bluuebunny/crossref_metadata_2025 huggingface dataset:
Human Cerebral Organoid Implantation Alleviated the Neurological Deficits of Traumatic Brain Injury in Mice
Authors: Bao Zhongyuan , Fang Kaiheng , Miao Zong , Li Chong , Yang Chaojuan , Yu Qiang , Zhang Chen , Miao Zengli , Liu Yan , Ji Jing
Published: November 2021

Traumatic brain injury (TBI) causes a high rate of mortality and disability, and its treatment is still limited. Loss of neurons in damaged area is hardly rescued by relative molecular therapies. Based on its disease characteristics, we transplanted human embryonic stem cell‐ (hESC‐) derived cerebral organoids in the brain lesions of controlled cortical impact‐ (CCI‐) modeled severe combined immunodeficient (SCID) mice. Grafted organoids survived and differentiated in CCI‐induced lesion pools in mouse cortical tissue. Implanted cerebral organoids differentiated into various types of neuronal cells, extended long projections, and showed spontaneous action, as indicated by electromyographic activity in the grafts. Induced vascularization and reduced glial scar were also found after organoid implantation, suggesting grafting could improve local situation and promote neural repair. More importantly, the CCI mice’s spatial learning and memory improved after organoid grafting. These findings suggest that cerebral organoid implanted in lesion sites differentiates into cortical neurons, forms long projections, and reverses deficits in spatial learning and memory, a potential therapeutic avenue for TBI.
Taohong Siwu-Containing Serum Enhances Angiogenesis in Rat Aortic Endothelial Cells by Regulating the VHL/HIF-1α/VEGF Signaling Pathway
Authors: Tang Zhi , Li Wangyang , Xie Hongzan , Jiang Shengping , Pu Yunqing , Xiong Hui
Published: November 2021

Background. The incidence of bone fracture and bone-related diseases is increasing every year. Angiogenesis plays a vital role in fracture healing and bone repair. This study assessed the benefits of Taohong Siwu (TSW) decoction on angiogenesis in isolated rat aortic endothelial cells (RAEC) treated with TSW-containing serum. Methods. The components of TSW decoction were analyzed by liquid chromatography-mass spectrometry (LC-MS). TSW-containing serum was prepared by gavage of TSW decoction to Sprague-Dawley (SD) rats. The effects of TSW-containing serum on the viability, migration, wound healing, and angiogenesis of RAEC were detected by the MTT, transwell, wound healing, and Matrigel lumen formation assays, respectively. In addition, the effects of an HIF-1α inhibitor on TSW-containing serum-induced RAEC were also assessed. The effects of TSW-containing serum on the expression of the HIF-1α signaling pathway were evaluated by qRT-PCR and western blot analysis. Results. LC-MS revealed that TSW decoction primarily contained isomaltulose, choline, D-gluconic acid, L-pipecolic acid, hypotaurine, albiflorin, and tryptophan. TSW-containing serum significantly increased the viability, migration, wound healing, and angiogenesis of RAEC in a dose-dependent manner. Furthermore, our results demonstrated that HIF-1α and VEGF expressions were increased in the cells of TSW-containing serum groups, whereas VHL expression was decreased. The effects of TSW-containing serum were reversed by treatment with an HIF-1α inhibitor. Conclusion. These results suggested that TSW decoction enhanced angiogenesis by regulating the VHL/HIF-1α/VEGF signaling pathway.
Chemical Kinetic Study on Dual-Fuel Combustion: The Ignition Properties of n-Dodecane/Methane Mixture
Authors: Zhou Weijian , Zhou Song , Xi Hongyuan , Shreka Majed , Zhang Zhao
Published: November 2021

The natural gas (NG)/diesel dual-fuel engine has attracted extensive attention in recent years, and the influence of ignition delay on the engine is very important. Therefore, the research on the ignition delay of NG/diesel dual fuel is of great significance. In this work, a simplified n-dodecane mechanism was used to study the effect of methane mixture ratio on the n-dodecane ignition process. The results showed that the ignition delay time increased with the increase of methane content by changing the mixing ratio of methane and n-dodecane. However, the effect of methane on the ignition delay time gradually decreases when the content of the n-dodecane mixing ratio is greater than 50%. It was also found that with the increase of n-dodecane content, the reduction degree of the ignition delay time of the whole reaction system decreased and the negative temperature coefficient (NTC) behavior increased. Moreover, when the initial pressure increased from 20 bar to 60 bar, the thermal effect of methane also increases from 7.03% to 9.55%. The relationship between ignition characteristics of methane-n-dodecane and temperature was studied by changing the initial temperature. Furthermore, the evolution of species in the ignition process of the whole reaction system was analyzed, and the decomposition of n-dodecane first occurs in the reaction n-C12H26 + O2 = R + HO2 to form R and free radicals; however, the reaction CH4 + OH = CH3 + H2O dominates with the increase of the methane mixing ratio and inhibits the ignition process. Through the analysis of reaction paths, sensitivity, and rates of production and consumption of methane/n-dodecane, it was explained how n-dodecane accelerates methane ignition through the rapidly formed free radicals.
Evaluation of the Effectiveness Computer-Assisted Language Teaching by Big Data Analysis
Authors: Wang Honglei , Du Yanjiao , Tsai Sang-Bing
Published: November 2021

This paper presents an in-depth study and evaluation analysis of the effects of the computer-assisted language teaching method on foreign language learning through its application. Using an empirical research approach, a practical study of computer-assisted English language teaching was conducted to verify the effects of CALL on oral language learning. In exploring the effects of CALL on students’ oral learning, including the effects on fluency, accuracy, and complexity of oral expressions, as well as the effects on learning attitudes, CALL is conducive to improving the fluency of oral expressions, reducing the number of pauses and repetitions in oral expressions, and enabling students to consciously use articulation words to facilitate smooth expressions. CALL is good for improving the accuracy of students’ speech, but it does not play a significant role in grammatical accuracy, and the grammatical errors are mainly in the third person singular of verbs, singular and plural of nouns, and passive voice. The use of CALL in teaching oral expressions does not improve the variety of sentences. However, the application of CALL in oral teaching stimulates students’ enthusiasm for learning, improves their interest in learning spoken English, and increases their confidence in oral expression.
hsa_circ_0013401 Accelerates the Growth and Metastasis and Prevents Apoptosis and Autophagy of Neuroblastoma Cells by Sponging miR‐195 to Release PAK2
Authors: Zhu Shibo , Tang Xiangliang , Gao Xiaofeng , Zhang Jingqi , Cui Yanhong , Li Dian , Jia Wei
Published: November 2021

Background. Increased levels of circRNAs have been identified in a variety of cancers. However, the specific functions and mechanisms of circRNAs in neuroblastoma (NB) have not been fully explored. Methods. The levels of hsa_circ_0045997, hsa_circ_0080307, hsa_circ_0013401, hsa_circ_0077578, and microRNA‐195 were confirmed by RT‐qPCR in NB. Gain‐ and loss‐of‐function assays and rescue experiments were conducted to determine the influence of hsa_circ_0013401, miR‐195, and P21‐activated kinase 2 (PAK2) on the proliferation, apoptosis, autophagy, migration, and invasion of NB cells. Regulatory gene targets were validated by the luciferase assay. A xenograft mouse model was used to determine the in vivo effects of hsa_circ_0013401. Results. hsa_circ_0013401 was highly expressed, miR‐195 was lowly expressed, and there was a negative correlation between hsa_circ_0013401 and miR‐195 in NB. The inhibitory effects of hsa_circ_0013401 knockdown suppressed the proliferation, migration, and invasion and induced the apoptosis and autophagy of NB cells by targeting miR‐195 to downregulate PAK2 expression. Luciferase reporter assays showed that miR‐195 was a direct target of hsa_circ_0013401, and PAK2 was the downstream target gene of miR‐195. In vivo studies showed that hsa_circ_0013401 promotes tumor formation. Conclusions. hsa_circ_0013401 induced NB progression through miR‐195 to enhance PAK2. Therefore, we might highlight a novel regulatory axis (hsa_circ_0013401/miR‐195/PAK2) in NB.
Analysis of the Estrogen Receptor-Associated LncRNA Landscape Identifies a Role for ERLC1 in Breast Cancer Progression
Authors: Yuan Hui , Yan Linlin , Wu Mingming , Shang Yinzhong , Guo Qianying , Ma Xin , Zhang Xiao , Zhu Yong , Wu Zhengsheng , Lobie Peter E. , Zhu Tao
Published: November 2021

Estrogen receptor alpha (ERα) plays a vital role in the development of normal breast tissue and in breast cancer. By cross-analyzing The Cancer Genome Atlas (TCGA) database, ERα-regulated long noncoding RNA 1 (ERLC1) was identified as a long noncoding RNA exhibiting a strong association with ERα signaling and high specificity of expression in breast tissue. ERLC1 was transcriptionally activated by ERα, and ERLC1 stabilized the ESR1 transcript by sequestering miR-129 and tethering FXR1 to maintain a positive feedback loop that potentiated ERα signaling. ERLC1 was elevated in tamoxifen-resistant breast cancer cells, where ERLC1 depletion restored sensitivity to tamoxifen and increased the efficacy of palbociclib or fulvestrant therapy. Collectively, these data warrant further investigation of ERLC1 as a modulator of therapeutic response and potential therapeutic target in ER+ breast cancer.

Significance:

This study identifies an estrogen-regulated lncRNA and the mechanism by which it positively regulates ERα activity, demonstrating a feedback loop that can promote resistance to antiestrogen therapies in ER+ breast cancer.
The Role of Circulating Protein and Metabolite Biomarkers in the Development of Pancreatic Ductal Adenocarcinoma (PDAC): A Systematic Review and Meta-analysis
Authors: Kumar Swati , Santos Ralph J. , McGuigan Andrew J. , Singh Urvashi , Johnson Peter , Kunzmann Andrew T. , Turkington Richard C.
Published: November 2021

Background:

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, and this is attributed to it being diagnosed at an advanced stage. Understanding the pathways involved in initial development may improve early detection strategies. This systematic review assessed the association between circulating protein and metabolite biomarkers and PDAC development.

Methods:

A literature search until August 2020 in MEDLINE, EMBASE, and Web of Science was performed. Studies were included if they assessed circulating blood, urine, or salivary biomarkers and their association with PDAC risk. Quality was assessed using the Newcastle-Ottawa scale for cohort studies. Random-effects meta-analyses were used to calculate pooled relative risk.

Results:

A total of 65 studies were included. Higher levels of glucose were found to be positively associated with risk of developing PDAC [n = 4 studies; pooled relative risk (RR): 1.61; 95% CI: 1.16–2.22]. Additionally, an inverse association was seen with pyridoxal 5′-phosphate (PLP) levels (n = 4 studies; RR: 0.62; 95% CI: 0.44–0.87). Meta-analyses showed no association between levels of C-peptide, members of the insulin growth factor signaling pathway, C-reactive protein, adiponectin, 25-hydroxyvitamin D, and folate/homocysteine and PDAC risk. Four individual studies also reported a suggestive positive association of branched-chain amino acids with PDAC risk, but due to differences in measures reported, a meta-analysis could not be performed.

Conclusions:

Our pooled analysis demonstrates that higher serum glucose levels and lower levels of PLP are associated with risk of PDAC.

Impact:

Glucose and PLP levels are associated with PDAC risk. More prospective studies are required to identify biomarkers for early detection.
Racial/Ethnic Differences in Cancer Diagnosed after Metastasis: Absolute Burden and Deaths Potentially Avoidable through Earlier Detection
Authors: Clarke Christina A. , Patel Alpa V. , Kurian Allison W. , Hubbell Earl , Gomez Scarlett Lin
Published: November 2021

Background:

Racial/ethnic disparities in cancer mortality are well described and are partly attributable to later stage of diagnosis. It is unclear to what extent reductions in the incidence of late-stage cancer could narrow these relative and absolute disparities.

Methods:

We obtained stage- and cancer-specific incidence and survival data from the Surveillance, Epidemiology, and End Results Program for persons ages 50 to 79 years between 2006 and 2015. For eight hypothetical cohorts of 100,000 persons defined by race/ethnicity and sex, we estimated cancer-related deaths if cancers diagnosed at stage IV were detected earlier, by assigning them outcomes of earlier stages.

Results:

We observed a 3-fold difference in the absolute burden of stage IV cancer between the group with the highest rate (non-Hispanic Black males, 337 per 100,000) and the lowest rate (non-Hispanic Asian/Pacific Islander females, 117 per 100,000). Assuming all stage IV cancers were diagnosed at stage III, 32–80 fewer cancer-related deaths would be expected across subgroups, a relative reduction of 13%–14%. Assuming one third of metastatic cancers were diagnosed at each earlier stage (I, II, and III), 52–126 fewer cancer-related deaths would be expected across subgroups, a relative reduction of 21%–23%.

Conclusions:

Across population subgroups, non-Hispanic Black males have the highest burden of stage IV cancer and would have the most deaths averted from improved detection of cancer before metastasis.

Impact:

Detecting cancer before metastasis could meaningfully reduce deaths in all populations, but especially in non-Hispanic Black populations.

See related commentary by Loomans-Kropp et al., p. 512
Concurrent Disruption of the Ras/MAPK and NF-κB Pathways Induces Circadian Deregulation and Hepatocarcinogenesis
Authors: Hanley Kaisa L. , Liang Yan , Wang Gaowei , Lin Xiaoxue , Yang Meixiang , Karin Michael , Fu Wenxian , Feng Gen-Sheng
Published: November 2021

The Ras/Erk and NF-κB pathways play critical roles in cell proliferation and are known to drive oncogenesis when overactivated. Herein we report a gatekeeper function of the two pathways by working in synergy to suppress liver tumorigenesis. Hepatocyte-specific deletion of both Shp2/Ptpn11 and Ikkβ in mice, which promote Ras/Erk and NF-κB signaling, respectively, exacerbated chemical carcinogenesis and even triggered spontaneous development of hepatocellular carcinoma (HCC). We show that the unanticipated severe tumor phenotype was contributed collectively by severe cholestasis, metabolic changes, upregulated cell-cycle progression, and disruption of circadian rhythm in mutant hepatocytes. Remarkably, human HCCs with dysregulated circadian gene expression displayed downregulation of Ras/Erk and NF-κB signaling and poor prognosis. Together, these data indicate that at the ground state, the two central pathways, previously known as oncogenic, cooperate to sustain tumor-suppressive physiologic homeostasis and to prevent hepatic damage. Disruption of this intricate signaling network is carcinogenic in the liver.

Implications:

We demonstrate here that basal levels of the Ras/MAPK and NF-κB pathways, while promoting tumorigenesis if overactivated, are required to maintain physiologic homeostasis and regulate circadian rhythm in the liver, which are antitumorigenic.
Health-Related Quality of Life according to Renal Function: Results from a Nationwide Health Interview and Examination Survey
Authors: Faulhaber Liv , Herget-Rosenthal Stefan , Jacobs Hannes , Hoffmann Falk
Published: November 2021

Background: Most studies on health-related quality of life (HRQoL) in chronic kidney disease (CKD) focus on patients with end-stage kidney disease although they represent a small proportion of patients with CKD. We aimed to analyze HRQoL according to glomerular filtration rate (GFR) categories in a population-based sample of adults living in Germany. Methods: Data from the German health interview and examination survey conducted from 2008 to 2011 were used. Participants with valid interview and examination data aged 40–79 years were included (n = 5,159). Serum creatinine levels were used to calculate estimated GFR via the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. We classified kidney function in GFR categories according to the Kidney Disease Improving Global Outcomes Initiative (KDIGO) guidelines on CKD: G1 (high): ≥90 mL/min/1.73 m2, G2 (normal): 60–89 mL/min/1.73 m2, G3a (mildly decreased): 45–59 mL/min/1.73 m2, G3b (moderately decreased): 30–44 mL/min/1.73 m2, G4/5 (severely decreased/end-stage kidney disease): <30 mL/min/1.73 m2. HRQoL was evaluated with the Short Form Health Survey (SF-36). Different multivariate linear and logistic regression models were used to analyze the association of HRQoL with GFR categories. Results: Overall, 5.9% had a GFR <60 mL/min/1.73 m2 (corresponding to categories G3a, G3b, and G4/5). Compared to category G2 linear regression showed a decline in physical HRQoL in categories G3a (−2.34, p = 0.004), G3b (−5.37, p = 0.009), and G4/5 (−4.82, p = 0.117). No decline in mental HRQoL was detected with increasing GFR categories. Categories G3a to G4/5 were significantly associated with a low perceived general state of health (G3a: odds ratio [OR] = 2.03, p = 0.001; G3b: OR = 3.01, p = 0.009; G4/5: OR = 8.70, p = 0.016) when compared to category G2. Conclusion: In a representative sample of adults living in Germany, both physical HRQoL and the perceived general state of health are already significantly reduced in category G3a.
Does Early Cerebral Near-Infrared Spectroscopy Monitoring Predict Outcome in Neonates with Hypoxic Ischaemic Encephalopathy? A Systematic Review of Diagnostic Test Accuracy
Authors: Garvey Aisling A. , Pavel Andreea M. , Murray Deirdre M. , Boylan Geraldine B. , Dempsey Eugene M.
Published: November 2021

Introduction: Hypoxic ischaemic encephalopathy (HIE) remains one of the top 10 contributors to the global burden of disease. Early objective biomarkers are required. Near-infrared spectroscopy (NIRS) may provide a valuable insight into cerebral perfusion and metabolism. We aimed to determine whether early NIRS monitoring (<6 h of age) can predict outcome as defined by grade of encephalopathy, brain MRI findings, and/or neurodevelopmental outcome at 1–2 years in infants with HIE. Methods: We searched PubMed, Scopus, Web of Science, Embase, and The Cochrane Library databases (July 2019). Studies of infants born ≥36+0 weeks gestation with HIE who had NIRS recording commenced before 6 h of life were included. We planned to provide a narrative of all the studies included, and if similar clinically and methodologically, the results would be pooled in a meta-analysis to determine test accuracy. Results: Seven studies were included with a combined total of 161 infants. Only 1 study included infants with mild HIE. A range of different oximeters and probes were utilized with varying outcome measures making comparison difficult. Although some studies showed a trend towards higher cSO2 values before 6 h in infants with adverse neurodevelopmental outcomes, in the majority, this was not significant until beyond 24 h of life. Conclusion: Very little data currently exists to assess the use of early NIRS to predict outcome in infants with HIE. Further studies using a standardized approach are required before NIRS can be evaluated as a potential objective assessment tool for early identification of at-risk infants.
Maternal Intrapartum Antibiotic Treatment and Gut Microbiota Development in Healthy Term Infants
Authors: Turta Olli , Selma-Royo Marta , Kumar Himanshu , Collado Maria Carmen , Isolauri Erika , Salminen Seppo , Rautava Samuli
Published: November 2021

Objective: The aim of the study was to investigate the impact of intrapartum antibiotic treatment (IAT) on the compositional development of gut microbiota in healthy term infants. Study Design: A case-control study of 24 infants exposed to and 24 matched infants not exposed to IAT was conducted. All subjects were born by vaginal delivery at term and breastfed. None of the infants received antibiotics during the immediate neonatal period. Fecal samples were obtained at the ages of 1 and 6 months. The composition of the intestinal microbiota was assessed by 16S rRNA gene sequencing. Results: IAT was associated with reduced microbial richness but not diversity at 1 month of age. Furthermore, the relative abundances of Clostridiaceae and Erysipelotrichaceae were significantly altered in infants exposed to IAT as compared to nonexposed infants at 1 month of age. The observed deviations in gut microbiota composition between infants exposed and not exposed to IAT diminished by the age of 6 months. Conclusions: IAT is associated with short-term perturbations in the gut microbiota development in healthy term, vaginally delivered, breastfed infants. The composition of the gut microbiota is mostly restored by the age of 6 months.
Influence of Postponed Follow-Up after Cochlear Implant Activation during the COVID-19 Pandemic on Aided Sound Field Detection and Speech Recognition
Authors: Vos Teresa G. , Brown Kevin D. , Buss Emily , Bucker Andrea L. , Dedmon Matthew M. , O’Connell Brendan P. , Raymond Jenna , Dillon Margaret T.
Published: November 2021

Introduction: The objective of this study was to assess the influence of postponing the first post-activation follow-up due to the COVID-19 pandemic on the aided sound field detection thresholds and speech recognition of cochlear implant (CI) users. Methods: A retrospective review was performed at a tertiary referral center. Two groups of adult CI recipients were evaluated: (1) patients whose first post-activation follow-up was postponed due to COVID-19 closures (postponed group; n = 10) and (2) a control group that attended recommended post-activation follow-ups prior to the COVID-19 pandemic (control group; n = 18). For both groups, electric thresholds were estimated at initial activation based on comfort levels and were measured behaviorally at subsequent post-activation follow-ups. For the control group, behavioral thresholds were measured at the 1-month follow-up. For the postponed group, behavioral thresholds were not measured until 3 months post-activation since the 1-month follow-up was postponed. The aided pure-tone average (PTA) and word recognition results were compared between groups at the 3-month follow-up and at an interim visit 2–9 weeks later. Results: At the 3-month follow-up, the postponed group had significantly poorer word recognition (23 vs. 42%, p = 0.027) and aided PTA (42 vs. 37 dB HL, p = 0.041) than the control group. No significant differences were observed between 3-month data from the control group and interim data from the postponed group. Conclusions: The postponed follow-up after CI activation was associated with poorer outcomes, both in terms of speech recognition and aided audibility. However, these detrimental effects were reversed following provision of an individualized map, with behaviorally measured electric threshold and comfort levels. While adult CI recipients demonstrate an improvement in speech recognition with estimated electric thresholds, the present results suggest that behavioral mapping within the initial weeks of device use may support optimal outcomes.
Thrombotic Microangiopathy Triggered by COVID-19: Case Reports
Authors: Korotchaeva Julia , Chebotareva Natalia , Andreeva Elena , Sorokin Yuri , McDonnell Valerie , Stolyarevich Ekaterina , Moiseev Sergey
Published: November 2021

SARS-CoV-2 causes thrombotic microangiopathy (TMA) through the activation of an alternative and lectin complement pathway. TMA is one of the main reasons for acute kidney injury development in patients with COVID-19. In this study, we present 3 TMA cases with severe kidney injury triggered by SARS-CoV-2. In the absence of other TMA causes, we diagnosed the atypical hemolytic uremic syndrome, triggered by SARS-CoV-2 due to abnormal complement activation. Because of both coagulation factors activation, and the high level of D-dimer in patients with COVID-19, it is crucial to differentiate disseminated intravascular coagulation from TMA. The use of anticomplement therapies such as eculizumab should be considered in refractory cases of progressive COVID-19. Controlled clinical trials are required before a definitive statement can be made.
Liraglutide for Weight Management in the Real World: Significant Weight Loss Even if the Maximal Daily Dose Is Not Achieved
Authors: Trenson Liesbet , Trenson Sander , van Nes Falco , Moyson Carolien , Lannoo Matthias , Deleus Ellen , Meulemans Ann , Matthys Christophe , Mertens Ann , Van der Schueren Bart , Vangoitsenhoven Roman
Published: November 2021

Introduction: Obesity is a global health challenge, and pharmacologic options are emerging. Once daily subcutaneous administration of 3 mg liraglutide, a glucagon like peptide-1 analogue, has been shown to induce weight loss in clinical trials, but real-world effectiveness data are scarce. Methods: It is a single-centre retrospective cohort study of patients who were prescribed liraglutide on top of lifestyle adaptations after multidisciplinary evaluation. In Belgium, liraglutide is only indicated for weight management if the BMI is >30 kg/m2 or ≥27 kg/m2 with comorbidities such as dysglycaemia, dyslipidaemia, hypertension, or obstructive sleep apnoea. No indication is covered by the compulsory health care insurance. Liraglutide was started at 0.6 mg/day and uptitrated weekly until 3 mg/day or the maximum tolerated dose. Treatment status and body weight were evaluated at the 4-month routine visit. Results: Between June 2016 and January 2020, liraglutide was prescribed to 115 patients (77% female), with a median age of 47 (IQR 37.7–54.0) years, a median body weight of 98.4 (IQR 90.0–112.2) kg, a BMI of 34.8 (IQR 32.2–37.4) kg/m2, and an HbA1c level of 5.6%. Five (4%) patients did not actually initiate treatment, 9 (8%) stopped treatment, and 8 (7%) were lost to follow-up. At the 4-month visit, the median body weight had decreased significantly by 9.2% to 90.8 (IQR 82.0–103.5) kg (p < 0.001). Patients using 3.0 mg/day (n = 60) had lost 8.0 (IQR 5.8–10.4) kg. The weight loss was similar (p = 0.9622) in patients that used a lower daily dose because of intolerance: 7.4 (IQR 6.2–9.6) kg for 1.2 mg (n = 3), 7.8 (IQR 4.1–7.8) kg for 1.8 mg (n = 16), and 9.0 (IQR 4.8–10.7) kg for 2.4 mg/day (n = 14). Weight loss was minimal if liraglutide treatment was not started or stopped prematurely (median 3.0 [IQR 0.3–4.8] kg, p < 0.001, vs. on treatment). Further analysis showed an additional weight reduction of 1.8 kg in the patients that had started metformin <3 months before the start of liraglutide (p < 0.001). The main reasons for liraglutide discontinuation were gastrointestinal complaints (n = 5/9) and drug cost (n = 2/9). Conclusion: In this selected group of patients, the majority complied with liraglutide treatment over the initial 4-month period and achieved a significant weight loss, irrespective of the maximally tolerated maintenance dose. Addition of metformin induced a small but significant additional weight loss.
Macular Choroidal Thickness: Evaluation of Variability among Measurements and Assessment of Predictive Value of Glaucomatous Visual Field Damage
Authors: Marenco Maria , Rissotto Federico , Palamini Andrea , Cutolo Carlo Alberto , Agosto Giulia , Ferreras Antonio , Traverso Carlo Enrico , Iester Michele
Published: November 2021

Introduction: This study aimed to investigate the relationship between the choroidal circulation and glaucoma, assessing macular choroidal thickness (MCT) as a predictive value of glaucomatous visual field damage. Methods: Twenty primary open-angle glaucoma patients were recruited. Patients underwent 2 SS-OCT scans: one with DRI OCT (Topcon) and the other with PLEX Elite 9000 (Zeiss). Standard OCT parameters were acquired by DRI OCT, while MCT was manually measured in 5 points on Plex ELITE 9000 images. The relationship among MCT, standard OCT parameters, and visual field indices was evaluated. Pearson’s r correlation was calculated to evaluate these relationships. Reproducibility of measurements was analyzed. Results: MCT measurements showed a good intra- and interobserver repeatability. A negative correlation appeared between MCT and BMI (r = −0.518, p = 0.023). Mean deviation showed a statistically significant correlation with MCT measured at subfoveal and at 1,000 μm nasally (r = 0.50, p = 0.03, and r = 0.52, p = 0.023). A correlation was found between the 2 MCT (Zeiss vs. Topcon) measurements and between MCT and peripapillary choroidal thickness (r = 0.944 and r = 0.740, p < 0.001, respectively). Conclusions: A good intra- and interobserver reproducibility was found. MCT showed a weak predictive value of glaucomatous visual field damage. A significant correlation was found between MCT and BMI.
Fetal Growth and Adipose Fat Tissue Trajectories in Twin Pregnancies after Gastric Bypass Surgery
Authors: Yerlikaya-Schatten Gülen , Schönleitner Theresa , Feichtinger Michael , Kotzaeridi Grammata , Eppel Daniel , Weißhaupt Karen , Henrich Wolfgang , Göbl Christian S.
Published: November 2021

Introduction: Previous studies demonstrated a continuous decline in fetal growth throughout singleton pregnancy after bariatric surgery. However, intrauterine growth in twin pregnancy is subjected to further underlying processes. This study was to investigate the longitudinal assessment of fetal biometry and abdominal fat thickness of twin pregnancies conceived after gastric bypass (GB) surgery and compare them to body mass index-matched (BMIM) and obese (OB) controls. Materials and Methods: We retrospectively assessed ultrasound data of 30 women with dichorionic-diamniotic twin pregnancy (11 women after GB surgery, 9 OB mothers with pregestational BMI ≥30 kg/m2, and 10 BMIM and age-matched controls). We assessed fetal growth parameters including fetal subcutaneous adipose tissue thickness (FSCTT) as well as newborn biometry after delivery. Patient characteristics were obtained from the medical records. Results: The rise in FSCTT curves was markedly slower in the twin offspring of women with history of GB as compared to the offspring of OB mothers and offspring of BMIM controls. Hence, FSCTT was significantly decreased in the GB offspring as compared to both control groups at 34 weeks of gestation. Also, growth curves of abdominal circumference were decreased in the offspring of GB patients as compared to OB mothers. Infants of mothers with history of GB showed significantly lower birth weight percentiles compared to newborns of OB mothers (27.2 vs. 48.8 pct, p = 0.025). There was no significant difference in inter-twin birth weight difference between the offspring of GB (median: 9.9%, interquartile ranges [IQR]: 6.5–20.0) versus OB (median: 14.6%, IQR: 8.2–21.6) and BMIM controls (median: 9.0%, IQR: 6.3–12.6, p = 0.714). Conclusions: In summary, intrauterine growth delay in twin pregnancies after GB is assumed to be a multifactorial event with altered metabolism as the most important factor. However, special attention must be paid to the particularity of twin pregnancies as they seem to be subject to other additional mechanism.
Long-Term Cognitive Changes after Revascularization Surgery in Adult Patients with Ischemic Moyamoya Disease
Authors: Uchida Shun , Kubo Yoshitaka , Oomori Daisuke , Yabuki Masahiro , Kitakami Kei , Fujiwara Shunrou , Yoshida Kenji , Kobayashi Masakazu , Terasaki Kazunori , Ogasawara Kuniaki
Published: November 2021

Introduction: Revascularization surgery for adult moyamoya disease (MMD) with ischemic presentation changes cognitive function and prevents further cerebral ischemic events. Most studies however repeated neuropsychological evaluation within 1 year after surgery. Our previous prospective cohort study of adult patients with MMD with misery perfusion who underwent direct revascularization surgery showed cognitive improvement and decline in 31% and 44%, respectively, of the patients 2 months after surgery. The present prospective study aimed to elucidate the 5-year cognitive changes after direct revascularization surgery in adult patients with cerebral misery perfusion due to ischemic MMD by following the same patients. Methods: In total, 31 patients were prospectively followed up for 5 years after direct revascularization surgery. Five types of neuropsychological tests were performed preoperatively, 2 months after surgery, and at the end of the 5-year follow-up. Cerebral blood flow (CBF) in the symptomatic cerebral hemisphere relative to that in the ipsilateral cerebellar hemisphere (hemispheric relative CBF [RCBF]) was measured using brain perfusion single-photon emission computed tomography preoperatively and at the end of the 5-year follow-up. Results: Based on results of pre- and postoperative neuropsychological tests, 11, 10, and 10 patients showed cognitive improvement, no change in cognitive function, and cognitive decline, respectively, at the end of the 5-year follow-up. These ratios were not significantly different compared with those 2 months after surgery (cognitive improvement, no change in cognitive function, and cognitive decline in 10, 8, and 13 patients, respectively). Although hemispheric RCBF was significantly greater at the end of the 5-year follow-up than before surgery in patients with cognitive improvement (80.7 ± 6.1% vs. 92.9 ± 5.5%; p = 0.0033) and in those showing no change in cognitive function (85.6 ± 3.5 vs. 91.5 ± 5.2%; p = 0.0093), this value was significantly lower at the end of the 5-year follow-up than before surgery in patients with cognitive decline (83.8 ± 3.7 vs. 81.0 ± 5.8%; p = 0.0367). Conclusion: One-third of adult patients with cerebral misery perfusion due to ischemic MMD who underwent direct revascularization surgery exhibited cognitive improvement, and one-third exhibited decline at the end of the 5-year follow-up. The former and latter patients had increased and decreased CBF, respectively, in the affected cerebral hemisphere at the end of the 5-year follow-up compared with preoperative brain perfusion.
Contemporary Management of Cardiogenic Shock: A RAND Appropriateness Panel Approach
Authors: Proudfoot Alastair G. , Kalakoutas Antonis , Meade Susanna , Griffiths Mark J.D. , Basir Mir , Burzotta Francesco , Chih Sharon , Fan Eddy , Haft Jonathan , Ibrahim Nasrien , Kruit Natalie , Lim Hoong Sern , Morrow David A. , Nakata Jun , Price Susanna , Rosner Carolyn , Roswell Robert , Samaan Mark A. , Samsky Marc D. , Thiele Holger , Truesdell Alexander G. , van Diepen Sean , Voeltz Michelle Doughty , Irving Peter M.
Published: November 2021

Background:

Current practice in cardiogenic shock is guided by expert opinion in guidelines and scientific statements from professional societies with limited high quality randomized trial data to inform optimal patient management. An international panel conducted a modified Delphi process with the intent of identifying aspects of cardiogenic shock care where there was uncertainty regarding optimal patient management.

Methods:

An 18-person multidisciplinary panel comprising international experts was convened. A modified RAND/University of California Los Angeles appropriateness methodology was used. A survey comprising 70 statements was completed. Participants anonymously rated the appropriateness of each statement on a scale of 1 to 9: 1 to 3 inappropriate, 4 to 6 uncertain, and 7 to 9 appropriate. A summary of the results was discussed as a group, and the survey was iterated and completed again before final analysis.

Results:

There was broad alignment with current international guidelines and consensus statements. Overall, 44 statements were rated as appropriate, 19 as uncertain, and 7 as inappropriate. There was no disagreement with a disagreement index <1 for all statements. Routine fluid administration was deemed to be inappropriate. Areas of uncertainty focused panel on pre-PCI interventions, the use of right heart catheterization to guide management, routine use of left ventricular unloading strategies, and markers of futility when considering escalation to mechanical circulatory support.

Conclusions:

While there was broad alignment with current guidance, an expert panel found several aspects of care where there was clinical equipoise, further highlighting the need for randomized controlled trials to better guide patient management and decision making in cardiogenic shock.
Efficacy and Safety of Dapagliflozin in Heart Failure With Reduced Ejection Fraction According to N-Terminal Pro-B-Type Natriuretic Peptide: Insights From the DAPA-HF Trial
Authors: Butt Jawad H. , Adamson Carly , Docherty Kieran F. , de Boer Rudolf A. , Petrie Mark C. , Inzucchi Silvio E. , Kosiborod Mikhail N. , Maria Langkilde Anna , Lindholm Daniel , Martinez Felipe A. , Bengtsson Olof , Schou Morten , O’Meara Eileen , Ponikowski Piotr , Sabatine Marc S. , Sjöstrand Mikaela , Solomon Scott D. , Jhund Pardeep S. , McMurray John J.V. , Køber Lars
Published: November 2021

Background:

Effective therapies for HFrEF usually reduce NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, and it is important to establish whether new treatments are effective across the range of NT-proBNP.

Methods:

We evaluated both these questions in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial. Patients in New York Heart Association functional class II to IV with a left ventricular ejection fraction ≤40% and a NT-proBNP level ≥600 pg/mL (≥600 ng/L; ≥400 pg/mL if hospitalized for HF within the previous 12 months or ≥900 pg/mL if atrial fibrillation/flutter) were eligible. The primary outcome was the composite of an episode of worsening HF or cardiovascular death.

Results:

Of the 4744 randomized patients, 4742 had an available baseline NT-proBNP measurement (median, 1437 pg/mL [interquartile range, 857–2650 pg/mL]). Compared with placebo, treatment with dapagliflozin significantly reduced NT-proBNP from baseline to 8 months (absolute least-squares mean reduction, −303 pg/mL [95% CI, −457 to −150 pg/mL]; geometric mean ratio, 0.92 [95% CI, 0.88–0.96]). Dapagliflozin reduced the risk of worsening HF or cardiovascular death, irrespective of baseline NT-proBNP quartile; the hazard ratio for dapagliflozin versus placebo, from lowest to highest quartile was 0.43 (95% CI, 0.27–0.67), 0.77 (0.56–1.04), 0.78 (0.60–1.01), and 0.78 (0.64–0.95);
P
for interaction=0.09. Consistent benefits were observed for all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement (≥5 points) in Kansas City Cardiomyopathy Questionnaire total symptom score (
P
for interaction=0.99) and decreased the proportion with a deterioration ≥5 points (
P
for interaction=0.87) across baseline NT-proBNP quartiles.

Conclusions:

In patients with HFrEF, dapagliflozin reduced NT-proBNP by 300 pg/mL after 8 months of treatment compared with placebo. In addition, dapagliflozin reduced the risk of worsening HF and death, and improved symptoms, across the spectrum of baseline NT-proBNP levels included in DAPA-HF.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03036124.
Extracellular Matrix in Heart Failure: Role of ADAMTS5 in Proteoglycan Remodeling
Authors: Barallobre-Barreiro Javier , Radovits Tamás , Fava Marika , Mayr Ursula , Lin Wen-Yu , Ermolaeva Elizaveta , Martínez-López Diego , Lindberg Eric L. , Duregotti Elisa , Daróczi László , Hasman Maria , Schmidt Lukas E. , Singh Bhawana , Lu Ruifang , Baig Ferheen , Siedlar Aleksandra Malgorzata , Cuello Friederike , Catibog Norman , Theofilatos Konstantinos , Shah Ajay M. , Crespo-Leiro Maria G. , Doménech Nieves , Hübner Norbert , Merkely Béla , Mayr Manuel
Published: November 2021

Background:

Remodeling of the extracellular matrix (ECM) is a hallmark of heart failure (HF). Our previous analysis of the secretome of murine cardiac fibroblasts returned ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) as one of the most abundant proteases. ADAMTS5 cleaves chondroitin sulfate proteoglycans such as versican. The contribution of ADAMTS5 and its substrate versican to HF is unknown.

Methods:

Versican remodeling was assessed in mice lacking the catalytic domain of ADAMTS5 (Adamts5
ΔCat
). Proteomics was applied to study ECM remodeling in left ventricular samples from patients with HF, with a particular focus on the effects of common medications used for the treatment of HF.

Results:

Versican and versikine, an ADAMTS-specific versican cleavage product, accumulated in patients with ischemic HF. Versikine was also elevated in a porcine model of cardiac ischemia/reperfusion injury and in murine hearts after angiotensin II infusion. In Adamts5
ΔCat
mice, angiotensin II infusion resulted in an aggravated versican build-up and hyaluronic acid disarrangement, accompanied by reduced levels of integrin β1, filamin A, and connexin 43. Echocardiographic assessment of Adamts5
ΔCat
mice revealed a reduced ejection fraction and an impaired global longitudinal strain on angiotensin II infusion. Cardiac hypertrophy and collagen deposition were similar to littermate controls. In a proteomics analysis of a larger cohort of cardiac explants from patients with ischemic HF (n=65), the use of β-blockers was associated with a reduction in ECM deposition, with versican being among the most pronounced changes. Subsequent experiments in cardiac fibroblasts confirmed that β1-adrenergic receptor stimulation increased versican expression. Despite similar clinical characteristics, patients with HF treated with β-blockers had a distinct cardiac ECM profile.

Conclusions:

Our results in animal models and patients suggest that ADAMTS proteases are critical for versican degradation in the heart and that versican accumulation is associated with impaired cardiac function. A comprehensive characterization of the cardiac ECM in patients with ischemic HF revealed that β-blockers may have a previously unrecognized beneficial effect on cardiac chondroitin sulfate proteoglycan content.
Abstract P357: Induction Of Soluble P-selectin And CD40 Ligand And, FXIII Deficiency Promote Aberrant Coagulation And Thromboembolism In Severe COVID-19
Authors: Al-Tamimi Abaher O , Yusuf Ayesha M , Jayakumar Manju N , Ansari Abdul W , Elhassan Mona , AbdulKarim Fatema , Kannan Meganathan , Halwani Rabih , Ahmad Firdos
Published: November 2021

Coagulation dysfunction and thromboembolism emerge as strong comorbidity factors in severe COVID-19. However, the underlying pathomechanisms are largely undefined. Here, we sought to identify the potential underlying molecular mechanisms of SARS-CoV-2 mediated coagulopathy and thromboembolism. In this series, 30 hospitalized COVID-19 patients presenting elevated D-dimer with (severe cases that required intensive care) or without pneumonia (moderate cases) were included in the study. Patients with anticoagulant/ antiplatelet therapy or with a history of cardiovascular diseases were excluded. Phenotypic and molecular characterizations were carried out employing basic coagulation tests, flow cytometry-based multiplex assays, and ELISA. The findings revealed slightly higher prothrombin and activated partial thromboplastin times (aPTT) with normal platelet counts. Elevated levels of plasma P-selectin and CD40 ligand (CD40L), markers of platelet activation, were observed in the moderate COVID-19 cases which were significantly abolished with the progression of COVID-19 severity. Moreover, analysis of the coagulation pathways revealed comparable FIX, prothrombin, and anti-thrombin levels, and a significantly higher level of fibrinogen was observed in both the moderate and severe patients vs. control group. Interestingly, the levels of plasma tissue factor pathway inhibitor (TFPI) and FXIII, a regulator of stable thrombus formation, were significantly lower particularly in the severe COVID-19 cases. Moreover, a dysregulated fibrinolysis was indicated by elevated tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI), and D-dimer levels in COVID-19 cases. In summary, SARS-CoV-2 infection-mediated endothelial cell lining damage potentially enhances soluble P-selectin and CD40L levels inducing platelet activation. Furthermore, in severe COVID-19, a decreased level of TFPI possibly contributes to additional thrombin generation through activation of the TF pathway and provides positive feedback to platelet activation and thrombus formation. FXIII deficiency plays a key role in thrombus instability which most likely promotes thromboembolism in the severe COVID-19.
Abstract P422: Sanal Flow Choking Leads To Hemorrhagic Stroke And Other Neurological Disorders In Earth And Human Spaceflight
Authors: V R Sanal Kumar ,   Indo-US Investigators on Asymptomatic Stroke and Acute MI
Published: November 2021

Background:
Evidences are escalating on the diverse neurological disorders associated with COVID-19pandemic due to the nanoscale Sanal-flow-choking
(PMC7267099)
. The Sanal-flow-chokingoccurs at relatively high and low blood viscosity. Sanal-flow-choking leads to aneurysm andhemorrhagic-stroke and other neurological-disorders if the vessel geometry is having divergence,bifurcation, stenosis and/or occlusion regions
(PMC7933821)
. Nanoscale Sanal flow choking ismore susceptible at microgravity condition due to altered variations of blood viscosity, turbulenceand the blood pressure ratio (BPR). Astronauts/Cosmonauts experienced neurological disordersduring human spaceflight and thereafter.

Methods:
Closed-form analytical, in vitro and in silico studies have been carried out for establishing thephenomenon of Sanal-flow-choking. Biofluid/blood heat capacity ratio (BHCR) of various healthysubjects are estimated.

Results:
The closed-form analytical models reveal that the relatively high and low blood viscosity arerisk factors of Sanal-flow-choking.
In vitro
study shows that N2, O2, and CO2 gases arepredominant in fresh-blood samples of the healthy human-being and
Guinea-pig
at a temperaturerange of 37-40
0
C (98.6-104
0
F), which increases the risk of Sanal-flow-choking. In silico resultsshows the Sanal-flow-choking followed by shock-waves and pressure-overshoot in a simulatedartery with the divergence region.

Conclusions:
As the pressure of the nanoscale biofluid/non-continuum-flows rises, fluid viscosityincreases and average-mean-free-path diminishes and thus, the
Knudsen number
lowers headingto a zero-slip wall-boundary condition with the compressible flow regime, which increases the riskof Sanal-flow-choking and the shock wave generation causing asymptomatic cardiovasculardisease. Microgravity environment decreases plasma volume and increases the hematocritcompared with the situation on the earth surface, which increases the relative viscosity of bloodcausing an early Sanal-flow-choking. Herein we established that the disproportionate blood-thinning treatment increases the risk of the nanoscale
Sanal-flow-choking
due to the enhancedboundary-layer-blockage factor. The risk could be diminished by concurrently reducing theviscosity of biofluid/blood and flow-turbulence by increasing thermal-tolerance-level in terms ofBHCR and/or by decreasing the BPR through new drug discovery or using companion medicinewith the traditional blood thinners or other health care management. We recommend allastronauts/cosmonauts should wear ambulatory blood pressure and thermal level monitoringdevices similar to a wristwatch throughout the space travel for the diagnosis, prognosis andprevention of internal flow choking leading to asymptomatic cardiovascular disease includingneurological disorders.