bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical significance of skeletal muscle density and sarcopenia in patients with pancreatic cancer undergoing first-line chemotherapy: a retrospective observational study
Authors: Kim In-Ho , Choi Moon Hyung , Lee In Seok , Hong Tae Ho , Lee Myung Ah.
Published: January 2021

Background

To investigate the clinical impact of sarcopenia and skeletal muscle density (SMD) among patients with metastatic pancreatic adenocarcinoma who underwent palliative first line gemcitabine-based chemotherapy.

Methods

A total of 330 patients treated with first line gemcitabine-based chemotherapy between January 2010 and March 2017 were included. CT scans before chemotherapy and after 8±2 weeks were evaluated. The L3 skeletal muscle index (SMI) was used to detect sarcopenia and calculated as the total area of the L3 skeletal muscle divided by the height-squared (cm2/m2). SMD was quantified as the mean muscle radiation attenuation of the muscle cross-sectional area across the L3 vertebral body level and was assessed between − 29 and + 150 Hounsfield units.

Results

A SMI to SMD comparison revealed a positive correlation (R2 = 0.058, P < 0.001). Compared with high SMD, the risks of low SMI were 1.516 (95% confidence interval [CI]: 1.164–1.973) among patients with low SMD. Kaplan–Meier analysis showed that the low SMD was related to poor overall survival (OS, median, 6.1 versus [vs.] 7.9 months, P = 0.010). Multivariate analysis using Cox regression showed that low SMI (hazard ratio [HR]: 1.35, 95% CI: 1.03–1.78, P = 0.032) and low SMD (HR: 1.45, 95% CI: 1.09–1.93, P = 0.011) were poor prognostic factors for OS, respectively. Co-presence of low SMI and low SMD had more powerful prognostic implication for OS (HR: 1.58, 95% CI: 1.12–2.23, P = 0.010). Grade 3 or higher toxicity of chemotherapy was more frequently observed in patients who have a low SMI (43% vs. 59%, P = 0.019) and low SMD (44% vs. 60%, P = 0.023). OS was not related to SMD status among patients who were chemotherapy responders (complete or partial responses). However, among non-responders (stable or progressive disease), low SMD groups had significantly poorer OS in comparison with high SMD groups (median, 5.6 vs 7.4 months, P = 0.006).

Conclusions

Sarcopenia and SMD status can be considered a prognostic factor in patients with metastatic pancreatic adenocarcinoma who received palliative first line gemcitabine-based chemotherapy. Severe chemotherapy toxicity occurred in the sarcopenia and low SMD groups. Our data suggest that a comprehensive assessment of skeletal muscle parameters may be more useful prognostic factors.
A comparison of accommodation and ocular discomfort change according to display size of smart devices
Authors: Kang Jeong Woo , Chun Yeoun Sook , Moon Nam Ju
Published: January 2021

Background

To evaluate the change of accommodation and ocular discomfort according to the display size, using quantitative measurements of accommodation and ocular discomfort through subjective and objective metrics.

Methods

Forty six subjects without any ophthalmic disease history were asked to watch the documentary movie, using two different sizes of smart devices; smartphones and tablets. Before and after using devices, the near point accommodation (NPA) and the near point convergence (NPC) were measured, and objective accommodation was measured using an auto refractometer/keratometer. The subjective ocular discomfort was assessed through a survey.

Results

Both devices showed a decrease in post-use NPA and NPC, and the change after use of the smartphone was significantly severe, 1.8 and 2.5 folds respectively, compared to tablet (p = 0.044, p = 0.033, respectively). Neither smartphone nor tablet showed significant changes in the accommodative response induced by dynamic accommodative stimulus of auto refractometer/keratometer (p = 0.240 and p = 0.199, respectively). Subjects showed a more severe increase in ocular discomfort after using smartphones (p = 0.035) and reported feeling tired even with shorter use times (p = 0.012).

Conclusions

Both devices showed significant decreases in NPA and NPC, and the larger changes were seen when using the small display smartphone. Even within 20minutes of using, subjects start to feel ocular discomfort, and it was more severe and faster after smartphones than tablets. Therefore, the smaller the display size, the greater the adverse impact on eyes, and thus, appropriate display size will need to be selected depending on the time and purpose of use.
Surgical outcomes of acute acquired comitant esotropia of adulthood
Authors: Kim Dae Hyun , Noh Ha Jeong
Published: January 2021

Background

Acute acquired comitant esotropia (AACE) is a type of strabismus characterized by a sudden onset of large angle esotropia with diplopia, which often occurs in children after infancy, teenagers, and young adolescents. However, studies on the surgical outcomes of only adults are rare. The purpose of this article is to analyze the surgical outcomes for adult patients diagnosed with AACE.

Methods

Medical records of 24 patients who had undergone surgery for AACE were retrospectively analyzed. The main outcome measures were the final motor and sensory success rate after surgery and factors affecting motor and sensory outcomes. Motor success was considered alignment within 8 prism diopter (PD) at both near and distance and sensory success was stereoacuity ≥ 60 sec/arc.

Results

The preoperative mean esodeviation angles were 33.1 ± 10.4 PD at distance and 33.3 ± 11.2 PD at near. The mean period of postoperative follow up was 7.5 ± 4.5 months (range 1–8 months). The postoperative mean esodeviation angles at final follow-up time were 3.4 ± 6.1 PD at distance and 3.8 ± 6.7 PD at near. The surgical motor success rate at final follow-up was 79.2% (19/24). The sensory success rate at final follow-up was 50.0% (12/24). The factor affecting the motor outcome was the type of surgery (p < 0.05). The factor affecting sensory outcome was postoperative follow-up time (p < 0.05).

Conclusions

Surgery type appears to affect surgical motor outcomes in adults with AACE. Although the sensory outcome was favorable, it seems that regaining bifoveal fixation takes time.
Mobilising people as assets for active ageing promotion: a multi-stakeholder perspective on peer volunteering initiatives
Authors: Stathi Afroditi , Withall Janet , Agyapong-Badu Sandra , Barrett Eva , Kritz Marlene , Wills Debbie , Thogersen-Ntoumani Cecilie , Fox Kenneth R.
Published: January 2021

Background

Successful peer volunteering is central to many community-based, active ageing initiatives. This study synthesises the perspectives of a range of stakeholders involved in peer volunteering initiatives and provides recommendations as to how peer volunteers can be effectively mobilised as community assets.

Methods

An evidence synthesis of qualitative data from (a) the evaluation of ACE (Active, Connected, Engaged), a feasibility trial of a peer volunteering active ageing intervention, and (b) interviews with volunteers and managers of third sector organisations providing peer volunteering programmes. Data were analysed using directed content analysis.

Results

Ten managers, 22 volunteers and 20 ACE participants were interviewed. The analysis identified six main themes, 33 higher and 22 sub themes. Main themes were: (i) Motives, (ii) Benefits, (iii) Skills and Characteristics, (iv) Challenges, (v) Training Needs, (vi) Recruitment and Retention. Altruism, changes in life circumstances, opportunities to reconnect with the community and personal fulfilment were the main reasons for volunteering. Volunteering was described as being personally rewarding, an avenue to acquire new skills and knowledge, and an opportunity for increased social connections and physical activity. Good peer volunteers are committed, reliable, have a good sense of humour, good interpersonal skills and are able to relate to participants. When pairing volunteers with participants, shared interests and geographical proximity are important to consider. Clarity of role, level of time commitment, regular feedback, recognition of effort and strong networks for on-going support are important strategies to facilitate volunteer retention.

Conclusions

The findings of this study support the value of peer volunteering as a strategy for mobilising community assets in promoting active ageing. To ensure success and longevity, these schemes require appropriate funding and efficient administrative support.
Early patellofemoral articular cartilage degeneration in a rat model of patellar instability is associated with activation of the NF-κB signaling pathway
Authors: Lin Wei , Kang Huijun , Dai Yike , Niu Yingzhen , Yang Guangmin , Niu Jinghui , Li Ming , Wang Fei
Published: January 2021

Background

Patellar instability (PI) often increases the possibility of lateral patellar dislocation and early osteoarthritis. The molecular mechanism of early articular cartilage degeneration during patellofemoral osteoarthritis (PFOA) still requires further investigation. However, it is known that the NF-κB signaling pathway plays an important role in articular cartilage degeneration. The aim of this study was to investigate the relationship between the NF-κB signaling pathway and patellofemoral joint cartilage degeneration.

Methods

We established a rat model of PI-induced PFOA. Female 4-week-old Sprague-Dawley rats (n = 120) were randomly divided into two groups: the PI (n = 60) and control group (n = 60). The distal femurs of the PI and control group were isolated and compared 4, 8, and 12 weeks after surgery. The morphological structure of the trochlear cartilage and subchondral bone were evaluated by micro-computed tomography and histology. The expression of NF-κB, matrix metalloproteinase (MMP)-13, collagen X, and TNF-ɑ were evaluated by immunohistochemistry and quantitative polymerase chain reaction.

Results

In the PI group, subchondral bone loss and cartilage degeneration were found 4 weeks after surgery. Compared with the control group, the protein and mRNA expression of NF-κB and TNF-ɑ were significantly increased 4, 8, and 12 weeks after surgery in the PI group. In addition, the markers of cartilage degeneration MMP-13 and collagen X were more highly expressed in the PI group compared with the control group at different time points after surgery.

Conclusions

This study has demonstrated that early patellofemoral joint cartilage degeneration can be caused by PI in growing rats, accompanied by significant subchondral bone loss and cartilage degeneration. In addition, the degeneration of articular cartilage may be associated with the activation of the NF-κB signaling pathway and can deteriorate with time as a result of PI.
Interventions to prevent anastomotic leak after esophageal surgery: a systematic review and meta-analysis
Authors: Grigor Emma J. M. , Kaaki Suha , Fergusson Dean A. , Maziak Donna E. , Seely Andrew J. E.
Published: January 2021

Background

Anastomotic leakage (AL) is a common and serious complication following esophagectomy. We aimed to provide an up-to-date review and critical appraisal of the efficacy and safety of all previous interventions aiming to reduce AL risk.

Methods

We searched MEDLINE and Embase from 1946 to January 2019 for randomized controlled trials (RCTs) evaluating interventions to minimize esophagogastric AL. Pooled risk ratios (RR) for AL were obtained using a random effects model.

Results

Two reviewers screened 441 abstracts and identified 17 RCTs eligible for inclusion; 11 studies were meta-analyzed. Omentoplasty significantly reduced the risk of AL by 78% [RR: 0.22; 95% CI: 0.10, 0.50] compared to conventional anastomosis (3 studies, n = 611 patients). Early removal of NG tube significantly reduced the risk of AL by 62% [RR: 0.38; 95% CI: 0.02, 0.65] compared to prolonged NG tube removal (2 studies, n = 293 patients); Stapled anastomosis did not significantly reduce the risk of AL [RR: 0.92; 95% CI: 0.45, 1.87] compared to hand-sewn anastomosis (6 studies, n = 1454 patients). The quality of evidence was high for omentoplasty (vs. conventional anastomosis), moderate for early NG tube removal (vs. prolonged NG tube removal), and very low for stapled anastomosis (vs. hand-sewn anastomosis).

Conclusions

This is the first meta-analysis to summarize the graded quality of evidence for all RCT interventions designed to reduce the risk of AL following esophagectomy. Our findings demonstrated that omentoplasty significantly reduced the risk of AL with a high quality of evidence. Although early NG tube removal significantly reduced AL risk, there is a need for further research to strengthen the quality of evidence for this finding. Evidence profiles presented in our review may help inform the development of future clinical practice recommendations.

Systematic review registration: CRD42019127181.
Effect of motor imagery and actual practice on learning professional medical skills
Authors: Collet Christian , Hajj Mahmoud El , Chaker Rawad , Bui-Xuan Bernard , Lehot Jean-Jacques , Hoyek Nady
Published: January 2021

Background

The peripheral venous catheter is the most frequently used medical device in hospital care to administer intravenous treatment or to take blood samples by introducing a catheter into a vein. The aim of this study was to examine the effect of motor imagery associated with actual training on the learning of peripheral venous catheter insertion into a simulated venous system.

Method

This was a prospective monocentre study in 3rd year medical students. Forty medical students were assigned to the experimental group (n = 20) performing both real practice and motor imagery of peripheral venous catheter insertion or to the control group (n = 20) trained through real practice only. We also recruited a reference group of 20 professional nurses defining the benchmark for a target performance.

Results

The experimental group learned the peripheral venous catheter insertion faster than the control group in the beginning of learning phase (p < 0.001), reaching the expected level after 4 sessions (p = .87) whereas the control group needed 5 sessions to reach the same level (p = .88). Both groups were at the same level at the end of the scheduled training.

Conclusions

Therefore, motor imagery improved professional motor skills learning, and limited the time needed to reach the expected level. Motor imagery may strengthen technical medical skill learning.
Model-based comorbidity clusters in patients with heart failure: association with clinical outcomes and healthcare utilization
Authors: Gulea Claudia , Zakeri Rosita , Quint Jennifer K.
Published: January 2021

Background

Comorbidities affect outcomes in heart failure (HF), but are not reflected in current HF classification. The aim of this study is to characterize HF groups that account for higher-order interactions between comorbidities and to investigate the association between comorbidity groups and outcomes.

Methods

Latent class analysis (LCA) was performed on 12 comorbidities from patients with HF identified from administrative claims data in the USA (OptumLabs Data Warehouse®) between 2008 and 2018. Associations with admission to hospital and mortality were assessed with Cox regression. Negative binomial regression was used to examine rates of healthcare use.

Results

In a population of 318,384 individuals, we identified five comorbidity clusters, named according to their dominant features: low-burden, metabolic-vascular, anemic, ischemic, and metabolic. Compared to the low-burden group (minimal comorbidities), patients in the metabolic-vascular group (exhibiting a pattern of diabetes, obesity, and vascular disease) had the worst prognosis for admission (HR 2.21, 95% CI 2.17–2.25) and death (HR 1.87, 95% CI 1.74–2.01), followed by the ischemic, anemic, and metabolic groups. The anemic group experienced an intermediate risk of admission (HR 1.49, 95% CI 1.44–1.54) and death (HR 1.46, 95% CI 1.30–1.64). Healthcare use also varied: the anemic group had the highest rate of outpatient visits, compared to the low-burden group (IRR 2.11, 95% CI 2.06–2.16); the metabolic-vascular and ischemic groups had the highest rate of admissions (IRR 2.11, 95% CI 2.08–2.15, and 2.11, 95% CI 2.07–2.15) and healthcare costs.

Conclusions

These data demonstrate the feasibility of using LCA to classify HF based on comorbidities alone and should encourage investigation of multidimensional approaches in comorbidity management to reduce admission and mortality risk among patients with HF.
The presence of antibiotic-resistant Staphylococcus spp. and Escherichia coli in smallholder pig farms in Uganda
Authors: Ikwap K. , Gertzell E. , Hansson I. , Dahlin L. , Selling K. , Magnusson U. , Dione M. , Jacobson M.
Published: January 2021

Background

The development of antimicrobial resistance is of global concern, and is commonly monitored by the analysis of certain bacteria. The aim of the present study was to study the antibiotic susceptibility in isolates of Staphylococcus spp. and Escherichia (E.) coli obtained from healthy pigs originating from nineteen herds enrolled in a study on herd health management in Lira district, northern Uganda. Skin and nasal swabs were analyzed for the presence of Staphylococcus spp., and selectively cultivated to investigate the presence of methicillin-resistant Staphylococcus (S.) aureus (MRSA), and rectal swabs were analyzed for the presence of E. coli. Antibiotic susceptibility was tested by broth micro-dilution. Information on the antibiotic usage and treatment regimens during the previous year was gathered using structured interviews and longitudinal data.

Results

In Staphylococcus spp., resistance to penicillin (10/19 isolates; 53%), fusidic acid (42%) and tetracycline (37%) were most commonly found. In E. coli, resistance to sulfamethoxazole (46/52 isolates; 88%), tetracycline (54%) and trimethoprim (17%) was most frequent. Methicillin-resistant S. aureus was found in one sample (1/50; 2%). Multi-drug resistant isolates of Staphylococcus spp. and E. coli were found in 54 and 47% of the herds, respectively. At the herd level, no associations could be made between antibiotic resistance and herd size or treatment regimens for either of the bacteria.

Conclusion

In conclusion, resistance to important antibiotics frequently used in animals in Uganda was common, and the presence of MRSA was demonstrated, in Ugandan pig herds.
Homeostasis model assessment, serum insulin and their relation to body fat in cats
Authors: Strage Emma M. , Ley Charles J. , Forkman Johannes , Öhlund Malin , Stadig Sarah , Bergh Anna , Ley Cecilia
Published: January 2021

Background

Obesity is associated with insulin resistance (IR) and considered a risk factor for diabetes mellitus (DM) in cats. It has been proposed that homeostasis model assessment (HOMA-IR), which is the product of fasting serum insulin (mU/L) and glucose (mmol/L) divided by 22.5, can be used to indicate IR. The objectives of this study were threefold: (i) to evaluate associations between body fat, fasting insulin, and HOMA-IR, (ii) to determine population-based reference interval of HOMA-IR in healthy lean cats, and (iii) to evaluate biological variation of HOMA-IR and fasting insulin in cats.

Results

150 cats were grouped as lean or overweight based on body condition score and in 68 of the cats body fat percentage (BF%) was estimated by computed tomography. Fasting serum insulin and glucose concentrations were analysed. Statistical differences in HOMA-IR and insulin between overweight or lean cats were evaluated using Wilcoxon rank-sum test. Robust method with Box-Cox transformation was used for calculating HOMA-IR reference interval in healthy lean cats. Relations between BF% and HOMA-IR and insulin were evaluated by regression analysis. Restricted maximum likelihood ratio was used to calculate indices of biological variation of HOMA-IR and insulin in seven cats.

There were significant differences between groups with overweight cats (n = 77) having higher HOMA-IR (p < 0.0001) and insulin (p = 0.0002) than lean cats (n = 73). Reference interval for HOMA-IR in lean cats was 0.1–3.0. HOMA-IR and fasting insulin concentrations showed similar significant positive association with BF% (p = 0.0010 andp = 0.0017, respectively). Within-animal coefficient of variation of HOMA-IR and insulin was 51% and 49%, respectively.

Conclusions

HOMA-IR and fasting insulin higher in overweight than lean cats and correlate to BF%. The established population-based reference interval for HOMA-IR as well as the indices of biological variation for HOMA-IR and fasting insulin may be used when interpreting HOMA-IR and fasting insulin in cats. Further studies are needed to evaluate if HOMA-IR or fasting insulin is useful for identifying cats at risk of developing DM.
Molecular characterisation of extended-spectrum ß-lactamase producing Escherichia coli in wild birds and cattle, Ibadan, Nigeria
Authors: Fashae Kayode , Engelmann Ines , Monecke Stefan , Braun Sascha D. , Ehricht Ralf
Published: January 2021

Background

Antimicrobial resistance (AMR) is an increasing global health concern reducing options for therapy of infections and also for perioperative prophylaxis. ManyEnterobacteriaceae cannot be treated anymore with third generation cephalosporins (3GC) due to the production of certain 3GC hydrolysing enzymes (extended spectrum beta-lactamases, ESBLs). The role of animals as carriers and vectors of multi-resistant bacteria in different geographical regions is poorly understood. Therefore, we investigated the occurrence and molecular characteristics of ESBL-producingEscherichia coli(E. coli) in wild birds and slaughtered cattle in Ibadan, Nigeria.

Cattle faecal samples (n= 250) and wild bird pooled faecal samples (cattle egrets,Bubulcus ibis,n= 28; white-faced whistling duck,Dendrocygna viduata, n= 24) were collected and cultured on cefotaxime-eosin methylene blue agar. Antimicrobial susceptibility was determined by agar diffusion assays and all 3GC resistant isolates were genotypically characterised for AMR genes, virulence associated genes (VAGs) and serotypes using DNA microarray-based assays.

Results

All 3GC resistant isolates wereE. coli: cattle (n= 53), egrets (n= 87) and whistling duck (n= 4); cultured from 32/250 (12.8%), 26/28 (92.9%), 2/24(8.3%), cattle, egrets and whistling duck faecal samples, respectively.blaCTX-M gene family was prevalent;blaCTX-M15 (83.3%) predominated overblaCTX-M9 (11.8%). All were susceptible to carbapenems. The majority of isolates were resistant to at least one of the other tested antimicrobials; multidrug resistance was highest in the isolates recovered from egrets.

The isolates harboured diverse repositories of other AMR genes (includingstrBand sul2), integrons (predominantly class 1) and VAGs. The isolates recovered from egrets harboured more AMR genes; eight were unique to these isolates includingtetG,gepA, andfloR. The prevalent VAGs includedhemLandiss; while 14 (includingsepA) were unique to certain animal isolates. E. coliserotypes O9:H9, O9:H30 and O9:H4 predominated. An identical phenotypic microarray profile was detected in three isolates from egrets and cattle, indicative of a clonal relationship amongst these isolates.

Conclusion

Wild birds and cattle harbour diverse ESBL-producingE. colipopulations with potential of inter-species dissemination and virulence. Recommended guidelines to balance public health and habitat conservation should be implemented with continuous surveillance.
Recombinant adenovirus expressing vesicular stomatitis virus G proteins induce both humoral and cell-mediated immune responses in mice and goats
Authors: Xue Xiaojuan , Yu Zhaorong , Jin Hongyan , Liang Lin , Li Jiayang , Li Xiaolu , Wang Yong , Cui Shangjin , Li Gang
Published: January 2021

Background

Vesicular stomatitis (VS) is an acute, highly contagious and economically important zoonotic disease caused by the vesicular stomatitis virus (VSV). There is a need for effective and safe stable recombinant vaccine for the control of the disease. The human type 5 replication-defective adenovirus expression vector is a good way to construct recombinant vaccines.

Results

Three recombinant adenoviruses (rAd) were successfully constructed that expressed the VSV Indiana serotype glycoprotein (VSV-IN-G), VSV New Jersey serotype glycoprotein (VSV-NJ-G), and the G fusion protein (both serotypes of G [VSV-IN-G-NJ-G]) with potentiality to induce protective immunity. G proteins were successfully expressed with good immunogenicity. The rAds could induce the production of VSV antibodies in mice, and VSV neutralizing antibodies in goats, respectively. The neutralizing antibody titers could reach 1:32 in mice and 1:64 in goats. The rAds induced strong lymphocyte proliferation in mice and goats, which was significantly higher compared to the negative control groups.

Conclusions

The three rAds constructed in the study expressed VSV-G proteins and induced both humoral and cellular immune responses in mice and goats. These results lay the foundation for further studies on the use of rAds in vaccines expressing VSV-G.
Aquaporin-4 protein expression in normal canine brains
Authors: Álvarez Patricia , Blasco Ester , Pumarola Martí , Wessmann Annette
Published: January 2021

Background

Aquaporin-4 (AQP4) is in growing recognition as potential marker for cancer progression, differentiation and therapeutic intervention. No information is available about AQP4 expression in the normal canine brain. The aim of this histopathological study is to confirm the presence of AQP4 by immunohistochemistry technique in a group of non-pathological canine brains and to describe its expression and distribution across the brain.

Results

Twelve non-pathological canine brains of various ages (ranging from 21 days to 17 years) and breeds were included in the study. Immunohistochemical expression of AQP4 was analyzed using formalin-fixed paraffin-embedded brain tissue sections. The findings were correlated between AQP4 expressing cells and astrocytes using glial fibrillary acidic protein (GFAP). AQP4 expression was more marked in the astrocyte foot processes of subpial, perivascular and periventricular surfaces in all specimens. The majority of the canine brain sections (9/12) presented with an AQP4 predilection for white matter tracts. Interestingly, the two youngest dogs (21 days and 3 months old) were characterized by diffuse AQP4 labelling in both grey and white matter tracts. This result may suggest that brain development and ageing may play a role in the AQP4 distribution throughout the canine brain.

Conclusions

This is the first study to describe immunohistochemical distribution of AQP4 in normal canine brains. The AQP4 expression and distribution in non-pathological canine brains was comparable to other species. Larger studies are needed to substantiate the influence of breed and ageing on AQP4 expression in the normal canine brain.
Dietary phenotype and advanced glycation end-products predict WTC-obstructive airways disease: a longitudinal observational study
Authors: Lam Rachel , Kwon Sophia , Riggs Jessica , Sunseri Maria , Crowley George , Schwartz Theresa , Zeig-Owens Rachel , Colbeth Hilary , Halpren Allison , Liu Mengling , Prezant David J. , Nolan Anna
Published: January 2021

Background

Diet is a modifier of metabolic syndrome which in turn is associated with World Trade Center obstructive airways disease (WTC-OAD). We have designed this study to (1) assess the dietary phenotype (food types, physical activity, and dietary habits) of the Fire Department of New York (FDNY) WTC-Health Program (WTC-HP) cohort and (2) quantify the association of dietary quality and its advanced glycation end product (AGE) content with the development of WTC-OAD.

Methods

WTC-OAD, defined as developing WTC-Lung Injury (WTC-LI; FEV1 < LLN) and/or airway hyperreactivity (AHR; positive methacholine and/or positive bronchodilator response). Rapid Eating and Activity Assessment for Participants-Short Version (REAP-S) deployed on 3/1/2018 in the WTC-HP annual monitoring assessment. Clinical and REAP-S data of consented subjects was extracted (7/17/2019). Diet quality [low-(15–19), moderate-(20–29), and high-(30–39)] and AGE content per REAP-S questionnaire were assessed for association with WTC-OAD. Regression models adjusted for smoking, hyperglycemia, hypertension, age on 9/11, WTC-exposure, BMI, and job description.

Results

N = 9508 completed the annual questionnaire, while N = 4015 completed REAP-S and had spirometry. WTC-OAD developed in N = 921, while N = 3094 never developed WTC-OAD. Low- and moderate-dietary quality, eating more (processed meats, fried foods, sugary drinks), fewer (vegetables, whole-grains),and having a diet abundant in AGEs were significantly associated with WTC-OAD. Smoking was not a significant risk factor of WTC-OAD.

Conclusions

REAP-S was successfully implemented in the FDNY WTC-HP monitoring questionnaire and produced valuable dietary phenotyping. Our observational study has identified low dietary quality and AGE abundant dietary habits as risk factors for pulmonary disease in the context of WTC-exposure. Dietary phenotyping, not only focuses our metabolomic/biomarker profiling but also further informs future dietary interventions that may positively impact particulate matter associated lung disease.
Surfactant therapy for COVID-19 related ARDS: a retrospective case–control pilot study
Authors: Piva Simone , DiBlasi Robert M. , Slee April E. , Jobe Alan H. , Roccaro Aldo M. , Filippini Matteo , Latronico Nicola , Bertoni Michele , Marshall John C. , Portman Michael A.
Published: January 2021

Background

COVID-19 causes acute respiratory distress syndrome (ARDS) and depletes the lungs of surfactant, leading to prolonged mechanical ventilation and death. The feasibility and safety of surfactant delivery in COVID-19 ARDS patients have not been established.

Methods

We performed retrospective analyses of data from patients receiving off-label use of exogenous natural surfactant during the COVID-19 pandemic. Seven COVID-19 PCR positive ARDS patients received liquid Curosurf (720 mg) in 150 ml normal saline, divided into five 30 ml aliquots) and delivered via a bronchoscope into second-generation bronchi. Patients were matched with 14 comparable subjects receiving supportive care for ARDS during the same time period. Feasibility and safety were examined as well as the duration of mechanical ventilation and mortality.

Results

Patients showed no evidence of acute decompensation following surfactant installation into minor bronchi. Cox regression showed a reduction of 28-days mortality within the surfactant group, though not significant. The surfactant did not increase the duration of ventilation, and health care providers did not convert to COVID-19 positive.

Conclusions

Surfactant delivery through bronchoscopy at a dose of 720 mg in 150 ml normal saline is feasible and safe for COVID-19 ARDS patients and health care providers during the pandemic. Surfactant administration did not cause acute decompensation, may reduce mortality and mechanical ventilation duration in COVID-19 ARDS patients. This study supports the future performance of randomized clinical trials evaluating the efficacy of meticulous sub-bronchial lavage with surfactant as treatment for patients with COVID-19 ARDS.
Hypoxia-induced Tie1 drives stemness and cisplatin resistance in non-small cell lung carcinoma cells
Authors: Li Chaojie , Yang Nannan , Chen Zhijin , Xia Ning , Shan Qungang , Wang Ziyin , Lu Jian , Shang Mingyi , Wang Zhongmin
Published: January 2021

Background

Drug resistance and metastasis involving hypoxic tumor environments and persistent stem cell populations are detrimental to the survival of patients with non-small cell lung carcinoma (NSCLC). Tie1 is upregulated in hypoxia and is believed to counteract the effectiveness of platinum agents by promoting the stemness properties in cells. We have investigated the association of Tie1 with HIF-1α and cisplatin resistance in NSCLC cell lines.

Methods

The expression of Tie1 in a pulmonary microvascular endothelial cell line (HPMEC) and NSCLC cell lines was detected using qRT-PCR and western blotting. The effect of Tie1 on cell stemness and migration was examined by sphere-forming and transwell assays in NSCLC cells with Tie1 silenced. The regulation of Tie1 by HIF-1α was evaluated by a dual-luciferase reporter assay and chromatin immunoprecipitation.

Results

We found that hypoxia could induce stemness and cisplatin resistance in vitro. Tie1 was expressed at low levels in NSCLC cells when compared with human pulmonary microvascular endothelial cells, however, its expression was increased by hypoxia. Additionally, Tie1 knockdown could reduce stemness properties and increase sensitivity to cisplatin in vitro and in a xenograft mouse model. The promoter of Tie1 contains two predicted hypoxia-response elements (HREs). We mutated both HRE sites and conducted chromatin immune-precipitation and promoter luciferase reporter assays and were able to conclude that the induction of Tie1 by hypoxia was HIF-1α-dependent.

Conclusions

Our findings indicated that Tie1 is upregulated in a hypoxic environment by HIF-1α and contributes to tumorigenesis and cisplatin resistance through the promotion of stemness in NSCLC cells.
The role of m6A, m5C and Ψ RNA modifications in cancer: Novel therapeutic opportunities
Authors: Nombela Paz , Miguel-López Borja , Blanco Sandra
Published: January 2021

RNA modifications have recently emerged as critical posttranscriptional regulators of gene expression programmes. Significant advances have been made in understanding the functional role of RNA modifications in regulating coding and non-coding RNA processing and function, which in turn thoroughly shape distinct gene expression programmes. They affect diverse biological processes, and the correct deposition of many of these modifications is required for normal development. Alterations of their deposition are implicated in several diseases, including cancer. In this Review, we focus on the occurrence of N6-methyladenosine (m6A), 5-methylcytosine (m5C) and pseudouridine (Ψ) in coding and non-coding RNAs and describe their physiopathological role in cancer. We will highlight the latest insights into the mechanisms of how these posttranscriptional modifications influence tumour development, maintenance, and progression. Finally, we will summarize the latest advances on the development of small molecule inhibitors that target specific writers or erasers to rewind the epitranscriptome of a cancer cell and their therapeutic potential.
The inflammatory kinase IKKα phosphorylates and stabilizes c-Myc and enhances its activity
Authors: Moser Bernhard , Hochreiter Bernhard , Basílio José , Gleitsmann Viola , Panhuber Anja , Pardo-Garcia Alan , Hoesel Bastian , Salzmann Manuel , Resch Ulrike , Noreen Mamoona , Schmid Johannes A.
Published: January 2021

Background

The IκB kinase (IKK) complex, comprising the two enzymes IKKα and IKKβ, is the main activator of the inflammatory transcription factor NF-κB, which is constitutively active in many cancers. While several connections between NF-κB signaling and the oncogene c-Myc have been shown, functional links between the signaling molecules are still poorly studied.

Methods

Molecular interactions were shown by co-immunoprecipitation and FRET microscopy. Phosphorylation of c-Myc was shown by kinases assays and its activity by improved reporter gene systems. CRISPR/Cas9-mediated gene knockout and chemical inhibition were used to block IKK activity. The turnover of c-Myc variants was determined by degradation in presence of cycloheximide and by optical pulse-chase experiments.. Immunofluorescence of mouse prostate tissue and bioinformatics of human datasets were applied to correlate IKKα- and c-Myc levels. Cell proliferation was assessed by EdU incorporation and apoptosis by flow cytometry.

Results

We show that IKKα and IKKβ bind to c-Myc and phosphorylate it at serines 67/71 within a sequence that is highly conserved. Knockout of IKKα decreased c-Myc-activity and increased its T58-phosphorylation, the target site for GSK3β, triggering polyubiquitination and degradation. c-Myc-mutants mimicking IKK-mediated S67/S71-phosphorylation exhibited slower turnover, higher cell proliferation and lower apoptosis, while the opposite was observed for non-phosphorylatable A67/A71-mutants. A significant positive correlation of c-Myc and IKKα levels was noticed in the prostate epithelium of mice and in a variety of human cancers.

Conclusions

Our data imply that IKKα phosphorylates c-Myc on serines-67/71, thereby stabilizing it, leading to increased transcriptional activity, higher proliferation and decreased apoptosis.
The immune response of T cells and therapeutic targets related to regulating the levels of T helper cells after ischaemic stroke
Authors: Lei Tian-Yu , Ye Ying-Ze , Zhu Xi-Qun , Smerin Daniel , Gu Li-Juan , Xiong Xiao-Xing , Zhang Hong-Fei , Jian Zhi-Hong
Published: January 2021

Through considerable effort in research and clinical studies, the immune system has been identified as a participant in the onset and progression of brain injury after ischaemic stroke. Due to the involvement of all types of immune cells, the roles of the immune system in stroke pathology and associated effects are complicated. Past research concentrated on the functions of monocytes and neutrophils in the pathogenesis of ischaemic stroke and tried to demonstrate the mechanisms of tissue injury and protection involving these immune cells. Within the past several years, an increasing number of studies have elucidated the vital functions of T cells in the innate and adaptive immune responses in both the acute and chronic phases of ischaemic stroke. Recently, the phenotypes of T cells with proinflammatory or anti-inflammatory function have been demonstrated in detail. T cells with distinctive phenotypes can also influence cerebral inflammation through various pathways, such as regulating the immune response, interacting with brain-resident immune cells and modulating neurogenesis and angiogenesis during different phases following stroke. In view of the limited treatment options available following stroke other than tissue plasminogen activator therapy, understanding the function of immune responses, especially T cell responses, in the post-stroke recovery period can provide a new therapeutic direction. Here, we discuss the different functions and temporal evolution of T cells with different phenotypes during the acute and chronic phases of ischaemic stroke. We suggest that modulating the balance between the proinflammatory and anti-inflammatory functions of T cells with distinct phenotypes may become a potential therapeutic approach that reduces the mortality and improves the functional outcomes and prognosis of patients suffering from ischaemic stroke.
Aging and CMV discordance are associated with increased immune diversity between monozygotic twins
Authors: Yan Zheng , Maecker Holden T. , Brodin Petter , Nygaard Unni C. , Lyu Shu Chen , Davis Mark M. , Nadeau Kari C. , Andorf Sandra
Published: January 2021

Background

Broadly, much of variance in immune system phenotype has been linked to the influence of non-heritable factors rather than genetics. In particular, two non-heritable factors: aging and human cytolomegavirus (CMV) infection, have been known to account for significant inter-individual immune variance. However, many specific relationships between them and immune composition remain unclear, especially between individuals over narrower age ranges. Further exploration of these relationships may be useful for informing personalized intervention development.

Results

To address this need, we evaluated 41 different cell type frequencies by mass cytometry and identified their relationships with aging and CMV seropositivity. Analyses were done using 60 healthy individuals, including 23 monozygotic twin pairs, categorized into young (12–31 years) and middle-aged (42–59 years). Aging and CMV discordance were associated with increased immune diversity between monozygotic twins overall, and particularly strongly in various T cell populations. Notably, we identified 17 and 11 cell subset frequencies as relatively influenced and uninfluenced by non-heritable factors, respectively, with results that largely matched those from studies on older-aged cohorts. Next, CD4+ T cell frequency was shown to diverge with age in twins, but with lower slope than in demographically similar non-twins, suggesting that much inter-individual variance in this cell type can be attributed to interactions between genetic and environmental factors. Several cell frequencies previously associated with memory inflation, such as CD27- CD8+ T cells and CD161+ CD4+ T cells, were positively correlated with CMV seropositivity, supporting findings that CMV infection may incur rapid aging of the immune system.

Conclusions

Our study confirms previous findings that aging, even within a relatively small age range and by mid-adulthood, and CMV seropositivity, both contribute significantly to inter-individual immune diversity. Notably, we identify several key immune cell subsets that vary considerably with aging, as well as others associated with memory inflation which correlate with CMV seropositivity.
Autophagy is involved in the replication of H9N2 influenza virus via the regulation of oxidative stress in alveolar epithelial cells
Authors: Zhang Rui-hua , Zhang Hong-liang , Li Pei-yao , Li Chun-hong , Gao Jing-ping , Li Jun , Xu Tong , Wang Xue-jing , Wang Cun-lian , Zhang Hui-chen , Xu Ming-ju , Tian Shu-fei
Published: January 2021

Background

Oxidative stress is an important pathogenic factor in influenza A virus infection. It has been found that reactive oxygen species induced by the H9N2 influenza virus is associated with viral replication. However, the mechanisms involved remain to be elucidated.

Methods

In this study, the role of autophagy was investigated in H9N2 influenza virus-induced oxidative stress and viral replication in A549 cells. Autophagy induced by H9N2 was inhibited by an autophagy inhibitor or RNA interference, the autophagy level, viral replication and the presence of oxidative stress were detected by western blot, TCID50 assay, and Real-time PCR. Then autophagy and oxidative stress were regulated, and viral replication was determined. At last, the Akt/TSC2/mTOR signaling pathways was detected by western blot.

Results

Autophagy was induced by the H9N2 influenza virus and the inhibition of autophagy reduced the viral titer and the expression of nucleoprotein and matrix protein. The blockage of autophagy suppressed the H9N2 virus-induced increase in the presence of oxidative stress, as evidenced by decreased reactive oxygen species production and malonaldehyde generation, and increased superoxide dismutase 1 levels. The changes in the viral titer and NP mRNA level caused by the antioxidant, N-acetyl-cysteine (NAC), and the oxidizing agent, H2O2, confirmed the involvement of oxidative stress in the control of viral replication. NAC plus transfection with Atg5 siRNA significantly reduced the viral titer and oxidative stress compared with NAC treatment alone, which confirmed that autophagy was involved in the replication of H9N2 influenza virus by regulating oxidative stress. Our data also revealed that autophagy was induced by the H9N2 influenza virus through the Akt/TSC2/mTOR pathway. The activation of Akt or the inhibition of TSC2 suppressed the H9N2 virus-induced increase in the level of LC3-II, restored the decrease in the expression of phospho-pAkt, phospho-mTOR and phospho-pS6 caused by H9N2 infection, suppressed the H9N2-induced increase in the presence of oxidative stress, and resulted in a decrease in the viral titer.

Conclusion

Autophagy is involved in H9N2 virus replication by regulating oxidative stress via the Akt/TSC2/mTOR signaling pathway. Thus, autophagy maybe a target which may be used to improve antiviral therapeutics.
The effect of improved dietary control on cognitive and psychiatric functioning in adults with phenylketonuria: the ReDAPT study
Authors: Burgess Nicholas M. , Kelso Wendy , Malpas Charles B. , Winton-Brown Toby , Fazio Timothy , Panetta Julie , De Jong Gerard , Neath Joanna , Atherton Sonny , Velakoulis Dennis , Walterfang Mark
Published: January 2021

Background

Phenylketonuria (PKU) is an autosomal recessive inherited disorder characterised by a deficiency in phenylalanine hydroxylase. Untreated, PKU is associated with a wide range of cognitive and psychiatric sequelae. Contemporary management guidelines recommend lifetime dietary control of phenylalanine (Phe) levels, however many individuals who discontinue dietary control subsequently suffer symptoms of anxiety, depression and disturbances to cognition. We undertook a prospective cohort study of patients with early-treated phenylketonuria who had ceased dietary control to test the hypothesis that resumption of dietary control of PKU is associated with improvements in measures of psychiatric morbidity and cognitive functioning.

Methods

We re-initiated dietary control for early-treated patients with PKU and monitored cognitive and psychiatric outcomes over a twelve-month period. Assessments included objective cognitive function (measured by cognitive proficiency index (CPI)), anxiety and depression scales. General linear mixed model (GLMM) analyses were performed to assess change in psychometric variables from baseline over twelve months after resumption of dietary control.

Results

A total of nine patients were recruited. Mean age was 33 years (SD = 8.75), five were female. Mean time off dietary control was 19.1 years (SD = 11.3), and mean baseline phenylalanine (Phe) levels were 1108 µmol/L (SD = 293). GLMM analysis demonstrated a positive relationship between CPI and time on diet (b = 0.56 [95% CI = 0.17, 0.95]). Age, time off diet, Phe levels and depression scores were not associated with cognitive function. There was a negative relationship between time on diet and anxiety (b = − 0.88 95% CI = [− 1.26, − 0.50]) and depression ratings (b = − 0.61, 95% CI = [− 0.95, − 0.26]).

Conclusions

This study demonstrated improvements in cognitive function, anxiety, and depression ratings associated with resumption of dietary control of PKU. Raw Phe levels were not strongly associated with psychiatric or cognitive scores in this cohort. These findings support the importance of lifelong treatment for PKU in improving the cognitive and psychiatric sequelae of the disease.