bluuebunny/crossref_metadata_2025 huggingface dataset:
“Cerberus” T Cells: A Glucocorticoid-Resistant, Multi-Pathogen Specific T Cell Product to Fight Infections in Severely Immunocompromised Patients
Authors: Koukoulias Kiriakos , Papayanni Penelope-Georgia , Georgakopoulou Aphrodite , Alvanou Maria , Laidou Stamatia , Kouimtzidis Anastasios , Pantazi Chrysoula , Gkoliou Glykeria , Vyzantiadis Timoleon-Achilleas , Spyridonidis Alexandros , Makris Antonios , Chatzidimitriou Anastasia , Psatha Nikoletta , Anagnostopoulos Achilles , Yannaki Evangelia , Papadopoulou Anastasia
Published: January 2021

Adoptive immunotherapy (AI) with pathogen-specific T cells is a promising alternative to pharmacotherapy for the treatment of opportunistic infections after allogeneic hematopoietic cell transplantation or solid organ transplantation. However, clinical implementation of AI is limited to patients not receiving high-dose steroids, a prerequisite for optimal T-cell function, practically excluding the most susceptible to infections patients from the benefits of AI. To address this issue, we here rapidly generated, clinical doses of a steroid-resistant T-cell product, simultaneously targeting four viruses (adenovirus, cytomegalovirus, Epstein Barr virus, and BK virus) and the fungus Aspergillus fumigatus, by genetic disruption of the glucocorticoid receptor (GR) gene using CRISPR/CAS9 ribonucleoprotein delivery. The product, “Cerberus” T cells (Cb-STs), was called after the monstrous three-headed dog of Greek mythology, due to its triple potential; specificity against viruses, specificity against fungi and resistance to glucocorticoids. Following efficient on-target GR disruption and minimal off-target editing, the generated Cb-STs maintained the characteristics of pentavalent-STs, their unedited counterparts, including polyclonality, memory immunophenotype, specificity, and cytotoxicity while they presented functional resistance to dexamethasone. Cb-STs may become a powerful, one-time treatment for severely immunosuppressed patients under glucocorticoids who suffer from multiple, life-threatening infections post-transplant, and for whom therapeutic choices are limited.
Case Report: Effective and Safe Treatment With Certolizumab Pegol in Pregnant Patients With Cogan’s Syndrome: A Report of Three Pregnancies in Two Patients
Authors: Venhoff Nils , Thiel Jens , Schramm Markus A. , Jandova Ilona , Voll Reinhard E. , Glaser Cornelia
Published: January 2021

Cogan’s syndrome is a rare autoimmune disease characterized by ocular inflammation and audiovestibular manifestations. Treatment consists of systemic glucocorticoids and other immunosuppressive agents including methotrexate, cyclophosphamide and TNF-α-inhibitors. Due to potential ovarian or fetal toxicity immunosuppressive treatment options are limited during pregnancies. Thus far there is a paucity of reports on pregnancies in Cogan’s syndrome. With minimal transplacental transfer, Certolizumab pegol is considered to be safe for the use in pregnant patients with underlying inflammatory diseases. However, there is no literature on the use of this TNF-α-inhibitor in Cogan’s syndrome in general and especially during gestation. Here we report three pregnancies in two Cogan’s Syndrome-patients treated with Certolizumab pegol. Treatment with Certolizumab pegol was effective and well tolerated in patients with Cogan’s syndrome and seems to be a safe treatment option during pregnancy.
Discrete Spawning Aggregations of the Loliginid Squid Doryteuthis gahi Reveal Life-History Interactions of a Dwarf Morphotype at the Center of Its Distribution Range
Authors: Carrasco Sergio A. , Bravo Macarena , Ibáñez Christian M. , Zapata-Hernández Germán
Published: January 2021

Heterogeneous environmental conditions along the Humboldt Current System (HCS) influence the life-history strategy of a variety of species in different ways. There is limited information on latitudinal traits of coastal cephalopods as part of the interacting species in pelagic and benthic environments. The present study used the loliginid squidDoryteuthis gahias a model organism to: (1) evaluate latitudinal traits on egg laying patterns, (2) characterize a particular spawning ground, (3) quantify the isotopic variation from different tissues, (4) evaluate potential trophic ontogenetic changes, (5) determinate trophic position, and (6) isotopically estimate the relative importance of putative preys in the squid’s assimilated diet. Results evidenced that egg-masses collected between 2014 and 2020 presented similar patterns along northern-central Chile (27–36°S), with females attaching small egg-capsules (10–50 mm length) through the year and over a variety of anthropogenic and natural substrates. At a small scale (Coquimbo; 29°S), early life history traits showed distinct patterns depending on SST, with warmer collection periods (∼18°C) evidencing larger capsules and smaller embryos, although small paralarvae were obtained over the 4-year sampling period. In this site, sampling of older ontogenetic stages supported the constant presence of small-sized squids (19–77 mm ML). Males had larger mean sizes compared to females and undetermined specimens, with a high proportion of mature stages. Observations in captivity were extended for up to 110 d, validating that small females (45–64 mm ML) spawn the small egg-capsules typically observed in the field. Differences in stable isotope composition between beaks and soft tissues of adult squids were lower for δ13C values (1.1 vs. 1.4‰, respectively) and higher for δ15N values (5.3 vs. 4.7‰, respectively). Isotopic composition through ontogeny found similar δ13C and δ15N values, suggesting that carbon sources (pelagic origin) and trophic position did not change significantly, with copepods, euphausiids and nereid polychaetes being the most important preys. This study unveils the permanent occurrence of a small reproductive morphotype ofD. gahiin shallow coastal habitats of northern-central Chile (i.e., center of the distribution range), providing the first insights for understanding the species’ potential adaptations to heterogeneous conditions in the HCS and the unexplored distribution gap between the two centers of abundance (Peru and the Falkland/Malvinas islands).
Association Between Anxiety and Depression and Nonalcoholic Fatty Liver Disease
Authors: Choi Ji Min , Chung Goh Eun , Kang Seung Joo , Kwak Min-Sun , Yang Jong In , Park Boram , Yim Jeong Yoon
Published: January 2021

Backgrounds: Depression and anxiety disorder are frequently seen in patients with nonalcoholic fatty liver disease (NAFLD). However, the associations between mood disorders and NAFLD have not been fully evaluated. In this study, we investigated the relationship between NAFLD and depression or anxiety in a Korean population.

Methods: We conducted a retrospective cross-sectional study that included subjects who underwent abdominal ultrasonography and completed a symptom questionnaire for a routine health check-up. NAFLD was diagnosed and graded according to the ultrasonography findings. Depression and anxiety were assessed using the Beck Depression Inventory and State-Trait Anxiety Inventory, respectively.

Results: Among the total of 25,333 subjects, the mean age was 47 years (men, 56.2%), and the prevalence rate of NAFLD was 30.9%. In the multivariate analysis, NAFLD showed a significant association with depression [adjusted odds ratio (OR) 1.43 and 95% confidence interval (CI) 1.14–1.80, p = 0.002] in women. Severe NAFLD significantly correlated with state anxiety and trait anxiety (adjusted OR 1.84 and 95% CI 1.01–3.37, p = 0.047 and adjusted OR 2.45 and 95% CI 1.08–4.85, p = 0.018, respectively) in women.

Conclusions: There was a higher tendency of women with NAFLD to suffer from depression with increase in steatosis, and severe stage of steatosis was significantly associated with anxiety in the female compared to non-NAFLD. Understanding the association between NAFLD and mood disorders may have clinical implications for reducing the prevalence of comorbidities.
Prognostic Value of a Clinical Biochemistry-Based Nomogram for Coronavirus Disease 2019
Authors: Yu Jing , Nie Lei , Wu Dongde , Chen Jian , Yang Zhifeng , Zhang Ling , Li Dongqing , Zhou Xia
Published: January 2021

Background: This study aimed to explore the predictive value of a clinical biochemistry-based nomogram in COVID-19.

Methods: The plasma or serum concentrations/levels of carcinoembryonic antigen (CEA) and other biomarkers, e.g., C-reactive protein (CRP), white blood cell (WBC), interleukin-6 (IL-6), ferritin (Fer), procalcitonin (PCT), lymphocyte percentage (L%), D-dimer (D2), and neutrophils percentage (Neu%), were assessed in 314 hospitalized patients with confirmed COVID-19. The area under the curve was used to estimate the diagnostic and prognostic value for COVID-19. Cox and logistic regression analyses were used to estimate the independent prognostic risk factors for the survival of patients with COVID-19.

Results: Receiver operating characteristic (ROC) curves were used to determine the area under the curve (AUC) values for CEA, IL-6, CRP, PCT, Fer, D-dimer levels and L%, Neu%, and WBC to assess disease classification. The critical values for these markers to predict severe disease type were then determined. The hazard ratio of prognosis for risk of COVID-19 identified CEA, WBC, CRP, PCT, Fer, D-dimer, Neu%, and L% as independent prognostic factors. For the nomogram of overall survival (OS), the C-index was 0.84, demonstrating a good discriminative performance.

Conclusions: An OS nomogram for the clinical diagnosis and treatment of COVID-19 was constructed using biomarkers. These data will be useful for the diagnosis, management, and therapy of COVID-19.
Acupuncture for Rehabilitation After Total Knee Arthroplasty: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Chen Zehua , Shen Zhen , Ye Xiangling , Xu Yanfei , Liu Jinqing , Shi Xiaodong , Chen Guoqian , Wu Jiatao , Chen Weijian , Jiang Tao , Liu Wengang , Xu Xuemeng
Published: January 2021

Background: There is an increasing interest in acupuncture for promoting post-operative rehabilitation, but the effectiveness of acupuncture for rehabilitation after total knee arthroplasty (TKA) remains controversial.

Objective: This study aims to investigate the effect of acupuncture on rehabilitation after TKA.

Methods: Database searches of PubMed, EMBASE, CINAHL, and China National Knowledge Infrastructure (CNKI) were conducted to obtain articles published until August 2020. All identified articles were screened, and data from each included study were extracted independently by two investigators. Meta-analysis was performed to examine the effects of acupuncture on pain, range of knee motion, function, and nausea/vomiting after TKA.

Results: A total of nine randomized clinical trials were included according to the inclusion and exclusion criteria in this review. Compared with routine treatment, acupuncture combined with routine treatment showed a significantly greater pain reduction at 8, 12, 24, and 48 h post-operatively after TKA. Meanwhile, we found that the acupuncture groups showed a significant function improvement and a lower percentage of nausea/vomiting in comparison with the control groups after operation. However, acupuncture groups demonstrated no statistically significant improvement in post-operative pain at 4 h, 7 days, 14 days, and more than 21 days, and no significant difference in range of knee motion was observed between the acupuncture groups and control groups after surgery.

Conclusions: Acupuncture, as a supplementary treatment after TKA, could improve function and reduce nausea/vomiting. However, the effect of acupuncture on pain relief may be mainly achieved within post-operative 48 h, and it had no efficacy in improving range of knee motion. More large-scale and high-quality studies are warranted.
Severe Influenza With Invasive Pulmonary Aspergillosis in Immunocompetent Hosts: A Retrospective Cohort Study
Authors: Duan Yishan , Ou Xinyan , Chen Yusha , Liang Binmiao , Ou Xuemei
Published: January 2021

Background: Influenza was an independent risk factor for invasive pulmonary aspergillosis (IPA). In light of increasing incidence and mortality of influenza associated aspergillosis, our study summarized risk factors, clinical characteristics, and prognostic factors of developing aspergillosis in immunocompetent hosts with influenza to further screen high-risk population and improve outcome.

Methods: We reviewed the patient characteristics, laboratory examinations, radiological imaging, and microbiology data of 72 influenza patients with IPA and 84 influenza patients without IPA admitted to West China Hospital.

Result: Our study shown that aspergillosis co-infection increased overall mortality of severe influenza from 22.6 to 52.8%, along with higher white blood count (WBC) (10.9 ± 5.0 vs. 8.4 ± 3.3, P = 0.016), Neutrophiles (9.5 ± 5.0 vs. 7.0 ± 3.8, P = 0.023), procalcitonin (PCT) (8.6 ± 15.9 vs. 1.2 ± 2.1, P = 0.009), and a lower CD4+ T cell count (189.2 ± 135.3 vs. 367.1 ± 280.0, P = 0.022) in death group. No impact of age, gender, underlying diseases, immunosuppressive agents and steroids use, CD4+ T cell count on incidence of influenza associated aspergillosis was observed. But influenza associated aspergillosis cases mostly accompanied with more H1N1 subtype (91.7 vs. 79.8%, P = 0.037) and higher level of C-reactive protein (CRP) (117.6 ± 88.1 vs. 78.5 ± 75.2, P = 0.017) and interleukin 6 (IL-6) (133.5 ± 149.2 vs. 69.9 ± 100.0, P = 0.021) than those without aspergillosis.

Conclusion: Aspergillosis co-infection in severe influenza patients can lead to a significant increased mortality, which was associated with severe respiratory failure due to mixed infection and immunosuppression. Pulmonary excessive inflammatory response was related with IPA co-infection.
Geographical Variability of Mineral Elements and Stability of Restrictive Mineral Elements in Terrestrial Cyanobacteria Across Gradients of Climate, Soil, and Atmospheric Wet Deposition Mineral Concentration
Authors: Wang Weibo , Li Hua , Guénon René , Yang Yuyi , Shu Xiao , Cheng Xiaoli , Zhang Quanfa
Published: January 2021

Terrestrial cyanobacteriaNostoc communeis an ideal species to study the geographical variation of mineral elements of soil cyanobacteria at the species level. Here, we first address the following questions: (1) from where are these mineral elements, (2) are there geographical variations for these mineral elements, and if so, (3) which environmental factors drive the geographical variation of these mineral elements? Second, we tested whether the soil cyanobacterial mineral elements followed the “restrictive element stability hypothesis” of higher plants. Finally, we explored the effect of mineral geographic variation on ecological adaptation of soil cyanobacteria. We collectedN. communesamples across gradients of climate, soil, and atmospheric wet deposition mineral concentration in mainland China. We measured fifteen minerals, including five macroelements (N, Ca, K, Fe, P), five microelements (Mn, Zn, Cu, Co, Se), and five heavy metals (Pb, Cr, As, Cd, Hg). We found that five elements (P, Cu, Zn, Co, Pb) had significant geographical variation. They increased as the distance from the equator increased and decreased as the distance from the prime meridian increased. Mean annual precipitation and mean annual temperature explained most of the variation. We did not find any significant correlations between the mineral element contents inN. communeand the minerals in soil and rainfall, except for P. There was no significant correlation between the variation coefficients of different elements and their actual detected contents and their potential physiological required contents. The statistical results of our experiment did not support the “restrictive element stability hypothesis.” We speculated that net accumulation of mineral elements in cyanobacterial cells and extracellular polysaccharides (EPS) might play an important role for terrestrial cyanobacteria in the adaptation to dry and cold conditions.
Polar Flagella Glycosylation in Aeromonas: Genomic Characterization and Involvement of a Specific Glycosyltransferase (Fgi-1) in Heterogeneous Flagella Glycosylation
Authors: Forn-Cuní Gabriel , Fulton Kelly M. , Smith Jeffrey C. , Twine Susan M. , Mendoza-Barberà Elena , Tomás Juan M. , Merino Susana
Published: January 2021

Polar flagella from mesophilic Aeromonas strains have previously been shown to be modified with a range of glycans. Mass spectrometry studies of purified polar flagellins suggested the glycan typically includes a putative pseudaminic acid like derivative; while some strains are modified with this single monosaccharide, others modified with a heterologous glycan. In the current study, we demonstrate that genes involved in polar flagella glycosylation are clustered in highly polymorphic genomic islands flanked by pseudaminic acid biosynthetic genes (pse). Bioinformatic analysis of mesophilic Aeromonas genomes identified three types of polar flagella glycosylation islands (FGIs), denoted Group I, II and III. FGI Groups I and III are small genomic islands present in Aeromonas strains with flagellins modified with a single monosaccharide pseudaminic acid derivative. Group II were large genomic islands, present in strains found to modify polar flagellins with heterogeneous glycan moieties. Group II, in addition to pse genes, contained numerous glycosyltransferases and other biosynthetic enzymes. All Group II strains shared a common glycosyltransferase downstream of luxC that we named flagella glycosylation island 1, fgi-1, in A. piscicola AH-3. We demonstrate that Fgi-1 transfers the first sugar of the heterogeneous glycan to the pseudaminic acid derivative linked to polar flagellins and could be used as marker for polysaccharidic glycosylation of Aeromonas polar flagella.
Genome-Based Analysis of a Sequence Type 1049 Hypervirulent Klebsiella pneumoniae Causing Bacteremic Neck Abscess
Authors: Lan Peng , Zhao Dongdong , Gu Jiong , Shi Qiucheng , Yan Rushuang , Jiang Yan , Zhou Jiancang , Yu Yunsong
Published: January 2021

Hypervirulent Klebsiella pneumoniae (hvKP) has raised grave concerns in recent years and can cause severe infections with diverse anatomic locations including liver abscess, meningitis, and endophthalmitis. However, there is limited data about neck abscess caused by hvKP. A K. pneumoniae strain Kp_whw was isolated from neck abscess. We characterized the genetic background, virulence determinates of the strain by genomic analysis and dertermined the virulence level by serum resistance assay. Kp_whw belonged to sequence type (ST) 1049 K locus (KL) 5. Kp_whw showed hypermucoviscosity phenotype and was resistant to ampicillin but susceptible to the majority of the other antimicrobial agents. A pLVPK-like virulence plasmid and a chromosomal ICEKp5-like mobile genetic element were carried by Kp_whw, resulting in the risk of dissemination of hypervirulence. The strain exhibited relative higher level of core genome allelic diversity than accessory genome profile, in comparison to hvKP of K1/K2 serotype. Kp_whw was finally demonstrated as virulent as the ST23 K1 serotype hvKP strain NTUH-K2044 in vitro. In conclusion, this work elaborates the genetic background of a clinical hvKP strain with an uncommon ST, reinforcing our understanding of virulence mechanisms of hvKP.
Whole-Genome Phylogenetic Analysis Reveals a Wide Diversity of Non-O157 STEC Isolated From Ground Beef and Cattle Feces
Authors: Gutiérrez Sebastián , Díaz Leonela , Reyes-Jara Angélica , Yang Xun , Meng Jianghong , González-Escalona Narjol , Toro Magaly
Published: January 2021

Shiga toxin-producing Escherichia coli (STEC) causes foodborne outbreaks that can lead to complications such as hemolytic uremic syndrome. Their main reservoir is cattle, and ground beef has been frequently associated with disease and outbreaks. In this study, we attempted to understand the genetic relationship among STEC isolated in Chile from different sources, their relationship to STEC from the rest of the world, and to identify molecular markers of Chilean STEC. We sequenced 62 STEC isolated in Chile using MiSeq Illumina. In silico typing was determined using tools of the Center Genomic Epidemiology, Denmark University (CGE/DTU). Genomes of our local STEC collection were compared with 113 STEC isolated worldwide through a core genome MLST (cgMLST) approach, and we also searched for distinct genes to be used as molecular markers of Chilean isolates. Genomes in our local collection were grouped based on serogroup and sequence type, and clusters were formed within local STEC. In the worldwide STEC analysis, Chilean STEC did not cluster with genomes of the rest of the world suggesting that they are not phylogenetically related to previously described STEC. The pangenome of our STEC collection was 11,650 genes, but we did not identify distinct molecular markers of local STEC. Our results showed that there may be local emerging STEC with unique features, nevertheless, no molecular markers were detected. Therefore, there might be elements such as a syntenic organization that might explain differential clustering detected between local and worldwide STEC.
CRISPR-Cas13-Mediated Knockdown of lncRNA-GACAT3 Inhibited Cell Proliferation and Motility, and Induced Apoptosis by Increasing p21, Bax, and E-Cadherin Expression in Bladder Cancer
Authors: Zhang Zhongfu , Chen Jieqing , Zhu Zhongshuang , Zhu Zhongqing , Liao Xinhui , Wu Jianting , Cheng Jianli , Zhang Xintao , Mei Hongbing , Yang Guosheng
Published: January 2021

The current study is to investigate the expression pattern and biological function of long non-coding RNA Focally gastric cancer-associated transcript3 (GACAT3) in bladder cancer. Real-time quantitative qPCR was used to detect the expression level of GACAT-3 in tumor tissues and paired normal tissues. Human bladder cancer T24 and 5637 cell lines were transiently transfected with specific CRISPR-Cas13 or negative control CRISPR-Cas13. Cell migration, proliferation, and apoptosis were measured by using wound healing assay CCK-8 assay and Caspase-3 ELISA assay, respectively. The expression changes of p21, Bax, and E-cadherin after knockdown of GACAT3 were detected by using Western blot. The results demonstrated that GACAT3 was up-regulated in bladder cancer tissues than that in the paired normal tissues. Inhibition of cell proliferation, increased apoptosis, and decreased motility were observed in T24 and 5637 cell lines transfected by CRISPR-Cas13 targeting GACAT3. Downregulation of GACAT3 increased p21, Bax, and E-cadherin expression and silencing these genes could eliminate the phenotypic changes induced by knockdown of GACAT3. A ceRNA mechanism for GACAT3 was also revealed. By using CRISPR-Cas13 biotechnology, we suggested that GACAT3 may be a novel target for diagnosis and treatment of bladder cancer.
Risk Factors of Vitamin D Deficiency in Chinese Ischemic Stroke Patients: A Cross-Sectional Study
Authors: Miao Hanpei , Zhu Hanyu , Luan Xiaoqian , Huang Guiqian , Chen Meixia , Yuan Zhengzhong , Wang Zhen
Published: January 2021

Purpose

Lower serum vitamin D has been reported to be associated with stroke. This study aimed to analyze the risk factors of vitamin deficiency in Chinese stroke patients, and further analyze its impact in different gender and their clinical variables.

Methods

982 stroke patients were enrolled. Laboratory parameters such as serum vitamin D, apolipoprotein A-I (ApoA-I), apolipoprotein B (ApoB), ApoA-I/ApoB, cholesterol (CH), fibrinogen (FIB), blood glucose (Glu), high-density lipoprotein (HDL), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were collected and recorded. The severity of stroke was assessed by National Institute of Health Stroke Scale (NIHSS) score. Based on their serum vitamin D level, patients were divided into three groups: Vitamin D deficiency (<50 nmol/L), vitamin D insufficiency (≥50–75 nmol/L) and vitamin D sufficiency (≥75 nmol/L) and differences were compared among the three groups. Statistical analyses were done to assess the risk factors for serum vitamin D deficiency in our ischemic stroke patients.

Results

Gender, NIHSS, and FIB showed significant differences among the vitamin D groups (P < 0.001 ∼ P = 0.002). The female gender (OR = 2.422, P < 0.001), severity of stroke using NIHSS (OR = 1.055, P = 0.008) and FIB (OR = 1.256, P = 0.005) were risk factors of vitamin D deficiency in ischemic stroke patients. In subgroup analysis, NIHSS was significantly associated with vitamin D deficiency in the male group (OR = 1.087, P = 0.002) and higher FIB group (OR = 1.078, P = 0.001).

Conclusions

The female gender, severity of stroke using NIHSS and FIB were risk factors for vitamin D deficiency in our incident stroke patients. NIHSS was more sensitive to vitamin D deficiency in male ischemic stroke patients. Besides, under higher FIB circumstance, the increasing NIHSS score was more related to the vitamin D deficiency. Levels of vitamin D in patients with ischemic stroke should be well monitored during the disease cascade.
Digging Signatures in 13-Month-Old 3xTg-AD Mice for Alzheimer's Disease and Its Disruption by Isolation Despite Social Life Since They Were Born
Authors: Gimenez-Llort Lydia , Alveal-Mellado Daniel
Published: January 2021

The severity of this pandemic's scenarios will leave significant psychological traces in low resistant and resilient individuals. Increased incidence of depression, anxiety, obsessive-compulsive disorder (OCD), and post-traumatic stress disorder has already been reported. The loss of human lives and the implementation of physical distance measures in the pandemic and post-COVID scenarios may have a greater impact on the elderly, mostly in those with dementia, as OCD and other neuropsychiatric symptoms (NPS) are quite prevalent in this population. Modeling NPS in animals relies in neuroethological perspectives since the response to new situations and traumatic events, critical for survival and adaptation to the environment, is strongly preserved in the phylogeny. In the laboratory, mice dig vigorously in deep bedding to bury food pellets or small objects they may find. This behavior, initially used to screen anxiolytic activity, was later proposed to model better meaningless repetitive and perseverative behaviors characteristic of OCD or autism spectrum disorders. Other authors found that digging can also be understood as part of the expression of the animals' general activity. In the present brief report, we studied the digging ethograms in 13-month-old non-transgenic and 3xTg-AD mice modeling normal aging and advanced Alzheimer's disease (AD), respectively. This genetic model presents AD-like cognitive dysfunction and NPS-like phenotype, with high mortality rates at this age, mostly in males. This allowed us to observe the digging pattern's disruption in a subgroup of 3xTg-AD mice that survived to their cage mates. Two digging paradigms involving different anxiogenic and contextual situations were used to investigate their behavior. The temporal course and intensity of digging were found to increase in those 3xTg-AD mice that had lost their “room partners” despite having lived in social structures since they were born. However, when tested under neophobia conditions, this behavior's incidence was low (delayed), and the temporal pattern was disrupted, suggesting worsening of this NPS-like profile. The outcomes showed that this combined behavioral paradigm unveiled distinct features of digging signatures that can be useful to study these perseverative behaviors and their interplay with anxiety states already present in the AD scenario and their worsening by naturalistic/forced isolation.
A Physical Perspective to the Inductive Function of Myelin—A Missing Piece of Neuroscience
Authors: Wang Hao , Wang Jiahui , Cai Guangyi , Liu Yonghong , Qu Yansong , Wu Tianzhun
Published: January 2021

Starting from the inductance in neurons, two physical origins are discussed, which are the coil inductance of myelin and the piezoelectric effect of the cell membrane. The direct evidence of the coil inductance of myelin is the opposite spiraling phenomenon between adjacent myelin sheaths confirmed by previous studies. As for the piezoelectric effect of the cell membrane, which has been well-known in physics, the direct evidence is the mechanical wave accompany with action potential. Therefore, a more complete physical nature of neural signals is provided. In conventional neuroscience, the neural signal is a pure electrical signal. In our new theory, the neural signal is an energy pulse containing electrical, magnetic, and mechanical components. Such a physical understanding of the neural signal and neural systems significantly improve the knowledge of the neurons. On the one hand, we achieve a corrected neural circuit of an inductor-capacitor-capacitor (LCC) form, whose frequency response and electrical characteristics have been validated by previous studies and the modeling fitting of artifacts in our experiments. On the other hand, a number of phenomena observed in neural experiments are explained. In particular, they are the mechanism of magnetic nerve stimulations and ultrasound nerve stimulations, the MRI image contrast issue and Anode Break Excitation. At last, the biological function of myelin is summarized. It is to provide inductance in the process of neural signal, which can enhance the signal speed in peripheral nervous systems and provide frequency modulation function in central nervous systems.
Efficacy of an Interdisciplinary Intensive Outpatient Program in Treating Combat-Related Traumatic Brain Injury and Psychological Health Conditions
Authors: DeGraba Thomas J. , Williams Kathy , Koffman Robert , Bell Jennifer L. , Pettit Wendy , Kelly James P. , Dittmer Travis A. , Nussbaum George , Grammer Geoffrey , Bleiberg Joseph , French Louis M , Pickett Treven C.
Published: January 2021

Background: Since 2000, over 413,000 US service members (SM) experienced at least one traumatic brain injury (TBI), and 40% of those with in-theater TBIs later screened positive for comorbid psychological health (PH) conditions, including post-traumatic stress disorder (PTSD), depression, and anxiety. Many SMs with these persistent symptoms fail to achieve a recovery that results in a desirable quality of life or return to full duty. Limited information exists though to guide treatment for SMs with a history of mild TBI (mTBI) and comorbid PH conditions. This report presents the methods and outcomes of an interdisciplinary intensive outpatient program (IOP) in the treatment of SMs with combat-related mTBI and PH comorbidities. The IOP combines conventional rehabilitation therapies and integrative medicine techniques with the goal of reducing morbidity in multiple neurological and behavioral health domains and enhancing military readiness.

Methods: SMs (n = 1,456) with residual symptoms from mTBI and comorbid PH conditions were treated in a 4-week IOP at the National Intrepid Center of Excellence (NICoE) at Walter Reed National Military Medical Center (WRNMMC). The IOP uses an interdisciplinary, holistic, and patient-centric rehabilitative care model. Interdisciplinary teams provide a diagnostic workup of neurological, psychiatric, and existential injuries, and from these assessments, individualized care plans are developed. Treatment response was assessed using the Neurobehavioral Symptom Inventory (NSI), PTSD Checklist—Military Version (PCL-M), Satisfaction With Life Scale (SWLS), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Epworth Sleepiness Scale (ESS), and Headache Impact Test-6 (HIT-6) and administered at admission, discharge, and at 1, 3, and 6 months post-discharge.

Findings: Following treatment in the IOP, the symptomatic patients had statistically significant and clinically meaningful improvements across all outcome measures. The largest effect size was seen with GAD-7 (r = 0.59), followed by PHQ-8 (r = 0.56), NSI (r = 0.55), PCL-M (r = 0.52), ESS (r = 0.50), SWLS (r = 0.49), and HIT-6 (r = 0.42). In cross-sectional follow ups, the significant improvements were sustained at 1, 3, and 6 months post-discharge.

Interpretation: This report demonstrates that an interdisciplinary IOP achieves significant and sustainable symptom recovery in SMs with combat-related mTBI and comorbid PH conditions and supports the further study of this model of care in complex medical conditions.
The Migraine-Anxiety Comorbidity Among Migraineurs: A Systematic Review
Authors: Karimi Leila , Wijeratne Tissa , Crewther Sheila Gillard , Evans Andrew E. , Ebaid Deena , Khalil Hanan
Published: January 2021

Background: Migraine is recognized as a neurological condition that is often associated with comorbid psychiatric symptoms such as anxiety, depression, bipolar disorder and/or panic disorder. Though some studies have demonstrated the link between migraine and anxiety disorders, there are no systematic reviews that have been published in this area to summarize the evidence. The aim of the present study is to systematically review the literature associated with comorbidity of migraine and anxiety disorders among migraineurs compared to non-migraineurs.

Methods: The present systematic review included population-based, cohort and cross-sectional studies if they were reporting the frequency of migraine with either anxiety or depression as diagnosed by a medical practitioner according to the International Classification of Headache Disorders (ICHD-2/3).

Results: Eight eligible studies from 2060 relevant citations were included in the review. All participants were migraine patients from both primary care and outpatient settings, as well as tertiary headache and anxiety centers, and were compared to non-migraineurs. The results of the systematic review showed that there is a strong and consistent relationship between migraine and anxiety. The co-morbidity of co-occurrence for migraine and anxiety has an average OR of 2.33 (2.20–2.47) among the prevalence and cross sectional studies and an average RR of 1.63 (1.37–1.93) for two cohort studies; The major limitations of included studies were small sample sizes and a lack of adjusting of confounding factors.

Conclusion: The results highlight the need for inclusion of an anxiety screening tool during initial assessments of migraine patients by medical practitioners and/or physicians and may explain why some anxiolytic medications work better than others for migraine mitigation.
Circadian and Sleep Dysfunctions in Neurodegenerative Disorders—An Update
Authors: Fifel Karim , Videnovic Aleksandar
Published: January 2021

Disruptions of sleep and circadian rhythms are among the most debilitating symptoms in patients with neurodegenerative diseases. Their underlying pathophysiology is multilayered and multifactorial. Recent evidence suggests that sleep and circadian disturbances may influence the neurodegenerative processes as well as be their consequence. In this perspective, we provide an update of the current understanding of sleep and circadian dysregulation in Alzheimer’s, Parkinson’s, and Huntington’s diseases.
Risk Factors for Renal Impairment in Adult Patients With Short Bowel Syndrome
Authors: Wang Peng , Yang Jianbo , Zhang Yupeng , Zhang Li , Gao Xuejin , Wang Xinying
Published: January 2021

Renal impairment is a common complication in patients with intestinal failure that is mostly caused by short bowel syndrome (SBS) and is associated with adverse outcomes that severely affect the quality of life or even survival. The prevalence and risk factors for renal impairment in patients with SBS remain unclarified. Therefore, we aimed to determine the prevalence of renal impairment and identify potential risk factors for renal impairment in adult patients with SBS. We retrospectively identified 199 patients diagnosed with SBS admitted to the Department of General Surgery between January 1, 2012 and January 1, 2019, from a prospectively maintained database. Overall, 56 patients (28.1%) with decreased renal function (eGFR < 90 mL/min/1.73 m2). The median duration of SBS was 7 months (IQR, 3–31 months) and the mean eGFR was 103.1 ± 39.4 mL/min/1.73 m2. Logistic regression modeling indicated that older age [odds ratio (OR), 1.074; 95% CI, 1.037–1.112,P< 0.001], kidney stones (OR, 4.887; 95% CI, 1.753–13.626;P= 0.002), decreased length of the small intestine (OR, 0.988; 95% CI, 0.979–0.998;P= 0.019), and prolonged duration of SBS (OR, 1.007; 95% CI, 1.001–1.013;P= 0.046) were significant risk factors for renal impairment. This is the largest study that has specifically explored the risk factors for renal impairment in a large cohort of adults with SBS. The present study showed that renal function should be closely monitored during treatment, and patients should be given prophylactic interventions if necessary. This retrospective study is a part of clinical study NCT03277014, registered in ClinicalTrials.gov PRS. And the PRS URL ishttp://register.clinicaltrials.gov.
Pulmonary Micro-Ecological Changes and Potential Microbial Markers in Lung Cancer Patients
Authors: Ran Zhuonan , Liu Jiexing , Wang Fen , Xin Caiyan , Xiong Bin , Song Zhangyong
Published: January 2021

The relationship between the microbiome and disease has been investigated for many years. As a highly malignant tumor, biomarkers for lung cancer are diverse. However, precision of these biomarkers has not yet been achieved. It has been confirmed that lung microecology changes in lung cancer patients compared with healthy individuals. Furthermore, the abundance of some bacterial species shows obvious changes, suggesting their potential use as a microbial marker for the detection of lung cancer. In addition, recent studies have confirmed that inflammation, immune response, virulence factors, and metabolism may be potential mechanisms linking the microbiome with carcinogenesis. In this review, microbiome studies of lung cancer, potential mechanisms, potential microbial markers, and the influence of the microbiome on the diagnosis and treatment of lung cancer are summarized, providing theoretical strategies for the diagnosis and treatment of lung cancer.
Chinese Medicine Formula PSORI-CM02 Alleviates Psoriatic Dermatitis via M-MDSCs and Th17 Crosstalk
Authors: Deng Jingwen , Tan Siyi , Liu Ruonan , Yu Wanlin , Chen Haiming , Tang Nan , Han Ling , Lu Chuanjian
Published: January 2021

Psoriasis is a chronic inflammatory skin disease that is associated with multiple coexisting conditions. Extensive literature suggests that psoriasis is a T-cell-mediated condition, and its pathogenesis is related to dysfunction of the immune system. Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous myeloid cells that have suppressive effects on T cells. MDSCs are present at very low levels in healthy individuals but can substantially expand in tumours or inflammatory conditions. PSORI-CM02, a Chinese medical formula designed based on the Chinese medicine theory (Blood Stasis), has been prescribed extensively for psoriasis therapy and shows a stable clinical effect and safety. This study discusses the mechanisms of MDSCs involved in disease development and therapeutic progress. Our data provides evidence that monocytic myeloid-derived suppressor cells (M-MDSCs) play a role in IMQ-induced psoriatic dermatitis. Functional characterization and correlation analysis indicated that MDSCs are positively correlated with Th17 cells. PSORI-CM02 alleviated IMQ-induced psoriatic dermatitis and suppressed the proliferation of Th17 cells via M-MDSC-induced Arg1 upregulation, suggesting M-MDSCs could be a novel therapeutic target for psoriasis, and PSORI-CM02 exerted its effects via the perturbation of M-MDSCs and Th17 cell crosstalk.
Tsantan Sumtang Restored Right Ventricular Function in Chronic Hypoxia-Induced Pulmonary Hypertension Rats
Authors: Yang Zhanting , Sun Haixia , Su Shanshan , Nan Xingmei , Li Ke , Jin Xueqin , Jin Guoen , Li Zhanqiang , Lu Dianxiang
Published: January 2021

Background: Tsantan Sumtang originated from Four Tantras, which consisted of Choerospondias axillaris (Roxb.) B. L. Burtt and A. W. Hill, Santalum album L., and Myristica fragrans Houtt. The three herbs are in ratio 1:1:1. This medication is widely used for cardiovascular diseases.

Aims: The purpose of this study was to explore the effect of Tsantan Sumtang on right ventricular (RV) function in hypoxia-induced pulmonary hypertension (HPH) rats and investigate the underlying mechanism.

Methods: Sixty male Sprague-Dawley (SD) rats were divided into control, hypoxia, and hypoxia + Tsantan Sumtang (1.0, 1.25, and 1.5 g•kg−1•d−1) groups. Chronic hypoxia was induced by putting the rats inside a hypobaric chamber for four weeks and adjusting the inner pressure and oxygen content to match an altitude of 4500 m. Echocardiography was used to assess RV function and right ventricular-pulmonary arterial (RV-PA) coupling. The physiological parameters of the animals were also evaluated. Morphological characteristics of RV were assessed by hematoxylin and eosin (H&E) staining and TEM. Masson’s trichrome staining, immunohistochemical staining, western blotting, and TUNEL assay were used to assess fibrosis and apoptosis levels. The antioxidant and anti-apoptosis properties of Tsantan Sumtang were also evaluated. The effect of Tsantan Sumtang on ROCK signaling pathway was evaluated using real-time quantitative PCR and western blotting.

Results: We established an HPH rat model as indicated by the significant increases in the physiological parameters of the rats. Tsantan Sumtang showed a significant cardiac-protective function and an improved effect on RV-PA coupling. Moreover, Tsantan Sumtang treatment inhibited fibrosis and alleviated apoptosis and oxidative stress in RV. In terms of mechanism, Tsantan Sumtang reduced the expression of ROCK (ROCK1, ROCK2) in RV, inhibited cardiac remodeling-related transcription factors (NFATc3, P-STAT3), and regulated apoptosis-related proteins.

Conclusion: Tsantan Sumtang was able to restore RV function, improve RV-PA coupling, recover hemodynamic and hematological indexes, and protect RV against structural maladaptive remodeling in the HPH rats. These findings demonstrated that Tsantan Sumtang protects the function of RV in HPH rats. The antioxidant and anti-apoptosis properties of Tsantan Sumtang may be responsible for inhibiting the ROCK signaling pathway.
The Prevalence of Selected Potential Drug-Drug Interactions of Analgesic Drugs and Possible Methods of Preventing Them: Lessons Learned From the Analysis of the Real-World National Database of 38 Million Citizens of Poland
Authors: Kardas Przemysław , Urbański Filip , Lichwierowicz Aneta , Chudzyńska Ewa , Czech Marcin , Makowska Katarzyna , Kardas Grzegorz
Published: January 2021

Introduction: Drug-drug interactions may lead to poor health outcomes, as well as increased costs and utilization of healthcare services. Unfortunately, real-world data continuously prove high prevalence of potential drug-drug interactions (pDDIs) worldwide. Among identified drivers, ageing, multimorbidity and polypharmacy play a very important role. With these factors being widespread, the need for implementation of strategies minimizing the burden of pDDIs becomes an urgency. This, however, requires a better understanding of the prevalence of pDDIs and the underlying causative factors.

Aim of study: To assess the real-world prevalence of pDDIs and its characteristics in the general population of Poland, using analgesic drugs as a model, and to find out whether pDDIs are caused by prescribing coming from the very same prescribers (co-prescribing).

Methods: A retrospective analysis of the 2018 dispensation data of the National Health Fund (NHF) - the only Polish public healthcare payer organization with nationwide coverage. We searched for selected pDDIs of non-steroidal anti-inflammatory drugs (NSAIDs) with antihypertensives, other NSAIDs (double use), oral glucocorticoids, oral anticoagulants, selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and antiplatelet drugs; as well as opioides with SSRIs, SNRIs, gabapentinoids, and benzodiazepines. A pDDI was deemed present if two drugs standing in a possible conflict were dispensed within the same calendar month.

Results: Out of 38.4 million citizens of Poland, 23.3 million were dispensed prescribed drugs reimbursed by NHF in 2018. In this cohort, we have identified 2,485,787 cases of analgesic drug pDDIs, corresponding with 6.47% of the Polish population. Out of these, the most prevalent pDDI was caused by “NSAIDs + antihypertensives” (1,583,575 cases, i.e., 4.12% of the Polish population), followed by “NSAIDs + NSAIDs” (538,640, 1.40%) and “NSAIDs + glucocorticoids” (213,504, 0.56%). The most persistent pDDIs among those studied were caused by “Opioids + Gabapentinoids” (2.19, 95%CI: 2.16–2.22 months). On average, 76.63% of all cases of pDDIs were caused by drugs prescribed by the very same prescribers.

Conclusion: Based on high-quality, nationwide data, we have found a high prevalence of analgesic drugs-related pDDIs in Poland. Over ¾ of the identified pDDIs were caused by co-prescribing, i.e., prescriptions issued by the same prescribers. The significance of the problem, illustrated with our findings on analgesic drugs-related pDDIs in Poland, deserves much more scientific and policymaker attention.
Gut Microbiota and Related Metabolites Were Disturbed in Ulcerative Colitis and Partly Restored After Mesalamine Treatment
Authors: Dai Liang , Tang Yingjue , Zhou Wenjun , Dang Yanqi , Sun Qiaoli , Tang Zhipeng , Zhu Mingzhe , Ji Guang
Published: January 2021

Mesalamine has been well used in the improvement of ulcerative colitis (UC) in clinics, however, the underlying mechanisms were not well illustrated. To explore its efficacy from the perspective of gut microbiota and related metabolites, we employed 16S rRNA sequencing and metabolomics approaches in stool samples across 14 normal healthy controls (NC group), 10 treatment-naïve UC patients (UC group) and 14 UC patients responded to mesalamine treatment (mesalamine group). We noted that the gut microbiota diversity and community composition were remarkably perturbed in UC group and partially restored by mesalamine treatment. The relative abundance of 192 taxa in genus level were significantly changed in UC group, and 168 genera were significantly altered after mesalamine intervention. Meanwhile, a total of 127 metabolites were significantly changed in UC group and 129 metabolites were significantly altered after mesalamine treatment. Importantly, we observed that many candidates including 49 genera (such as Escherichia-shigella, Enterococcus and Butyricicoccus) and 102 metatoblites (such as isoleucine, cholic acid and deoxycholic acid) were reversed by mesalamine. Spearman correlation analysis revealed that most of the candidates were significantly correlated with Mayo score of UC, and the relative abundance of specific genera were significant correlated with the perturbation of metabolites. Pathway analysis demonstrated that genera and metabolites candidates were enriched in many similar molecular pathways such as amino acid metabolism and secondary metabolites biosynthesis. Importantly, ROC curve analysis identified a gut microbiota signature composed of five genera including Escherichia-Shigella, Streptococcus, Megamonas, Prevotella_9 and [Eubacterium] _coprostanoligenes _group which might be used to distinguish UC group from both NC and mesalamine group. In all, our results suggested that mesalamine might exert a beneficial role in UC by modulating gut microbiota signature with correlated metabolites in different pathways, which may provide a basis for developing novel candidate biomarkers and therapeutic targets of UC.