bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcranial Sonography in the Diagnosis of Pituitary Tumor—A Direct Comparison With MRI
Authors: He Lei , Zhang Jinghan , Yu Tengfei , Du Yue , Liu Xinyao , He Wen
Published: December 2021

Background

Transcranial sonography (TCS) is a convenient tool for detecting certain brain diseases, such as brain tumors. Few studies have reported on the use of TCS in the area of Sella turcica. The accuracy and repeatability of Sella turcica with or without pituitary tumor is not clear.

Purpose

This study aimed to investigate the feasibility and accuracy of TCS to measure the size of Sella turcica according to the measurement in MRI and determine its diagnostic performance in individuals with pituitary tumor.

Materials and Methods

In this cross-sectional comparative study, healthy volunteers and patients with pituitary tumor were enrolled for examination of TCS and MRI between October 2020 and July 2021. The transverse diameter (D1, cm) of Sella turcica and the volume of the pituitary tumor were measured by TCS and MRI, respectively, and compared by using Student’s t-test or Mann–Whitney test, using the receiver operating characteristic (ROC) curve to analyze the diagnostic value of D1 in TCS for pituitary tumor.

Results

A total of 75 healthy volunteers and 51 patients with pituitary tumor were evaluated. In healthy volunteers, the mean D1 was 1.30 ± 0.35 (range, 0.82–3.22) by TCS and 1.32 ± 0.29 (range, 0.94–3.02) by MRI (P = 0.054). In patients with pituitary tumor, the mean D1 was 2.0 ± 0.65 (range, 0.90–3.48) by TCS and 2.42 ± 1.0 (range, 0.80–4.70) by MRI (P = 0.000). The median measurement volume was 4.41 and 6.59 cm3 in TCS and MR, respectively (P = 0.000). The mean D1 was 1.31 ± 0.35 in healthy volunteers and 2.0 ± 0.65 cm in patients with pituitary tumor (P = 0.000). In the ROC curve analysis, the area under the curve was 0.836, and the optimal cutoff value (1.56) exhibited a sensitivity and specificity of 67.31 and 88.0%, respectively.

Conclusion

The consistency between the two imaging technologies performed well in D1 measurement, while the volume of the pituitary tumor was smaller as assessed by TCS than by MRI. D1 in TCS had good diagnostic performance in pituitary tumor.
Health-Related Quality of Life of Children and Adolescents With Congenital Hyperinsulinism – A Scoping Review
Authors: Kristensen Kaja , Quitmann Julia , Witt Stefanie
Published: December 2021

Introduction

Despite improvements in diagnosis and therapeutic advances in treatment, congenital hyperinsulinism (CHI) remains a severe disease with high patient impairment. We aimed to review the literature on Health-related Quality of Life in children and adolescents with congenital hyperinsulinism and summarize the findings.

Materials and Methods

For this scoping review, a literature search was conducted in PubMed and Web of Science in May 2021. Inclusion and exclusion criteria for the selection of articles were defined a priori.

Results

Two hundred and forty-five (245) articles were identified through the search and screened on the basis of title and abstract. The full texts of forty articles were then assessed. Finally, four articles (published 2012-2020) describing Health-related Quality of Life in children and adolescents with congenital hyperinsulinism were included. The study designs were heterogeneous and included cross-sectional observational studies (n=2), clinical trials (n =1), and case reports (n=1) with different sample sizes. Three studies were conducted in European countries and one in Japan. The results for Health-related Quality of Life revealed inconsistencies.

Conclusion

There are only a few studies looking at Health-related Quality of Life in children and adolescents with congenital hyperinsulinism. To gain a comprehensive understanding of the impact of congenital hyperinsulinism on Health-related Quality of Life in children and adolescents, it is necessary to use both generic and condition-specific instruments to measure Health-related Quality of Life of young patients in larger samples, to collect longitudinal data, and to consider qualitative research approaches.
Small Prey Animal Habitat Use in Landscapes of Fear: Effects of Predator Presence and Human Activity Along an Urban Disturbance Gradient
Authors: Fardell Loren L. , Nano Catherine E. M. , Pavey Chris R. , Dickman Christopher R.
Published: December 2021

Human activity can impose additional stressors to wildlife, both directly and indirectly, including through the introduction of predators and influences on native predators. As urban and adjacent environments are becoming increasingly valuable habitat for wildlife, it is important to understand how susceptible taxa, like small prey animals, persist in urban environments under such additional stressors. Here, in order to determine how small prey animals’ foraging patterns change in response to habitat components and distances to predators and human disturbances, we used filmed giving-up density (GUD) trials under natural conditions along an urban disturbance gradient. We then ran further GUD trials with the addition of experimentally introduced stressors of: the odors of domestic cat (Felis catus)/red fox (Vulpes vulpes) as predator cues, light and sound as human disturbance cues, and their combinations. Small mammals were mostly observed foraging in the GUD trials, and to a lesser degree birds. Animals responded to proximity to predators and human disturbances when foraging under natural conditions, and used habitat components differently based on these distances. Along the urban disturbance gradient situation-specific responses were evident and differed under natural conditions compared to additional stressor conditions. The combined predator with human disturbance treatments resulted in responses of higher perceived risk at environments further from houses. Animals at the urban-edge environment foraged more across the whole site under the additional stressor conditions, but under natural conditions perceived less risk when foraging near predators and further from human disturbance (houses). Contrastingly, at the environments further from houses, foraging near human disturbance (paths/roads) when close to a predator was perceived as lower risk, but when foraging under introduced stressor conditions these disturbances were perceived as high risk. We propose that sensory and behavioral mechanisms, and stress exposure best explain our findings. Our results indicate that habitat components could be managed to reduce the impacts of high predation pressure and human activity in disturbed environments.
Evaluating the Effects of Symptom Monitoring on Menopausal Health Outcomes: A Systematic Review and Meta-Analysis
Authors: Andrews Robin , Hale Gabrielle , John Bev , Lancastle Deborah
Published: December 2021

Evidence suggests that monitoring and appraising symptoms can result in increased engagement in medical help-seeking, improved patient-doctor communication, and reductions in symptom prevalence and severity. To date, no systematic reviews have investigated whether symptom monitoring could be a useful intervention for menopausal women. This review explored whether symptom monitoring could improve menopausal symptoms and facilitate health-related behaviours. Results suggested that symptom monitoring was related to improvements in menopausal symptoms, patient-doctor communication and medical decision-making, heightened health awareness, and stronger engagement in setting treatment goals. Meta-analyses indicated large effects for the prolonged use of symptom diaries on hot flush frequencies. Between April 2019 and April 2021, PsychInfo, EMBASE, MEDLINE, CINAHL, Cochrane, ProQuest, PsychArticles, Scopus, and Web of Science were searched. Eighteen studies met the eligibility criteria and contributed data from 1,718 participants. Included studies quantitatively or qualitatively measured the impact of symptom monitoring on menopausal populations and symptoms. Research was narratively synthesised using thematic methods, 3 studies were examined via meta-analysis. Key themes suggest that symptom monitoring is related to improvements in menopausal symptoms, improved patient-doctor communication and medical decision-making, increased health awareness, and stronger engagement in goal-setting behaviours. Meta-analysis results indicated large effects for the prolonged use of symptom diaries on hot flush frequency: 0.73 [0.57, 0.90]. This review is limited due to the low number of studies eligible for inclusion, many of which lacked methodological quality. These results indicate that symptom monitoring has potential as an effective health intervention for women with menopausal symptoms. This intervention may be beneficial within healthcare settings, in order to improve patient-doctor relations and adherence to treatment regimes. However, findings are preliminary and quality assessments suggest high risk of bias. Thus, further research is needed to support these promising outcomes.

Systematic Review Registration Number:https://www.crd.york.ac.uk/prospero/display_record.php?, PROSPERO, identifier: CRD42019146270.
Hyperoside Suppresses Renal Inflammation by Regulating Macrophage Polarization in Mice With Type 2 Diabetes Mellitus
Authors: Liu Jialing , Zhang Yanmei , Sheng Hongqin , Liang Chunling , Liu Huazhen , Moran Guerrero Jose Alberto , Lu Zhaoyu , Mao Wei , Dai Zhenhua , Liu Xusheng , Zhang Lei
Published: December 2021

Accumulating evidence reveals that both inflammation and lymphocyte dysfunction play a vital role in the development of diabetic nephropathy (DN). Hyperoside (HPS) or quercetin-3-O-galactoside is an active flavonoid glycoside mainly found in the Chinese herbal medicine Tu-Si-Zi. Although HPS has a variety of pharmacological effects, including anti-oxidative and anti-apoptotic activities as well as podocyte-protective effects, its underlying anti-inflammatory mechanisms remain unclear. Herein, we investigated the therapeutic effects of HPS on murine DN and the potential mechanisms responsible for its efficacy. We used C57BLKS/6J Lepdb/db mice and a high glucose (HG)-induced bone marrow-derived macrophage (BMDM) polarization system to investigate the potentially protective effects of HPS on DN. Our results showed that HPS markedly reduced diabetes-induced albuminuria and glomerular mesangial matrix expansion, accompanied with a significant improvement of fasting blood glucose level, hyperlipidaemia and body weight. Mechanistically, pretreatment with HPS effectively regulated macrophage polarization by shifting proinflammatory M1 macrophages (F4/80+CD11b+CD86+) to anti-inflammatory M2 ones (F4/80+CD11b+CD206+) in vivo and in bone marrow-derived macrophages (BMDMs) in vitro, resulting in the inhibition of renal proinflammatory macrophage infiltration and the reduction in expression of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF-α) and inducible nitric oxide synthase (iNOS) while increasing expression of anti-inflammatory cytokine Arg-1 and CD163/CD206 surface molecules. Unexpectedly, pretreatment with HPS suppressed CD4+ T cell proliferation in a coculture model of IL-4-induced M2 macrophages and splenic CD4+ T cells while promoting their differentiation into CD4+IL-4+ Th2 and CD4+Foxp3+ Treg cells. Taken together, we demonstrate that HPS ameliorates murine DN via promoting macrophage polarization from an M1 to M2 phenotype and CD4+ T cell differentiation into Th2 and Treg populations. Our findings may be implicated for the treatment of DN in clinic.
Beta Diversity of Antarctic and Sub-Antarctic Benthic Communities Reveals a Major Role of Stochastic Assembly Processes
Authors: Valdivia Nelson , Garcés-Vargas José , Garrido Ignacio , Gómez Iván , Huovinen Pirjo , Navarro Nelso P. , Macaya Erasmo C. , Pardo Luis Miguel
Published: December 2021

Community assembly is the result of both, deterministic and stochastic processes. The former encompasses niche-based local-scale mechanisms such as environmental filtering and biotic interactions; the latter includes ecological drift, probabilistic colonisation, and random extinctions. Using standardised sampling protocols, we show that the spatial variation in species composition (beta diversity) of shallow subtidal macrobenthic communities of sub-Antarctic (Strait of Magellan and Yendegaia Fjord [Beagle Channel]) and Antarctic (Fildes Bay [King George Island, West Antarctic Peninsula]) localities reflects a high contribution of stochastic processes to community assembly. Null model analyses indicated that random sampling from species pools of different sizes drove the observed among-locality differences in incidence- and abundance-based beta diversity. We analysed a normalised stochasticity ratio (NST), which delimits between more deterministic (<50%) and more stochastic (>50%) assembly. NST was notably larger than 50%, with mean values of 69.5% (95% CI = 69.2–69.8%), 62.5% (62.1–62.9%), and 72.8% (72.5–73.2%) in Strait of Magellan, Yendegaia Fjord, and Fildes Bay, respectively. Accordingly, environmental factors, such as depth, seawater temperature, salinity, and underwater light penetration, accounted for a small fraction of the spatial variation in community composition across the three localities. In this region, therefore, stochastic processes could have stronger effects on community assembly than deterministic niche-based factors. As anthropogenic biotic homogenisation continues apace, our study can give useful insights into the major ecological processes in Southern Ocean’ coastal marine communities.
The Prevalence of Adherent-Invasive Escherichia coli and Its Association With Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis
Authors: Kamali Dolatabadi Razie , Feizi Awat , Halaji Mehrdad , Fazeli Hossein , Adibi Peyman
Published: December 2021

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are known as chronic gastrointestinal inflammatory disorders. The present systematic review and meta analysis was conducted to estimate the prevalence of adherent-invasive Escherichia coli (AIEC) isolates and their phylogenetic grouping among IBD patients compared with the controls. A systematic literature search was conducted among published papers by international authors until April 30, 2020 in Web of Science, Scopus, EMBASE, and PubMed databases. The pooled prevalence of AIEC isolates and their phylogenetic grouping among IBD patients as well as in controls was estimated using fixed or random effects models. Furthermore, for estimating the association of colonization by AIEC with IBD, odds ratio along with 95% confidence interval was reported. A total of 205 articles retrieved by the initial search of databases, 13 case–control studies met the eligibility criteria for inclusion in the meta analysis. There were 465 IBD cases (348 CD and 117 UC) and 307 controls. The pooled prevalence of AIEC isolates were 28% (95% CI: 18–39%), 29% (95% CI: 20–40%), 13% (95% CI: 1–30%), and 9% (95% CI: 3–19%), respectively among IBD, CD, UC, and control group, respectively. Our results revealed that the most frequent AIEC phylogroup in the IBD, CD, and control groups was B2. Fixed-effects meta analysis showed that colonization of AIEC is significantly associated with IBD (OR: 2.93; 95% CI: 1.90–4.52; P < 0.001) and CD (OR: 3.07; 95% CI: 1.99–4.74; P < 0.001), but not with UC (OR: 2.29; 95% CI: 0.81–6.51; P = 0.11). In summary, this meta analysis revealed that colonization by AIEC is more frequent in IBD and is associated with IBD (CD and UC). Our results suggested that the affects of IBD in patients colonized with the AIEC pathovar is not random, it is in fact a specific disease-related pathovar.
Prescription Patterns for Pulmonary Vasodilators in the Treatment of Pulmonary Hypertension Associated With Chronic Lung Diseases: Insights From a Clinician Survey
Authors: Thomas Christopher A. , Lee Justin , Bernardo Roberto J. , Anderson Ryan J. , Glinskii Vladimir , Sung Yon K. , Kudelko Kristina , Hedlin Haley , Sweatt Andrew , Kawut Steven M. , Raj Rishi , Zamanian Roham T. , de Jesus Perez Vinicio
Published: December 2021

Background: Pulmonary hypertension is a complication of chronic lung diseases (PH-CLD) associated with significant morbidity and mortality. Management guidelines for PH-CLD emphasize the treatment of the underlying lung disease, but the role of PH-targeted therapy remains controversial. We hypothesized that treatment approaches for PH-CLD would be variable across physicians depending on the type of CLD and the severity of PH.

Methods and Results: Between May and July 2020, we conducted an online survey of PH experts asking for their preferred treatment approach in seven hypothetical cases of PH-CLD of varying severity. We assessed agreement amongst clinicians for initial therapy choice using Fleiss' kappa calculations. Over 90% of respondents agreed that they would treat cases of severe PH in the context of mild lung disease with some form of PH-targeted therapy. For cases of severe PH in the context of severe lung disease, over 70% of respondents agreed to use PH-targeted therapy. For mild PH and mild lung disease cases, <50% of respondents chose to start PH-specific therapy. There was overall poor agreement between respondents in the choice to use mono-, double or triple combination therapy with PH-specific agents in all cases.

Conclusion: Although management guidelines discourage the routine use of PH-targeted therapies to treat PH-CLD patients, most physicians choose to treat patients with some form of PH-targeted therapy. The choice of therapy and treatment approach are variable and appear to be influenced by the severity of the PH and the underlying lung disease.
Comparison of Machine Learning Approaches to Improve Diagnosis of Optic Neuropathy Using Photopic Negative Response Measured Using a Handheld Device
Authors: Diao Tina , Kushzad Fareshta , Patel Megh D. , Bindiganavale Megha P. , Wasi Munam , Kochenderfer Mykel J. , Moss Heather E.
Published: December 2021

The photopic negative response of the full-field electroretinogram (ERG) is reduced in optic neuropathies. However, technical requirements for measurement and poor classification performance have limited widespread clinical application. Recent advances in hardware facilitate efficient clinic-based recording of the full-field ERG. Time series classification, a machine learning approach, may improve classification by using the entire ERG waveform as the input. In this study, full-field ERGs were recorded in 217 eyes (109 optic neuropathy and 108 controls) of 155 subjects. User-defined ERG features including photopic negative response were reduced in optic neuropathy eyes (p < 0.0005, generalized estimating equation models accounting for age). However, classification of optic neuropathy based on user-defined features was only fair with receiver operating characteristic area under the curve ranging between 0.62 and 0.68 and F1 score at the optimal cutoff ranging between 0.30 and 0.33. In comparison, machine learning classifiers using a variety of time series analysis approaches had F1 scores of 0.58–0.76 on a test data set. Time series classifications are promising for improving optic neuropathy diagnosis using ERG waveforms. Larger sample sizes will be important to refine the models.
The Efficacy and Prognostic Factors of the Combination of TACE and Apatinib for the Treatment of BCLC Stage C Hepatocellular Carcinoma
Authors: Liu Shun , Liu Kai-Cai , Lv Wei-Fu , Lu Dong , Zhu Xian-Hai , Jiang Bo , Tan Yu-Lin , Wang Guo-Xiang
Published: December 2021

Objective: Apatinib is a inhibitor of vascular endothelial growth factor receptor-2. To explore the efficacy and prognostic factors of transarterial chemoembolization (TACE) combined with apatinib in the treatment of Barcelona Clinic Liver Cancer stage C (BCLC C) hepatocellular carcinoma (HCC).

Methods: Clinical data of 146 HCC patients with BCLC stage C admitted to our hospital were collected and analyzed retrospectively, of which 76 cases were treated with TACE combined with apatinib (TACE-apatinib) and 70 with TACE alone. The tumor response, survival time, and adverse events were compared between the two groups, and the factors affecting the prognosis were analyzed.

Results: The objective response rate (ORR) and disease control rate (DCR) in the TACE-apatinib group were higher than in the TACE-alone group (ORR: 42.10 vs. 25.71%, P = 0.03; DCR: 84.21 vs. 55.71%, P = 0.001). The median time to progression (TTP) and overall survival (OS) in the TACE-apatinib group were longer than in the TACE-alone group (TTP: 5.5 vs. 3.7 months, P = 0.02; OS: 10.0 vs. 6.2 months, P = 0.01). Univariate and multivariate Cox regression analysis showed that tumor size, Child-Pugh class, and the presence of the portal vein tumor thrombus affect the prognosis of patients. Subgroup analysis revealed that TACE-apatinib therapy resulted in a higher OS in patients with tumor size <10 cm, without portal vein tumor thrombus, and with Child-Pugh class A (P < 0.05). The likelihood of adverse events (hand-foot syndrome, hypertension, oral ulcer) was significantly higher in the increased in the TACE-apatinib group than in the TACE alone group (P < 0.05).

Conclusion: TACE-apatinib is an effective and safe method for the treatment of BCLC stage C HCC. Tumor size, Child-Pugh class, and portal vein tumor thrombus affect survival time in HCC patients with BCLC stage C.
An Interpretable Early Dynamic Sequential Predictor for Sepsis-Induced Coagulopathy Progression in the Real-World Using Machine Learning
Authors: Cui Ruixia , Hua Wenbo , Qu Kai , Yang Heran , Tong Yingmu , Li Qinglin , Wang Hai , Ma Yanfen , Liu Sinan , Lin Ting , Zhang Jingyao , Sun Jian , Liu Chang
Published: December 2021

Sepsis-associated coagulation dysfunction greatly increases the mortality of sepsis. Irregular clinical time-series data remains a major challenge for AI medical applications. To early detect and manage sepsis-induced coagulopathy (SIC) and sepsis-associated disseminated intravascular coagulation (DIC), we developed an interpretable real-time sequential warning model toward real-world irregular data. Eight machine learning models including novel algorithms were devised to detect SIC and sepsis-associated DIC 8n (1 ≤ n ≤ 6) hours prior to its onset. Models were developed on Xi'an Jiaotong University Medical College (XJTUMC) and verified on Beth Israel Deaconess Medical Center (BIDMC). A total of 12,154 SIC and 7,878 International Society on Thrombosis and Haemostasis (ISTH) overt-DIC labels were annotated according to the SIC and ISTH overt-DIC scoring systems in train set. The area under the receiver operating characteristic curve (AUROC) were used as model evaluation metrics. The eXtreme Gradient Boosting (XGBoost) model can predict SIC and sepsis-associated DIC events up to 48 h earlier with an AUROC of 0.929 and 0.910, respectively, and even reached 0.973 and 0.955 at 8 h earlier, achieving the highest performance to date. The novel ODE-RNN model achieved continuous prediction at arbitrary time points, and with an AUROC of 0.962 and 0.936 for SIC and DIC predicted 8 h earlier, respectively. In conclusion, our model can predict the sepsis-associated SIC and DIC onset up to 48 h in advance, which helps maximize the time window for early management by physicians.
Supporting Decision Making in Intensive Care: Ethical Principles for Managing Access to Care During the COVID-19 Pandemic
Authors: D'Errico Stefano , Padovano Martina , Scopetti Matteo , Manetti Federico , Zanon Martina , Santurro Alessandro , Frati Paola , Fineschi Vittorio
Published: December 2021

The pandemic from COVID-19 causes a health threat for many countries and requires an internationally coordinated response due to the high spread of the infection. The current local and international situation gives rise to logistical and ethical considerations regarding the imbalance between needs for assistance and availability of health resources in the continuation of the emergency. A shortage condition will require healthcare professionals to choose between patients who will have access to respiratory support and those who will have to continue without. The sharing of criteria for the introduction of patients to the different therapeutic paths is fundamental to prevent the onset of ethical issues. The present paper analyzes the critical issues related to the scarcity of healthcare resources and the limitation of access to intensive care with the aim of proposing ethically sustainable principles for the management of the current pandemic situation.
Longitudinal Metabolomics Reveals Ornithine Cycle Dysregulation Correlates With Inflammation and Coagulation in COVID-19 Severe Patients
Authors: Li Tao , Ning Nianzhi , Li Bo , Luo Deyan , Qin Enqiang , Yu Wenjing , Wang Jianxin , Yang Guang , Nan Nan , He Zhili , Yang Ning , Gong Saisai , Li Jiajia , Liu Aixia , Sun Yakun , Li Zhan , Jia Tianye , Gao Jie , Zhang Wang , Huang Yanyu , Hou Jun , Xue Ying , Li Deyu , Wei Zhen , Zhang Liangyan , Li Boan , Wang Hui
Published: December 2021

COVID-19 is a severe disease in humans, as highlighted by the current global pandemic. Several studies about the metabolome of COVID-19 patients have revealed metabolic disorders and some potential diagnostic markers during disease progression. However, the longitudinal changes of metabolomics in COVID-19 patients, especially their association with disease progression, are still unclear. Here, we systematically analyzed the dynamic changes of the serum metabolome of COVID-19 patients, demonstrating that most of the metabolites did not recover by 1–3 days before discharge. A prominent signature in COVID-19 patients comprised metabolites of amino acids, peptides, and analogs, involving nine essential amino acids, 10 dipeptides, and four N-acetylated amino acids. The levels of 12 metabolites in amino acid metabolism, especially three metabolites of the ornithine cycle, were significantly higher in severe patients than in mild ones, mainly on days 1–3 or 4–6 since onset. Integrating blood metabolomic, biochemical, and cytokine data, we uncovered a highly correlated network, including 6 cytokines, 13 biochemical parameters, and 49 metabolites. Significantly, five ornithine cycle-related metabolites (ornithine, N-acetylornithine, 3-amino-2-piperidone, aspartic acid, and asparagine) highly correlated with “cytokine storms” and coagulation index. We discovered that the ornithine cycle dysregulation significantly correlated with inflammation and coagulation in severe patients, which may be a potential mechanism of COVID-19 pathogenicity. Our study provided a valuable resource for detailed exploration of metabolic factors in COVID-19 patients, guiding metabolic recovery, understanding the pathogenic mechanisms, and creating drugs against SARS-CoV-2 infection.
Function and Inhibitory Mechanisms of Multidrug Efflux Pumps
Authors: Nishino Kunihiko , Yamasaki Seiji , Nakashima Ryosuke , Zwama Martijn , Hayashi-Nishino Mitsuko
Published: December 2021

Multidrug efflux pumps are inner membrane transporters that export multiple antibiotics from the inside to the outside of bacterial cells, contributing to bacterial multidrug resistance (MDR). Postgenomic analysis has demonstrated that numerous multidrug efflux pumps exist in bacteria. Also, the co-crystal structural analysis of multidrug efflux pumps revealed the drug recognition and export mechanisms, and the inhibitory mechanisms of the pumps. A single multidrug efflux pump can export multiple antibiotics; hence, developing efflux pump inhibitors is crucial in overcoming infectious diseases caused by multidrug-resistant bacteria. This review article describes the role of multidrug efflux pumps in MDR, and their physiological functions and inhibitory mechanisms.
Peptide OPTX-1 From Ornithodoros papillipes Tick Inhibits the pS273R Protease of African Swine Fever Virus
Authors: Wang Jingjing , Ji Mengyao , Yuan Bingqian , Luo Anna , Jiang Zhenyuan , Zhu Tengyu , Liu Yang , Kamau Peter Muiruri , Jin Lin , Lai Ren
Published: December 2021

African swine fever virus (ASFV) is a large double-stranded DNA virus and causes high mortality in swine. ASFV can be transmitted by biological vectors, including soft ticks in genus Ornithodoros but not hard ticks. However, the underlying mechanisms evolved in the vectorial capacity of soft ticks are not well-understood. Here, we found that a defensin-like peptide toxin OPTX-1 identified from Ornithodoros papillipes inhibits the enzyme activity of the ASFV pS273R protease with a Ki=0.821±0.526μM and shows inhibitory activity on the replication of ASFV. The analogs of OPTX-1 from hard ticks show more inhibitory efficient on pS273R protease. Considering that ticks are blood-sucking animals, we tested the effects of OPTX-1 and its analogs on the coagulation system. At last, top 3D structures represented surface analyses of the binding sites of pS273R with different inhibitors that were obtained by molecular docking based on known structural information. In summary, our study provides evidence that different inhibitory efficiencies between soft tick-derived OPTX-1 and hard tick-derived defensin-like peptides may determine the vector and reservoir competence of ticks.
Metabolic and Metabolomic Insights Regarding the Omega-3 PUFAs Intake in Type 1 Diabetes Mellitus
Authors: Purdel Carmen , Ungurianu Anca , Margina Denisa
Published: December 2021

Type 1 diabetes mellitus (T1DM) is currently considered an autoimmune disease characterized by the destruction of pancreatic β-cells, insulin deficiency, and dysglycemia. Dietary factors, including omega-3 polyunsaturated fatty acids (ω-3 PUFAs), were reported to influence T1DM. Therefore, a better understanding of the potential role of ω-3 PUFAs in the development and progression of T1DM will help to improve the clinical management of the disease. In this review, we explored the current understanding of molecular mechanisms and signaling pathways induced by ω-3 PUFAs and the beneficial effects of ω-3 PUFAs intake in the prevention and treatment of T1DM, as well as the underlying possible metabolomic (lipidomics) changes.
Viral-Mediated Knockdown of Nucleus Accumbens Shell PAC1 Receptor Promotes Excessive Alcohol Drinking in Alcohol-Preferring Rats
Authors: Minnig Margaret A. , Park Tayun , Echeveste Sanchez Maria , Cottone Pietro , Sabino Valentina
Published: December 2021

Alcohol use disorder (AUD) is a chronic, relapsing disorder whose genetic and environmental susceptibility components are not fully understood. Neuropeptidergic signaling has been repeatedly implicated in modulating excessive alcohol drinking, especially within sub-regions of the striatum. Here, we investigated the potential involvement of the selective receptor for pituitary adenylate cyclase-activating polypeptide (PACAP), PAC1R, in the nucleus accumbens shell (NAcc Shell) in excessive alcohol drinking in alcohol-preferring rats, an established animal model of the genetic propensity for alcoholism. Scr:sP alcohol-preferring rats were trained to operantly self-administer alcohol and then either an AAV virus short-hairpin RNA (shRNA) targeted to knockdown PAC1R, or an AAV control virus were microinfused into the NAcc Shell. NAcc Shell PAC1R shRNA knockdown virus was confirmed to significantly decrease PAC1R levels in the NAcc Shell. The effects of NAcc Shell PAC1R shRNA knockdown on ethanol self-administration were investigated using a Fixed Ratio (FR) 1 and a Progressive Ratio (PR) schedule of reinforcement. The effect of PAC1R knockdown on self-administration of an alternative reinforcer, saccharin, was also assessed. The results showed that the reduction in PAC1R in the NAcc Shell led to excessive ethanol drinking, increased preference for ethanol, and higher motivation to drink. NAcc Shell PAC1R shRNA knockdown did not comparably increase saccharin self-administration, suggesting selectivity of action. These data suggest that NAcc Shell PAC1R may serves as a “brake” on alcohol drinking, and thereby the loss of function of PAC1R leads to excessive alcohol consumption. Therefore, the PACAP/PAC1R system may represent a novel target for the treatment of AUD.
Telestroke Assessment With Perfusion CT Improves the Diagnostic Accuracy of Stroke vs. Mimic
Authors: Tran Lucinda , Lin Longting , Spratt Neil , Bivard Andrew , Chew Beng Lim Alvin , Evans James W. , O'Brien William , Levi Christopher , Ang Timothy , Alanati Khaled , Pepper Elizabeth , Garcia-Esperon Carlos , Parsons Mark
Published: December 2021

Background and Purpose: CT perfusion (CTP) has been implemented widely in regional areas of Australia for telestroke assessment. The aim of this study was to determine if, as part of telestroke assessment, CTP provided added benefit to clinical features in distinguishing between strokes and mimic and between transient ischaemic attack (TIA) and mimic.

Methods: We retrospectively analysed 1,513 consecutively recruited patients referred to the Northern New South Wales Telestroke service, where CTP is performed as a part of telestroke assessment. Patients were classified based on the final diagnosis of stroke, TIA, or mimic. Multivariate regression models were used to determine factors that could be used to differentiate between stroke and mimic and between TIA and mimic.

Results: There were 693 strokes, 97 TIA, and 259 mimics included in the multivariate regression models. For the stroke vs. mimic model using symptoms only, the area under the curve (AUC) on the receiver operator curve (ROC) was 0.71 (95% CI 0.67–0.75). For the stroke vs. mimic model using the absence of ischaemic lesion on CTP in addition to clinical features, the AUC was 0.90 (95% CI 0.88–0.92). The multivariate regression model for predicting mimic from TIA using symptoms produced an AUC of 0.71 (95% CI 0.65–0.76). The addition of absence of an ischaemic lesion on CTP to clinical features for the TIA vs. mimic model had an AUC of 0.78 (95% CI 0.73–0.83)

Conclusions: In the telehealth setting, the absence of an ischaemic lesion on CTP adds to the diagnostic accuracy in distinguishing mimic from stroke, above that from clinical features.
Robust Multi-TE ASL-Based Blood–Brain Barrier Integrity Measurements
Authors: Mahroo Amnah , Buck Mareike Alicja , Huber Jörn , Breutigam Nora-Josefin , Mutsaerts Henk J. M. M. , Craig Martin , Chappell Michael , Günther Matthias
Published: December 2021

Multiple echo-time arterial spin labelling (multi-TE ASL) offers estimation of blood–tissue exchange dynamics by probing the T2 relaxation of the labelled spins. In this study, we provide a recipe for robust assessment of exchange time (Texch) as a proxy measure of blood–brain barrier (BBB) integrity based on a test-retest analysis. This includes a novel scan protocol and an extension of the two-compartment model with an “intra-voxel transit time” (ITT) to address tissue transit effects. With the extended model, we intend to separate the underlying two distinct mechanisms of tissue transit and exchange. The performance of the extended model in comparison with the two-compartment model was evaluated in simulations. Multi-TE ASL sequence with two different bolus durations was used to acquire in vivo data (n = 10). Cerebral blood flow (CBF), arterial transit time (ATT) and Texch were fitted with the two models, and mean grey matter values were compared. Additionally, the extended model also extracted ITT parameter. The test-retest reliability of Texch was assessed for intra-session, inter-session and inter-visit pairs of measurements. Intra-class correlation coefficient (ICC) and within-subject coefficient of variance (CoV) for grey matter were computed to assess the precision of the method. Mean grey matter Texch and ITT values were found to be 227.9 ± 37.9 ms and 310.3 ± 52.9 ms, respectively. Texch estimated by the extended model was 32.6 ± 5.9% lower than the two-compartment model. A significant ICC was observed for all three measures of Texch reliability (P < 0.05). Texch intra-session CoV, inter-session CoV and inter-visit CoV were found to be 6.6%, 7.9%, and 8.4%, respectively. With the described improvements addressing intra-voxel transit effects, multi-TE ASL shows good reproducibility as a non-invasive measure of BBB permeability. These findings offer an encouraging step forward to apply this potential BBB permeability biomarker in clinical research.
Allopregnanolone Improves Locomotor Activity and Arousal in the Aged CGG Knock-in Mouse Model of Fragile X-Associated Tremor/Ataxia Syndrome
Authors: Schwartzer Jared J. , Garcia-Arocena Dolores , Jamal Amanda , Izadi Ali , Willemsen Rob , Berman Robert F.
Published: December 2021

Carriers of the fragile X premutation (PM) can develop a variety of early neurological symptoms, including depression, anxiety and cognitive impairment as well as being at risk for developing the late-onset fragile X-associated tremor/ataxia syndrome (FXTAS). The absence of effective treatments for FXTAS underscores the importance of developing efficacious therapies to reduce the neurological symptoms in elderly PM carriers and FXTAS patients. A recent preliminary study reported that weekly infusions of Allopregnanolone (Allop) may improve deficits in executive function, learning and memory in FXTAS patients. Based on this study we examined whether Allop would improve neurological function in the aged CGG knock-in (CGG KI) dutch mouse, B6.129P2(Cg)-Fmr1tm2Cgr/Cgr, that models much of the symptomatology in PM carriers and FXTAS patients. Wild type and CGG KI mice received 10 weekly injections of Allop (10 mg/kg, s.c.), followed by a battery of behavioral tests of motor function, anxiety, and repetitive behavior, and 5-bromo-2′-deoxyuridine (BrdU) labeling to examine adult neurogenesis. The results provided evidence that Allop in CGG KI mice normalized motor performance and reduced thigmotaxis in the open field, normalized repetitive digging behavior in the marble burying test, but did not appear to increase adult neurogenesis in the hippocampus. Considered together, these results support further examination of Allop as a therapeutic strategy in patients with FXTAS.
Sex and Genotype Modulate the Dendritic Effects of Developmental Exposure to a Human-Relevant Polychlorinated Biphenyls Mixture in the Juvenile Mouse
Authors: Keil Stietz Kimberly P. , Sethi Sunjay , Klocke Carolyn R. , de Ruyter Tryssa E. , Wilson Machelle D. , Pessah Isaac N. , Lein Pamela J.
Published: December 2021

While many neurodevelopmental disorders (NDDs) are thought to result from interactions between environmental and genetic risk factors, the identification of specific gene-environment interactions that influence NDD risk remains a critical data gap. We tested the hypothesis that polychlorinated biphenyls (PCBs) interact with human mutations that alter the fidelity of neuronal Ca2+ signaling to confer NDD risk. To test this, we used three transgenic mouse lines that expressed human mutations known to alter Ca2+ signals in neurons: (1) gain-of-function mutation in ryanodine receptor-1 (T4826I-RYR1); (2) CGG-repeat expansion in the 5′ non-coding portion of the fragile X mental retardation gene 1 (FMR1); and (3) a double mutant (DM) that expressed both mutations. Transgenic and wildtype (WT) mice were exposed throughout gestation and lactation to the MARBLES PCB mix at 0.1, 1, or 6 mg/kg in the maternal diet. The MARBLES mix simulates the relative proportions of the twelve most abundant PCB congeners found in serum from pregnant women at increased risk for having a child with an NDD. Using Golgi staining, the effect of developmental PCB exposure on dendritic arborization of pyramidal neurons in the CA1 hippocampus and somatosensory cortex of male and female WT mice was compared to pyramidal neurons from transgenic mice. A multilevel linear mixed-effects model identified a main effect of dose driven by increased dendritic arborization of cortical neurons in the 1 mg/kg PCB dose group. Subsequent analyses with genotypes indicated that the MARBLES PCB mixture had no effect on the dendritic arborization of hippocampal neurons in WT mice of either sex, but significantly increased dendritic arborization of cortical neurons of WT males in the 6 mg/kg PCB dose group. Transgene expression increased sensitivity to the impact of developmental PCB exposure on dendritic arborization in a sex-, and brain region-dependent manner. In conclusion, developmental exposure to PCBs present in the gestational environment of at-risk humans interfered with normal dendritic morphogenesis in the developing mouse brain in a sex-, genotype- and brain region-dependent manner. Overall, these observations provide proof-of-principle evidence that PCBs interact with heritable mutations to modulate a neurodevelopmental outcome of relevance to NDDs.
Brain Relatively Inert Network: Taking Adult Attention Deficit Hyperactivity Disorder as an Example
Authors: Zhang Hua , Zeng Weiming , Deng Jin , Shi Yuhu , Zhao Le , Li Ying
Published: December 2021

Resting-state functional MRI (rs-fMRI) has been increasingly applied in the research of brain cognitive science and psychiatric diseases. However, previous studies only focused on specific activation areas of the brain, and there are few studies on the inactivation areas. This may overlook much information that explains the brain’s cognitive function. In this paper, we propose a relatively inert network (RIN) and try to explore its important role in understanding the cognitive mechanism of the brain and the study of mental diseases, using adult attention deficit hyperactivity disorder (ADHD) as an example. Here, we utilize methods based on group independent component analysis (GICA) and t-test to identify RIN and calculate its corresponding time series. Through experiments, alterations in the RIN and the corresponding activation network (AN) in adult ADHD patients are observed. And compared with those in the left brain, the activation changes in the right brain are greater. Further, when the RIN functional connectivity is introduced as a feature to classify adult ADHD patients from healthy controls (HCs), the classification accuracy rate is 12% higher than that of the original functional connectivity feature. This was also verified by testing on an independent public dataset. These findings confirm that the RIN of the brain contains much information that will probably be neglected. Moreover, this research provides an effective new means of exploring the information integration between brain regions and the diagnosis of mental illness.
A Dichoptic Optokinetic Nystagmus Paradigm for Interocular Suppression Quantification in Intermittent Exotropia
Authors: Cai Xiaoxiao , Chen Zidong , Liu Yanping , Deng Daming , Yu Minbin
Published: December 2021

Purposes: To investigate the effectiveness of a dichoptic optokinetic nystagmus (dOKN) test to objectively quantify interocular suppression in intermittent exotropia (IXT) patients during the states of orthotropia and exodeviation.

Methods: The OKN motion in subjects (15 controls and 59 IXT subjects) who viewed dichoptic oppositely moving gratings with different contrast ratios was monitored and recorded by an eye tracker. Interocular suppression in control subjects was induced using neutral density (ND) filters. The OKN direction ratios were fitted to examine the changes of interocular suppression in subjects under different viewing states. Two established interocular suppression tests (phase and motion) were conducted for a comparative study.

Results: The dOKN test, which requires a minimal response from subjects, could accurately quantify the interocular suppression in both IXT and control subjects, which is in line with the established interocular suppression tests. Overall, although comparative, the strength of interocular suppression detected by the dOKN test (0.171 ± 0.088) was stronger than those of the phase (0.293 ± 0.081) and the motion tests (0.212 ± 0.068) in the control subjects with 1.5 ND filters. In IXT patients, when their eyes kept aligned, the dOKN test (0.58 ± 0.09) measured deeper visual suppression compared with the phase (0.73 ± 0.17) or the motion test (0.65 ± 0.14). Interestingly, strong interocular suppression (dOKN: 0.15 ± 0.12) was observed in IXT subjects during the periods of exodeviation, irrespective of their binocular visual function as measured by synoptophore.

Conclusion: The dOKN test provides efficient and objective quantification of interocular suppression in IXT, and demonstrates how it fluctuates under different eye positions.
Non-linear Functional Brain Co-activations in Short-Term Memory Distortion Tasks
Authors: Ceglarek Anna , Ochab Jeremi K. , Cifre Ignacio , Fafrowicz Magdalena , Sikora-Wachowicz Barbara , Lewandowska Koryna , Bohaterewicz Bartosz , Marek Tadeusz , Chialvo Dante R.
Published: December 2021

Recent works shed light on the neural correlates of true and false recognition and the influence of time of day on cognitive performance. The current study aimed to investigate the modulation of the false memory formation by the time of day using a non-linear correlation analysis originally designed for fMRI resting-state data. Fifty-four young and healthy participants (32 females, mean age: 24.17 ± 3.56 y.o.) performed in MR scanner the modified Deese-Roediger-McDermott paradigm in short-term memory during one session in the morning and another in the evening. Subjects’ responses were modeled with a general linear model, which includes as a predictor the non-linear correlations of regional BOLD activity with the stimuli, separately for encoding and retrieval phases. The results show the dependence of the non-linear correlations measures with the time of day and the type of the probe. In addition, the results indicate differences in the correlations measures with hippocampal regions between positive and lure probes. Besides confirming previous results on the influence of time-of-day on cognitive performance, the study demonstrates the effectiveness of the non-linear correlation analysis method for the characterization of fMRI task paradigms.