quantitative neuromuscular function in the postoperative period due to its retrospective design, the results should be interpreted carefully. Future prospective studies with quantitative neuromuscular monitoring in the postoperative period should be performed to confirm these results.
Whole grain food diet slightly reduces cardiovascular risks in obese/overweight adults: a systematic review and meta-analysis
Authors: Wang Weihao , Li Jianan , Chen Xiaoxi , Yu Miao , Pan Qi , Guo Lixin
Published: February 2020

Background

The effects of whole grain diet on cardiovascular risks in obese and overweight adults is not well established. Our goal was to conduct a systematic review and meta-analysis on the effect of whole grain diet on cardiovascular risks in obese/overweight adults.

Methods

PubMed, Embase and Cochrane were systematically scanned for randomized controlled trials (RCTs), and studies were selected based on certain inclusion and exclusion criteria. The primary outcome was the effectiveness of whole grain food consumption in reducing body weight. The secondary outcomes were the effect of whole grain food consumption on cardiovascular disease (CVD) risk factors including plasma low-density lipoprotein cholesterol (LDL-C), insulin resistance index, blood pressure, body mass index (BMI), C-reactive protein (CRP), and waist circumference in obese/overweight adults.

Results

Our results showed that whole grain consumption was associated with lower body weight (mean difference (MD) = − 0.5, 95% confidence intervals (CI) [− 0.74, 0.25], I2 = 35%, P < 0.0001) and lower CRP (MD = -0.36, 95% CI [− 0.54, − 0.18], I2 = 69%, P < 0.0001), compared with the control group. However, there were no significant differences in LDL-C (MD = -0.08, 95% CI [− 0.16, 0.00], I2 = 27%, P = 0.05), waist circumference (MD = -0.12, 95% CI [− 0.92, 0.68], I2 = 44%, P = 0.76), systolic blood pressure (MD = -0.11, 95% CI [− 1.55, 1.33], I2 = 3%, P = 0.88), diastolic blood pressure (MD = -0.44, 95% CI [− 1.44, 0.57], I2 = 15%, P = 0.39), and fasting glucose (MD = -0.05, 95% CI [− 0.12, 0.01], I2 = 31%, P = 0.11) between the two groups.

Conclusion

This study suggests that whole grain food consumption can slightly reduce body weight and CRP in obese/overweight population.
Seroprevalence of Brucella infection and associated factors among pregnant women receiving antenatal care around human, wildlife and livestock interface in Ngorongoro ecosystem, Northern Tanzania. A cross-sectional study
Authors: Makala Robert , Majigo Mtebe V. , Bwire George M. , Kibwana Upendo , Mirambo Mariam M. , Joachim Agricola
Published: February 2020

Background

Brucellosis is a zoonotic disease transmitted to humans through contact with infected animals, animal products or consumption of infected dairy products. Brucella infection during pregnancy is of special interest due to association with adverse pregnancy outcomes. This study determined the seroprevalence and factors associated with Brucella infection among pregnant women around the human-wildlife-livestock interface area in Ngorongoro ecosystem, Northern Tanzania.

Methods

A facility-based cross-sectional study was conducted between May and June 2018 at six health facilities that provide antenatal services. Pregnant women receiving antenatal care were invited to participate. A structured questionnaire was used to collect socio-demographic and obstetric characteristics in addition to behavior and practices related to the occurrence of human brucellosis. The presence of serum immunoglobulin against Brucella was determined using Rose Bengal Plate Test (RBPT). The positive samples were further assayed for the presence of IgG and IgM using The enzyme-linkedimmunosorbent assay. Bivariate analysis was conducted to determine the variables associated with Brucella seropositivity. Multivariable logistic regression analysis was performed to examine the factors independently associations with Brucella seropositivity after adjustment for other explanatory variables.

Results

A total of 313 participants were enrolled in the study. The overall seroprevalence of Brucella infection was 10.9% (34/313) determined by Rose Bengal plate test. Of 34 positive individuals, 27(79.4%) and 8(23.5%) were positive in the ELISA specific for IgG and IgM Brucella antibodies respectively. Regular contact with manure (AOR 3.16, 95%CI 1.27–7.83) and preference for animal fresh milk (AOR 3.80, 95% CI 1.23–11.69), raw meat (AOR 2.58, 95% CI 1.14–5.81) and raw animal blood (AOR 2.71, 95% CI 1.15–6.35) increased the odds of being Brucella seropositive. Contact with the animal placenta were not associated with Brucella seropositivity after adjustment.

Conclusion

This study has found that brucellosis is an important public health problem among pregnant women in areas with interactions of humans; livestock and wildlife. The risk of infection increased with the regular contact with manure and preference of raw foodstuffs like animal blood, meat, and milk. We emphasize the need for interventional strategies to reduce the risk of exposure.
Association of tympanostomy tubes with future assistive hearing devices–a population based study
Authors: Beyea Jason A. , Cooke Bonnie , Rosen Emily , Nguyen Paul
Published: February 2020

Background

Ear (tympanostomy) tube (TT) placement is a common ambulatory surgery in children. Despite the commonality of this treatment, the long-term effects are unknown. The objective of this study was to determine the rate of permanent hearing loss, as measured by use of a rehabilitative hearing device.

Methods

A retrospective comprehensive population-based cohort study was performed, evaluating all hospitals in the Canadian province of Ontario. Three cohorts of children were constructed: TT – at least one ear tube procedure (n = 193,880), No-TT –recurrent visits to a physician for middle ear disease, did not undergo ear tubes (n = 203,283), and Control – an age/sex matched group who had not undergone ear tubes and who didn’t have repeat physician visits for middle ear disease (n = 961,168). The main outcome measures were risk and odds ratio (OR) of rehabilitative hearing devices.

Results

The TT cohort had a higher risk of obtaining a hearing aid (OR 4.53 vs. No-TT, p < 0.001; OR 10.81 vs. Control, p < 0.001), an FM system (OR 3.84 vs. No-TT, p < 0.001; OR 15.13 vs. Control, p < 0.001), and an implanted bone conduction device (OR 5.08 vs. No-TT, p < 0.001; OR 15.67 vs. Control, p < 0.001).

Conclusions

An association between ear tube placement and long-term need for a rehabilitative hearing device was found. This association warrants future prospective research in this area.
Meaning in life as a protective factor against suicidal tendencies in Chinese University students
Authors: Lew Bob , Chistopolskaya Ksenia , Osman Augustine , Huen Jenny Mei Yiu , Abu Talib Mansor , Leung Angel Nga Man
Published: February 2020

Background

A substantial increase in rates of suicide worldwide, especially among late adolescents and young adults, has been observed. It is important to identify specific risk and protective factors for suicide-related behaviors among late adolescents and young adults. Identifying specific factors across the masses, not only in the Western, but also in the Asian context, helps researchers develop empirically informed intervention methods for the management of protective and risk factors of suicide.

Methods

In the current study, 2074 students (706 males), filled out the Meaning in Life Questionnaire, with subscales of Search for Meaning (MLQ-S) and Presence of Meaning (MLQ-P); the Future Disposition Inventory-24 (FDI-24), with subscales of Positive Focus (PF), Suicide Orientation (SO), and Negative Focus (NF); and the Beck Hopelessness Scale (BHS). These scales measure protective and risk factors that are linked to suicidal behaviors; while suicidal behaviors were measured by the Suicidal Behaviors Questionnaire-Revised (SBQ-R). Mediation analyses were performed to test the models with both the MLQ-S and MLQ-P as the mediators between a) hopelessness, as measured by BHS and suicidal behaviors; and b) PF, SO, and NF, as measured by FDI-24, and suicidal behaviors.

Results

We found that only MLQ-P mediated the relation between hopelessness and suicidal behaviors; while both MLQ-P and MLQ-S mediated PF, SO, and NF (as measured by FDI-24), and suicidal behaviors, respectively.

Conclusion

Meaning in life, including both the presence of meaning in life and search for meaning, can be good protective factors against suicidal behaviors.
Etiology and characteristics of patients with bronchiectasis in Taiwan: a cohort study from 2002 to 2016
Authors: Huang Hung-Yu , Chung Fu-Tsai , Lo Chun-Yu , Lin Horng-Chyuan , Huang Yu-Tung , Yeh Chih-Hsin , Lin Chang-Wei , Huang Yu-Chen , Wang Chun-Hua
Published: February 2020

Background

Bronchiectasis is a chronic infectious respiratory disease with diverse causes and ethnic or geographic differences. However, few large-scale studies of its etiology have been conducted in Asia. This study aimed to determine the etiology and clinical features of bronchiectasis in Taiwan.

Methods

This longitudinal cohort study investigated the etiology and clinical features of newly diagnosed non-cystic fibrosis bronchiectasis patients from January 2002 to December 2016. The clinical, functional and microbiological data of patients were retrieved from the Chang Gung Research Database, which includes seven medical facilities throughout Taiwan. The index date was the date of the first bronchiectasis diagnosis. Known diseases that were diagnosed before the index date were regarded as etiologies of bronchiectasis.

Results

The cohort comprised 15,729 adult patients with bronchiectasis. Idiopathic (32%) was the most common cause, followed by post-pneumonia (24%). Other causes included post-tuberculosis (12%), chronic obstructive pulmonary disease (14%), asthma (10%), gastroesophageal reflux disease (2%) and rheumatic diseases (2%). At diagnosis, 8487 patients had sputum culture.Pseudomonas aeruginosa(5.3%) was the most common bacteria, followed by non-tuberculosis mycobacteria (3.6%),Haemophilus influenzae(3.4%) andKlebsiella pneumoniae(3.1%), but 6155 (72.1%) had negative sputum cultures. Patients with post-tuberculosis had a higher sputum isolation rate of non-tuberculosis mycobacteria thanP. aeruginosa. Patients with post-tuberculosis and post-pneumonia bronchiectasis had a higher frequency of chronic lung infection than other groups (p < 0.05). Clinical characteristics, such as gender, lung function, comorbidities and microbiology, were significantly different between idiopathic and known etiologies.

Conclusions

Idiopathic, post-infection and tuberculosis constitute major bronchiectasis etiologies in Taiwan. Clinical characteristics and sputum microbiology were distinct among separate etiology phenotypes.
Reduced hypertrophy in vitro after chondrogenic differentiation of adult human mesenchymal stem cells following adenoviral SOX9 gene delivery
Authors: Weissenberger M. , Weissenberger M. H. , Gilbert F. , Groll J. , Evans C. H. , Steinert A. F.
Published: February 2020

Background

Mesenchymal stem cell (MSC) based-treatments of cartilage injury are promising but impaired by high levels of hypertrophy after chondrogenic induction with several bone morphogenetic protein superfamily members (BMPs). As an alternative, this study investigates the chondrogenic induction of MSCs via adenoviral gene-delivery of the transcription factor SOX9 alone or in combination with other inducers, and comparatively explores the levels of hypertrophy and end stage differentiation in a pellet culture system in vitro.

Methods

First generation adenoviral vectors encoding SOX9, TGFB1 or IGF1 were used alone or in combination to transduce human bone marrow-derived MSCs at 5 × 102 infectious particles/cell. Thereafter cells were placed in aggregates and maintained for three weeks in chondrogenic medium. Transgene expression was determined at the protein level (ELISA/Western blot), and aggregates were analysed histologically, immunohistochemically, biochemically and by RT-PCR for chondrogenesis and hypertrophy.

Results

SOX9 cDNA was superior to that encoding TGFB1, the typical gold standard, as an inducer of chondrogenesis in primary MSCs as evidenced by improved lacuna formation, proteoglycan and collagen type II staining, increased levels of GAG synthesis, and expression of mRNAs associated with chondrogenesis. Moreover, SOX9 modified aggregates showed a markedly lower tendency to progress towards hypertrophy, as judged by expression of the hypertrophy markers alkaline phosphatase, and collagen type X at the mRNA and protein levels.

Conclusion

Adenoviral SOX9 gene transfer induces chondrogenic differentiation of human primary MSCs in pellet culture more effectively than TGFB1 gene transfer with lower levels of chondrocyte hypertrophy after 3 weeks of in vitro culture. Such technology might enable the formation of more stable hyaline cartilage repair tissues in vivo.
TGF-β pathway activation by idiopathic pulmonary fibrosis (IPF) fibroblast derived soluble factors is mediated by IL-6 trans-signaling
Authors: Epstein Shochet Gali , Brook Elizabetha , Bardenstein-Wald Becky , Shitrit David
Published: February 2020

Background

Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease characterized by a progressive decline in lung function. Fibrotic diseases, such as IPF, are characterized by uncontrolled activation of fibroblasts. Since the microenvironment is known to affect cell behavior, activated fibroblasts can in turn activate healthy neighboring cells. Thus, we investigated IPF paracrine signaling in human lung fibroblasts (HLFs) derived from patients with IPF.

Methods

Primary human fibroblast cultures from IPF (IPF-HLF) and control donor (N-HLF) lung tissues were established and their supernatants were collected. These supernatants were then added to N-HLFs for further culture. Protein and RNA were extracted from IPF/ N-HLFs at baseline. Interleukin-6 (IL-6) and TGF-β-related signaling factors (e.g. STAT3, Smad3) were evaluated by western blot and qPCR. IL-6 levels were measured by ELISA. IL-6 signaling was blocked by Tocilizumab (TCZ) (10 ng/ml).

Results

IPF-HLFs were found to significantly overexpress IL-6 receptor (IL-6R), suppressor of cytokine signaling 3 (SOCS3), phospho-STAT3-Y705 and phospho-Smad3 in comparison to N-HLFs (p < 0.05). In addition, they were found to proliferate faster, secrete more IL-6 and express higher levels of the soluble IL-6R. IPF-HLF increased proliferation was inhibited by TCZ. Moreover, IPF-HLF derived supernatants induced both direct and indirect STAT3 activation that resulted in Smad3 phosphorylation and elevated Gremlin levels in N-HLFs. These effects were also successfully blocked by TCZ.

Conclusions

IPF-HLF paracrine signaling leads to IL-6R overexpression, which in turn, affects N-HLF survival. The IL-6/STAT3/Smad3 axis facilitates cellular responses that could potentially promote fibrotic disease. This interplay was successfully blocked by TCZ.
In vitro antibacterial activity and cytocompatibility of magnesium-incorporated poly(lactide-co-glycolic acid) scaffolds
Authors: Ma Rui , Wang Wei , Yang Pei , Wang Chunsheng , Guo Dagang , Wang Kunzheng
Published: February 2020

Background

Bone defects are often combined with the risk of infection in the clinic, and artificial bone substitutes are often implanted to repair the defective bone. However, the implant materials are carriers for bacterial growth, and biofilm can form on the implant surface, which is difficult to eliminate using antibiotics and the host immune system. Magnesium (Mg) was previously reported to possess antibacterial potential.

Methods

In this study, Mg was incorporated into poly(lactide-co-glycolic acid) (PLGA) to fabricate a PLGA/Mg scaffold using a low-temperature rapid-prototyping technique. All scaffolds were divided into three groups: PLGA (P), PLGA/10 wt% Mg with low Mg content (PM-L) and PLGA/20 wt% Mg with high Mg content (PM-H). The degradation test of the scaffolds was conducted by immersing them into the trihydroxymethyl aminomethane–hydrochloric acid (Tris–HCl) buffer solution and measuring the change of pH values and concentrations of Mg ions. The antibacterial activity of the scaffolds was investigated by the spread plate method, tissue culture plate method, scanning electron microscopy and confocal laser scanning microscopy. Additionally, the cell attachment and proliferation of the scaffolds were evaluated by the cell counting kit-8 (CCK-8) assay using MC3T3-E1 cells.

Results

The Mg-incorporated scaffolds degraded and released Mg ions and caused an increase in the pH value. Both PM-L and PM-H inhibited bacterial growth and biofilm formation, and PM-H exhibited higher antibacterial activity than PM-L after incubation for 24 and 48 h. Cell tests revealed that PM-H exerted a suppressive effect on cell attachment and proliferation.

Conclusions

These findings demonstrated that the PLGA/Mg scaffolds possessed favorable antibacterial activity, and a higher content of Mg (20%) exhibited higher antibacterial activity and inhibitory effects on cell attachment and proliferation than low Mg content (10%).
Addressing noncommunicable diseases among urban refugees in the Middle East and North Africa - a scoping review
Authors: McNatt Zahirah Z.
Published: February 2020

Background

More than 5.5 million Syrian refugees have fled violence and settled in mostly urban environments in neighboring countries. The Middle East and North Africa (MENA) region accounts for 6% of the global population but 25% of the population are ‘of concern’ to the UN Refugee Agency. In addition to large amounts of forced migration, the region is also undergoing an epidemiologic transition towards a heavier burden of noncommunicable diseases (NCDs), which in 2018 accounted for 74% of all deaths in the region. To address NCD needs globally, a myriad of policies and interventions have been implemented in low-income stable country settings. However, little is known about which policies and interventions are currently being implemented or are best suited for refugee hosting countries across the Middle East and North Africa.

Methods

A scoping review of peer-reviewed literature was conducted to identify policies and interventions implemented in the Middle East and North Africa to address the needs of urban refugees with noncommunicable diseases.

Results

This scoping review identified 11 studies from Jordan, Lebanon, Iran, West Bank, Gaza and Syria. These studies addressed three foci of extant work, (1) innovative financing for expensive treatments, (2) improvements to access and quality of treatment and, (3) efforts to prevent new diagnoses and secondary complications. All interventions targeted refugee populations including Palestinians, Sudanese, Syrians, Afghans and Iraqis.

Discussion

The scoping review highlighted five key findings. First, very few studies focused on the prevention of noncommunicable diseases among displaced populations. Second, several interventions made use of health information technologies, including electronic medical records and mHealth applications for patients. Third, the vast majority of publications were solely focused on tackling NCDs through primary care efforts. Fourth, the literature was very sparse in regard to national policy development, and instead favored interventions by NGOs and UN agencies. Last, the perspectives of refugees were notably absent.

Conclusion

Opportunities exist to prioritize prevention efforts, scale up eHealth interventions, expand access to secondary and tertiary services, address the scarcity of research on national policy, and incorporate the perspectives of affected persons in the broader discourse.
Adapting a family intervention to reduce risk factors for sexual exploitation
Authors: Bounds Dawn T. , Otwell Caitlin H. , Melendez Adrian , Karnik Niranjan S. , Julion Wrenetha A.
Published: February 2020

Background

Sexually exploited youth are disconnected from societal tethers and need support systems, which makes them some of the most vulnerable of youth. This heightened level of vulnerability increases their risk for violence, abuse, ongoing sexual exploitation and all its sequelae. The purpose of this study was to examine an evidence-based intervention called STRIVE (support to reunite, involve and value each other) that has been a successful family re-engagement strategy with newly homeless youth. We sought to explore its contextual relevance for youth with risk factors for sexual exploitation and identify necessary adaptations to reduce risk factors for sexual exploitation. We deliberately took an intersectional approach in conducting this study.

Methods

Six community-based focus groups were conducted with youth at risk for sexual exploitation and their service providers. Each group was recorded, transcribed, coded, and thematically analyzed.

Results

Results from 29 youth and 11 providers indicate that there are unique considerations that must be taken into account while working with youth at risk for sexual exploitation to ensure effective service delivery and/or ethical research. Emergent themes included: setting the stage by building rapport and acknowledging experiences of structural violence, protect and hold which balances youth’s need for advocacy/support with their caregivers’ need for validation/understanding, and walking the safety tightrope by assessing risks and safety planning.

Discussion

Focus groups are an effective methodology when working with traditionally disempowered populations particularly in gaining a range of perspectives to meet unique needs/preferences. Youth at risk for commercial sexual exploitation needs require strengths-based, individualized, multi-systemic approaches.
TBCRC 002: a phase II, randomized, open-label trial of preoperative letrozole with or without bevacizumab in postmenopausal women with newly diagnosed stage 2/3 hormone receptor-positive and HER2-negative breast cancer
Authors:   on behalf of the Translational Breast Cancer Research Consortium (TBCRC), Vaklavas Christos , Roberts Brian S. , Varley Katherine E. , Lin Nancy U. , Liu Minetta C. , Rugo Hope S. , Puhalla Shannon , Nanda Rita , Storniolo Anna Maria , Carey Lisa A. , Saleh Mansoor N. , Li Yufeng , Delossantos Jennifer F. , Grizzle William E. , LoBuglio Albert F. , Myers Richard M. , Forero-Torres Andres
Published: February 2020

Background

In preclinical studies, the expression of vascular endothelial growth factor (VEGF) in hormone receptor-positive breast cancer is associated with estrogen-independent tumor growth and resistance to endocrine therapies. This study investigated whether the addition of bevacizumab, a monoclonal antibody against VEGF, to letrozole enhanced the antitumor activity of the letrozole in the preoperative setting.

Methods

Postmenopausal women with newly diagnosed stage 2 or 3 estrogen and/or progesterone receptor-positive, HER2-negative breast cancer were randomly assigned (2:1) between letrozole 2.5 mg PO daily plus bevacizumab 15 mg/kg IV every 3 weeks (Let/Bev) and letrozole 2.5 mg PO daily (Let) for 24 weeks prior to definitive surgery. Primary objective was within-arm pathologic complete remission (pCR) rate. Secondary objectives were safety, objective response, and downstaging rate.

Results

Seventy-five patients were randomized (Let/Bev n = 50, Let n = 25). Of the 45 patients evaluable for pathological response in the Let/Bev arm, 5 (11%; 95% CI, 3.7–24.1%) achieved pCR and 4 (9%; 95% CI, 2.5–21.2%) had microscopic residual disease; no pCRs or microscopic residual disease was seen in the Let arm (0%; 95% CI, 0–14.2%). The rates of downstaging were 44.4% (95% CI, 29.6–60.0%) and 37.5% (95% CI, 18.8–59.4%) in the Let/Bev and Let arms, respectively. Adverse events typically associated with letrozole (hot flashes, arthralgias, fatigue, myalgias) occurred in similar frequencies in the two arms. Hypertension, headache, and proteinuria were seen exclusively in the Let/Bev arm. The rates of grade 3 and 4 adverse events and discontinuation due to adverse events were 18% vs 8% and 16% vs none in the Let/Bev and Let arms, respectively. A small RNA-based classifier predictive of response to preoperative Let/Bev was developed and confirmed on an independent cohort.

Conclusion

In the preoperative setting, the addition of bevacizumab to letrozole was associated with a pCR rate of 11%; no pCR was seen with letrozole alone. There was additive toxicity with the incorporation of bevacizumab. Responses to Let/Bev can be predicted from the levels of 5 small RNAs in a pretreatment biopsy.

Trial registration

This trial is registered with ClinicalTrials.gov (Identifier: NCT00161291), first posted on September 12, 2005, and is completed.
A framework for transcriptome-wide association studies in breast cancer in diverse study populations
Authors: Bhattacharya Arjun , García-Closas Montserrat , Olshan Andrew F. , Perou Charles M. , Troester Melissa A. , Love Michael I.
Published: February 2020

Background

The relationship between germline genetic variation and breast cancer survival is largely unknown, especially in understudied minority populations who often have poorer survival. Genome-wide association studies (GWAS) have interrogated breast cancer survival but often are underpowered due to subtype heterogeneity and clinical covariates and detect loci in non-coding regions that are difficult to interpret. Transcriptome-wide association studies (TWAS) show increased power in detecting functionally relevant loci by leveraging expression quantitative trait loci (eQTLs) from external reference panels in relevant tissues. However, ancestry- or race-specific reference panels may be needed to draw correct inference in ancestrally diverse cohorts. Such panels for breast cancer are lacking.

Results

We provide a framework for TWAS for breast cancer in diverse populations, using data from the Carolina Breast Cancer Study (CBCS), a population-based cohort that oversampled black women. We perform eQTL analysis for 406 breast cancer-related genes to train race-stratified predictive models of tumor expression from germline genotypes. Using these models, we impute expression in independent data from CBCS and TCGA, accounting for sampling variability in assessing performance. These models are not applicable across race, and their predictive performance varies across tumor subtype. Within CBCS (N = 3,828), at a false discovery-adjusted significance of 0.10 and stratifying for race, we identify associations in black women nearAURKA,CAPN13,PIK3CA, andSERPINB5via TWAS that are underpowered in GWAS.

Conclusions

We show that carefully implemented and thoroughly validated TWAS is an efficient approach for understanding the genetics underpinning breast cancer outcomes in diverse populations.