bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Cricothyroid Membrane Puncture Anesthesia and Topical Anesthesia for Awake Fiberoptic Intubation: A Double-Blinded Randomized Controlled Trial
Authors: Wang Shaocheng , Hu Chaoli , Zhang Tingting , Zhao Xuan , Li Cheng
Published: November 2021

Background: Awake fiberoptic intubation (AFOI) is commonly used for patients with a difficult airway. The purpose of this study was to evaluate the efficacy of cricothyroid membrane puncture anesthesia and topical anesthesia during AFOI.

Methods: A total of 70 patients (the American Society of Anesthesiologists score I-III) with anticipated difficult airways scheduled for nonemergency surgery with AFOI were randomly slated to receive cricothyroid membrane puncture anesthesia (n = 35) or topical anesthesia (n = 35). Each group received dexmedetomidine at a dose of 1.0 μg/kg and sufentanil at a dose of 0.2 μg/kg over 10 min for conscious sedation before intubation. The endoscopy intubation, post-intubation condition, and endoscopy tolerance as scored by the anesthetists were observed. The satisfaction of the operator regarding the procedure and the satisfaction of the patient 24 h after the surgery were also recorded. We recorded the success rate of the first intubation, intubation time, and hemodynamic changes during the procedure and also the adverse events.

Results: Better intubation scores, operator satisfaction, and satisfaction of the patient were observed in the cricothyroid membrane puncture anesthesia group than in the topical anesthesia group (p < 0.05). The intubation time in the cricothyroid membrane puncture anesthesia group was less than that in the topical anesthesia group (p < 0.05). There were no significant differences in the patient tolerance scores, the success rate of the first intubation, hemodynamic changes, and adverse events between both the groups.

Conclusion: Compared with topical anesthesia, cricothyroid membrane puncture anesthesia provided better intubation conditions and less intubation time with greater satisfaction of the patient and operator during endoscopic intubation.

Clinical Trial Registration: URL: http://www.chictr.org.cn/showproj.aspx?proj=42636, Identifier: ChiCTR 1900025820.
Metabolic Risk Factors Associated With Chronic Kidney Disease in a Middle-Aged and Elderly Taiwanese Population: A Cross-Sectional Study
Authors: Lu Mei-Chun , Chen I-Ju , Hsu Le-Tien , Chen Ying-Jen , Tsou Meng-Ting , Tung Tao-Hsin , Chen Jau-Yuan
Published: November 2021

Background: This study aimed to quantify the proportion of participants with chronic kidney disease (CKD) and associated metabolic risk factors in a middle-aged and elderly population in Guishan District, Taoyuan City, Taiwan.

Methods: This cross-sectional study enrolled residents aged 50–90 years living in one community. All participants received a standardized personal interview, including a structured questionnaire, anthropometric measurements, and blood samples collected for laboratory testing. CKD was defined as the presence of kidney damage (urine albumin-creatinine ratio ≥30 mg/g) or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. Multiple logistic regression models were used to evaluate the risk factors associated with CKD.

Results: A total of 400 participants were enrolled. The overall proportion of participants with CKD was 20.5% (95% confidence interval [CI]: 16.54–24.46%). The proportions of participants with CKD among those aged 50–64, 65–74, and 75 years and over were 17.7, 18.8, and 35.7%, respectively (p = 0.01). Multiple logistic regression model revealed that elevated blood pressure (odds ratio [OR] = 2.23, 95% CI: 1.16–4.30), hyperglycemia (OR = 2.87, 95% CI: 1.64–5.00), hyperuricemia (OR = 1.38, 95% CI: 1.14–1.69), and metabolic syndrome (OR = 2.30, 95% CI: 1.31–4.06) were significantly associated with CKD.

Conclusions: The prevalence of CKD in the study population was high. Hypertension, hyperglycemia, hyperuricemia, and metabolic syndrome are significantly associated with CKD in a middle-aged and elderly population in Taiwan.
Early Fresh Frozen Plasma Transfusion: Is It Associated With Improved Outcomes of Patients With Sepsis?
Authors: Qin Xiaoyi , Zhang Wei , Zhu Xiaodan , Hu Xiang , Zhou Wei
Published: November 2021

Background: So far, no study has investigated the effects of plasma transfusion in the patients with sepsis, especially in the terms of prognosis. Therefore, we aimed to explore the association of early fresh frozen plasma (FFP) transfusion with the outcomes of patients with sepsis.

Methods: We performed a cohort study using data extracted from the Medical Information Mart for Intensive Care III database (v1.4). External validation was obtained from the First Affiliated Hospital of Wenzhou Medical University, China. We adopted the Sepsis-3 criteria to extract the patients with sepsis and septic shock. The occurrence of transfusion during the first 3-days of intensive care unit (ICU) stay was regarded as early FFP transfusion. The primary outcome was 28-day mortality. We assessed the association of early FFP transfusion with the patient outcomes using a Cox regression analysis. Furthermore, we performed the sensitivity analysis, subset analysis, and external validation to verify the true strength of the results.

Results: After adjusting for the covariates in the three models, respectively, the significantly higher risk of death in the FFP transfusion group at 28-days [e.g., Model 2: hazard ratio (HR) = 1.361, P = 0.018, 95% CI = 1.054–1.756] and 90-days (e.g., Model 2: HR = 1.368, P = 0.005, 95% CI = 1.099–1.704) remained distinct. Contrarily, the mortality increased significantly with the increase of FFP transfusion volume. The outcomes of the patients with sepsis with hypocoagulable state after early FFP transfusion were not significantly improved. Similar results can also be found in the subset analysis of the septic shock cohort. The results of external validation exhibited good consistency.

Conclusions: Our study provides a new understanding of the rationale and effectiveness of FFP transfusion for the patients with sepsis. After recognizing the evidence of risk-benefit and cost-benefit, it is important to reduce the inappropriate use of FFP and avoid unnecessary adverse transfusion reactions.
Spot Urine Protein Excretion in the First Year Following Kidney Transplantation Associates With Allograft Rejection Phenotype at 1-Year Surveillance Biopsies: An Observational National-Cohort Study
Authors: Oblak Manca , Mlinšek Gregor , Kojc Nika , Frelih Maja , Buturović-Ponikvar Jadranka , Arnol Miha
Published: November 2021

Introduction: Urine protein excretion is routinely measured to assess kidney allograft injury, but the diagnostic value of this measurement for kidney transplant pathology remains unclear. Here we investigated whether spot urine protein excretion in the first year following transplantation associates with allograft rejection phenotype at 1-year surveillance biopsies and de-novo occurrence of donor-specific antibodies (DSA).

Patients and Methods: This prospective, observational national-cohort study included 139 non-sensitized patients who received a deceased donor kidney transplant between December 2014 and 2018. All patients received basiliximab induction and tacrolimus-based immunosuppression. Estimated protein excretion rate (ePER) was calculated monthly from spot urine protein-to-creatinine ratios. At 1-year, all recipients underwent surveillance graft biopsy and were screened for de-novo DSA. Screening-positive sera were subjected to single antigen bead (SAB) testing. The occurrence of de-novo DSA was determined based on SAB reactivity patterns using a mean fluorescence intensity threshold >1,000.

Results: Among the 139 study patients, 27 patients (19%) had histologic evidence of T cell-mediated rejection (TCMR), and 9 patients (7%) had histologic evidence of antibody-mediated rejection (AMR) at 1-year surveillance biopsy. One year after transplant, 19 patients (14%) developed de-novo DSA. Compared with patients without rejection and no de-novo DSA, mixed-effects linear regression analysis showed a significant difference in slope of ePER during the first year in patients with AMR and de-novo DSA at 1-year (46, 95% CI 25–68 mg/day/1.73 m2 per month and 34, 95% CI 20–49 mg/day/1.73 m2 per month, respectively). Patients with vascular TCMR also showed a significant difference in ePER slope over time compared with patients with non-rejection findings (31, 95% CI 9–52 mg/day/1.73 m2 per month). The discriminatory power of ePER for intragraft rejection processes was better in patients with AMR (AUC 0.95, 95% CI 0.90–0.99; P < 0.001) than in those with TCMR (AUC 0.68, 95% CI 0.59–0.79; P = 0.002), with 89% sensitivity and 93% specificity for proteinuria >550 mg/day/1.73m2.

Conclusions: An increase in ePER in the first year following kidney transplantation associates with AMR, vascular TCMR and de-novo DSA at 1-year and may be used as a non-invasive clinical marker of intragraft endothelial cell injury.
Methylation and Expression of the Exercise-Related TLR1 Gene Is Associated With Low Grade Glioma Prognosis and Outcome
Authors: Lu Lichun , Hu Yifang , Wang Chen , Jiang Feng , Wu Chuyan
Published: November 2021

Background: Exercise improves function, reduces disability, maintains independence, and improves quality of life for low-grade glioma (LGG) patients. Exercise can also improve the effectiveness of cancer treatment. The goal of this research was to find potential exercise related genes that may be used to predict exercise levels and may be used as a biomarker for cancer outcomes.

Methods: The GSE111551 database was thoroughly examined in this research, and the resulting conclusion of exercise-related genes was reached. The protein interaction network (PPI) was used to examine the differentially expressed genes (DEGs). Then the exercise-related gene TLR1 was chosen. The expression, methylation degree, prognosis, and immune relevance of TLR1 were investigated using bioinformatics. In addition, we verified the role of TLR1 in Glioma cell lines.

Results: LGG patients with reduced TLR1 expression and hypermethylation had a better overall survival (OS) and progression free survival (PFS), using the TCGA database. Low TLR1 expression and hypermethylation of TLR1 were found to be independent biomarkers for OS using Cox regression. Furthermore, the CGGA database was used to confirm the prognostic function of TLR1 in this cancer. Finally, most methylation sites of TLR1 were strongly correlated with immune infiltration and immune checkpoint. Then, reducing TLR1 expression substantially slowed the cell cycle and decreased LGG cell proliferation, emigration, and infiltration in vitro.

Conclusions: Exercise-related gene TLR1 has the potential to be a useful prognostic biomarker, and it is thought to be involved in immune cell infiltration and immunotherapy in LGG.
Application of Machine Vision in Classifying Gait Frailty Among Older Adults
Authors: Liu Yixin , He Xiaohai , Wang Renjie , Teng Qizhi , Hu Rui , Qing Linbo , Wang Zhengyong , He Xuan , Yin Biao , Mou Yi , Du Yanping , Li Xinyi , Wang Hui , Liu Xiaolei , Zhou Lixing , Deng Linghui , Xu Ziqi , Xiao Chun , Ge Meiling , Sun Xuelian , Jiang Junshan , Chen Jiaoyang , Lin Xinyi , Xia Ling , Gong Haoran , Yu Haopeng , Dong Birong
Published: November 2021

Background: Frail older adults have an increased risk of adverse health outcomes and premature death. They also exhibit altered gait characteristics in comparison with healthy individuals.

Methods: In this study, we created a Fried’s frailty phenotype (FFP) labelled casual walking video set of older adults based on the West China Health and Aging Trend study. A series of hyperparameters in machine vision models were evaluated for body key point extraction (AlphaPose), silhouette segmentation (Pose2Seg, DPose2Seg, and Mask R-CNN), gait feature extraction (Gaitset, LGaitset, and DGaitset), and feature classification (AlexNet and VGG16), and were highly optimised during analysis of gait sequences of the current dataset.

Results: The area under the curve (AUC) of the receiver operating characteristic (ROC) at the physical frailty state identification task for AlexNet was 0.851 (0.827–0.8747) and 0.901 (0.878–0.920) in macro and micro, respectively, and was 0.855 (0.834–0.877) and 0.905 (0.886–0.925) for VGG16 in macro and micro, respectively. Furthermore, this study presents the machine vision method equipped with better predictive performance globally than age and grip strength, as well as than 4-m-walking-time in healthy and pre-frailty classifying.

Conclusion: The gait analysis method in this article is unreported and provides promising original tool for frailty and pre-frailty screening with the characteristics of convenience, objectivity, rapidity, and non-contact. These methods can be extended to any gait-related disease identification processes, as well as in-home health monitoring.
Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer’s Disease and Stroke
Authors: Lemon Nicole , Canepa Elisa , Ilies Marc A. , Fossati Silvia
Published: November 2021

The Neurovascular Unit (NVU) is an important multicellular structure of the central nervous system (CNS), which participates in the regulation of cerebral blood flow (CBF), delivery of oxygen and nutrients, immunological surveillance, clearance, barrier functions, and CNS homeostasis. Stroke and Alzheimer Disease (AD) are two pathologies with extensive NVU dysfunction. The cell types of the NVU change in both structure and function following an ischemic insult and during the development of AD pathology. Stroke and AD share common risk factors such as cardiovascular disease, and also share similarities at a molecular level. In both diseases, disruption of metabolic support, mitochondrial dysfunction, increase in oxidative stress, release of inflammatory signaling molecules, and blood brain barrier disruption result in NVU dysfunction, leading to cell death and neurodegeneration. Improved therapeutic strategies for both AD and stroke are needed. Carbonic anhydrases (CAs) are well-known targets for other diseases and are being recently investigated for their function in the development of cerebrovascular pathology. CAs catalyze the hydration of CO2 to produce bicarbonate and a proton. This reaction is important for pH homeostasis, overturn of cerebrospinal fluid, regulation of CBF, and other physiological functions. Humans express 15 CA isoforms with different distribution patterns. Recent studies provide evidence that CA inhibition is protective to NVU cells in vitro and in vivo, in models of stroke and AD pathology. CA inhibitors are FDA-approved for treatment of glaucoma, high-altitude sickness, and other indications. Most FDA-approved CA inhibitors are pan-CA inhibitors; however, specific CA isoforms are likely to modulate the NVU function. This review will summarize the literature regarding the use of pan-CA and specific CA inhibitors along with genetic manipulation of specific CA isoforms in stroke and AD models, to bring light into the functions of CAs in the NVU. Although pan-CA inhibitors are protective and safe, we hypothesize that targeting specific CA isoforms will increase the efficacy of CA inhibition and reduce side effects. More studies to further determine specific CA isoforms functions and changes in disease states are essential to the development of novel therapies for cerebrovascular pathology, occurring in both stroke and AD.
Glucosamine/β-Alanine Carbon Dots Use as DNA Carriers Into E. coli Cells
Authors: Devkota Asmita , Pandey Anju , Yadegari Zeinab , Dumenyo Korsi , Taheri Ali
Published: November 2021

Introducing foreign DNA into bacterial cells is essential in functional genomics and molecular research. Currently, heat shock and electroporation are the two major techniques of gene delivery in bacterial cells. However, both the techniques are time and resource consuming and are limited to a few species or strains of bacteria and there is a need to develop new transformation alternatives. Carbon dots with unique features such as facile synthesis, ease of functionalization, nontoxicity, and biocompatibility are considered novel biomolecule nanocarriers. In this study, we synthesized and evaluated DNA delivery potential of four carbon dots including: 1) amine-coated carbon dots (NH2-FCDs); 2) carboxylate carbon dots (COOH-FCDs); 3) L-arginine and glucose carbon dots (N-CDs), and 4) citric acid and polyethyleneimine (PEI) carbon dots into Escherichia. coli cells. We evaluated the minimum incubation time required for the plasmid DNA delivery and the maximum plasmid size that can be delivered into E. coli cells using these CDs. Bacteria were incubated with carbon dots solution for different lengths of time and plated on selection media. Transformed colonies were counted and data were analyzed to identify the optimum incubation time and measure DNA delivery of these CDs with plasmids of different sizes. Our study demonstrated that among all these CDs, only carboxylate carbon dots (COOH-FCDs) prepared from glucosamine and β-alanine were able to deliver plasmid DNA into E. coli cells and the best incubation time was between 30 and 60 min. The maximum plasmid size that could be delivered using these CDs was approximately 10 kb and transformation efficiency decreased with larger plasmids. This study shows the capacity of COOH-CDs to deliver plasmid DNA into bacteria with an immense potential to combine with modern genome-editing tools. However, further studies are needed to evaluate their potential in DNA delivery in other bacterial strains.
Activation of Adenosine Monophosphate-Activated Protein Kinase Drives the Aerobic Glycolysis in Hippocampus for Delaying Cognitive Decline Following Electroacupuncture Treatment in APP/PS1 Mice
Authors: Li Jianhong , Zhang Bingxue , Jia Weiwei , Yang Minguang , Zhang Yuhao , Zhang Jiayong , Li Le , Jin Tingting , Wang Zhifu , Tao Jing , Chen Lidian , Liang Shengxiang , Liu Weilin
Published: November 2021

Aerobic glycolysis (AG), an important pathway of glucose metabolism, is dramatically declined in Alzheimer’s disease (AD). AMP-activated protein kinase (AMPK) is a key regulator to maintain the stability of energy metabolism by promoting the process of AG and regulating glucose metabolism. Interestingly, it has been previously reported that electroacupuncture (EA) treatment can improve cognitive function in AD through the enhancement of glucose metabolism. In this study, we generated AMPK-knockdown mice to confirm the EA effect on AMPK activation and further clarify the mechanism of EA in regulating energy metabolism and improving cognitive function in APP/PS1 mice. The behavioral results showed that EA treatment can improve the learning and memory abilities in APP/PS1 mice. At the same time, the glucose metabolism in the hippocampus was increased detected by MRI-chemical exchange saturation transfer (MRI-CEST). The expression of proteins associated with AG in the hippocampus was increased simultaneously, including hexokinase II (HK2), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), and pyruvate kinase M2 (PKM2). Moreover, the knockdown of AMPK attenuated AG activated by EA treatment. In conclusion, this study proves that EA can activate AMPK to enhance the process of AG in the early stage of AD.
Facial Paresthesia, a Rare Manifestation of Hereditary Neuropathy With Liability to Pressure Palsies: A Case Report
Authors: De Kock Lisa , Van der Cruyssen Fréderic , Gruijthuijsen Leonore , Politis Constantinus
Published: November 2021

Trigeminal sensory neuropathy can be caused by a variety of conditions, including local, traumatic, iatrogenic, or systemic causes. Diagnosis and management remain a challenge for maxillofacial surgeons and neurologists. Therefore, a good clinical examination and objective tests and imaging are needed when diagnosing patients who present with facial numbness. We present a case with spontaneous episodes of facial paresthesia. He was diagnosed with hereditary neuropathy with liability to pressure palsies (HNPP), a rare condition that affects the peripheral nerves. Only a few case reports that describe involvement of the cranial nerves in patients with HNPP were found in the literature, and facial paresthesia has not been previously reported.
Investigating Different Levels of Bimanual Interaction With a Novel Motor Learning Task: A Behavioural and Transcranial Alternating Current Stimulation Study
Authors: Schoenfeld Marleen J. , Grigoras Ioana-Florentina , Stagg Charlotte J. , Zich Catharina
Published: November 2021

Many tasks require the skilled interaction of both hands, such as eating with knife and fork or keyboard typing. However, our understanding of the behavioural and neurophysiological mechanisms underpinning bimanual motor learning is still sparse. Here, we aimed to address this by first characterising learning-related changes of different levels of bimanual interaction and second investigating how beta tACS modulates these learning-related changes. To explore early bimanual motor learning, we designed a novel bimanual motor learning task. In the task, a force grip device held in each hand (controlling x- and y-axis separately) was used to move a cursor along a path of streets at different angles (0°, 22.5°, 45°, 67.5°, and 90°). Each street corresponded to specific force ratios between hands, which resulted in different levels of hand interaction, i.e., unimanual (Uni, i.e., 0°, 90°), bimanual with equal force (Bieq, 45°), and bimanual with unequal force (Biuneq 22.5°, 67.5°). In experiment 1, 40 healthy participants performed the task for 45 min with a minimum of 100 trials. We found that the novel task induced improvements in movement time and error, with no trade-off between movement time and error, and with distinct patterns for the three levels of bimanual interaction. In experiment 2, we performed a between-subjects, double-blind study in 54 healthy participants to explore the effect of phase synchrony between both sensorimotor cortices using tACS at the individual’s beta peak frequency. The individual’s beta peak frequency was quantified using electroencephalography. 20 min of 2 mA peak-to-peak amplitude tACS was applied during task performance (40 min). Participants either received in-phase (0° phase shift), out-of-phase (90° phase shift), or sham (3 s of stimulation) tACS. We replicated the behavioural results of experiment 1, however, beta tACS did not modulate motor learning. Overall, the novel bimanual motor task allows to characterise bimanual motor learning with different levels of bimanual interaction. This should pave the way for future neuroimaging studies to further investigate the underlying mechanism of bimanual motor learning.
Cross-Task Consistency of Electroencephalography-Based Mental Workload Indicators: Comparisons Between Power Spectral Density and Task-Irrelevant Auditory Event-Related Potentials
Authors: Ke Yufeng , Jiang Tao , Liu Shuang , Cao Yong , Jiao Xuejun , Jiang Jin , Ming Dong
Published: November 2021

Mental workload (MWL) estimators based on ongoing electroencephalography (EEG) and event-related potentials (ERPs) have shown great potentials to build adaptive aiding systems for human–machine systems by estimating MWL in real time. However, extracting EEG features which are consistent in indicating MWL across different tasks is still one of the critical challenges. This study attempts to compare the cross-task consistency in indexing MWL variations between two commonly used EEG-based MWL indicators, power spectral density (PSD) of ongoing EEG and task-irrelevant auditory ERPs (tir-aERPs). The verbal N-back and the multi-attribute task battery (MATB), both with two difficulty levels, were employed in the experiment, along with task-irrelevant auditory probes. EEG was recorded from 17 subjects when they were performing the tasks. The tir-aERPs elicited by the auditory probes and the relative PSDs of ongoing EEG between two consecutive auditory probes were extracted and statistically analyzed to reveal the effects of MWL and task type. Discriminant analysis and support vector machine were employed to examine the generalization of tir-aERP and PSD features in indexing MWL variations across different tasks. The results showed that the amplitudes of tir-aERP components, N1, early P3a, late P3a, and the reorienting negativity, significantly decreased with the increasing MWL in both N-back and MATB. Task type had no obvious influence on the amplitudes and topological layout of the MWL-sensitive tir-aERP features. The relative PSDs in θ, α, and low β bands were also sensitive to MWL variations. However, the MWL-sensitive PSD features and their topological patterns were significantly affected by task type. The cross-task classification results based on tir-aERP features also significantly outperformed the PSD features. These results suggest that the tir-aERPs should be potentially more consistent MWL indicators across very different task types when compared to PSD. The current study may provide new insights to our understanding of the common and distinctive neuropsychological essences of MWL across different tasks.
The Impact of Multimorbidity Burden, Frailty Risk Scoring, and 3-Directional Morphological Indices vs. Testing for CSF Responsiveness in Normal Pressure Hydrocephalus
Authors: Soon Shereen X. Y. , Kumar A. Aravin , Tan Audrey J. L. , Lo Yu Tung , Lock Christine , Kumar Sumeet , Kwok Janell , Keong Nicole C.
Published: November 2021

Objective: Multimorbidity burden across disease cohorts and variations in clinico-radiographic presentations within normal pressure hydrocephalus (NPH) confound its diagnosis, and the assessment of its amenability to interventions. We hypothesized that novel imaging techniques such as 3-directional linear morphological indices could help in distinguishing between hydrocephalus vs. non-hydrocephalus and correlate with responsiveness to external lumbar drainage (CSF responsiveness) within NPH subtypes.

Methodology: Twenty-one participants with NPH were recruited and age-matched to 21 patients with Alzheimer’s Disease (AD) and 21 healthy controls (HC) selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Patients with NPH underwent testing via the NPH programme with external lumbar drainage (ELD); pre- and post-ELD MRI scans were obtained. The modified Frailty Index (mFI-11) was used to stratify the NPH cohort, including Classic and Complex subtypes, by their comorbidity and frailty risks. The quantitative imaging network tool 3D Slicer was used to derive traditional 2-dimensional (2d) linear measures; Evans Index (EI), Bicaudate Index (BCI) and Callosal Angle (CA), along with novel 3-directional (3d) linear measures; z-Evans Index and Brain per Ventricle Ratio (BVR). 3-Dimensional (3D) ventricular volumetry was performed as an independent correlate of ventriculomegaly to CSF responsiveness.

Results: Mean age for study participants was 71.14 ± 6.3 years (18, 85.7% males). The majority (15/21, 71.4%) of participants with NPH comprised the Complex subtype (overlay from vascular risk burden and AD); 12/21 (57.1%) were Non-Responders to ELD. Frailty alone was insufficient in distinguishing between NPH subtypes. By contrast, 3d linear measures distinguished NPH from both AD and HC cohorts, but also correlated to CSF responsiveness. The z-Evans Index was the most sensitive volumetric measure of CSF responsiveness (p = 0.012). Changes in 3d morphological indices across timepoints distinguished between Responders vs. Non-Responders to lumbar testing. There was a significant reduction of indices, only in Non-Responders and across multiple measures (z-Evans Index; p = 0.001, BVR at PC; p = 0.024). This was due to a significant decrease in ventricular measurement (p = 0.005) that correlated to independent 3D volumetry (p = 0.008).

Conclusion. In the context of multimorbidity burden, frailty risks and overlay from neurodegenerative disease, 3d morphological indices demonstrated utility in distinguishing hydrocephalus vs. non-hydrocephalus and degree of CSF responsiveness. Further work may support the characterization of patients with Complex NPH who would best benefit from the risks of interventions.
Effects of Perioperative Dexmedetomidine on Immunomodulation in Uterine Cancer Surgery: A Randomized, Controlled Trial
Authors: Cho Jin Sun , Seon Kieun , Kim Min-Yu , Kim Sang Wun , Yoo Young Chul
Published: November 2021

Objective

Dexmedetomidine has sympatholytic, anti-inflammatory, and analgesic effects and may exert anti-tumor effect by acting on α2A adrenoreceptor. We investigated whether perioperative dexmedetomidine preserves immune function in patients undergoing uterine cancer surgery.

Methods

One hundred patients were randomly assigned to the control or dexmedetomidine groups (50 patients each). Dexmedetomidine was infused at rates of 0.4 μg/kg/h intraoperatively and 0.15 μg/kg/h during the first 24 h postoperatively. The primary outcome was natural killer (NK) cell activity, which was measured preoperatively and 1, 3, and 5 days postoperatively. The inflammatory response was measured by interleukin-6, interferon-γ, and neutrophil/lymphocyte ratio, and pain scores and opioid consumption were assessed. Cancer recurrence or metastasis and death were evaluated 2 years postoperatively.

Results

NK cell activity decreased postoperatively in both groups and changes over time were not different between groups (P=0.496). Interferon-γ increased postoperatively in the dexmedetomidine group, whereas it maintained at the baseline value in the control group. Change in interferon-γ differed significantly between groups (P=0.003). Changes in interleukin-6 and neutrophil-lymphocyte ratio were comparable between groups. Both pain score with activity during the first 1 h and opioid consumption during the first 1–24 h postoperatively were lower in the dexmedetomidine group. Rates of cancer recurrence/metastasis (16.3% vs. 8.7%, P=0.227) and death within 2 years postoperatively (6.7% vs. 2.2%, P=0.318) were not different between groups.

Conclusions

Perioperative dexmedetomidine had no favorable impacts on NK cell activity, inflammatory responses, or prognosis, whereas it increased interferon-γ and reduced early postoperative pain severity and opioid consumption in uterine cancer surgery patients.
Lenvatinib Plus Immune Checkpoint Inhibitors Improve Survival in Advanced Hepatocellular Carcinoma: A Retrospective Study
Authors: Huang Xiaozhun , Xu Lin , Ma Teng , Yin Xin , Huang Zhangkan , Ran Yihong , Ni Yong , Bi Xinyu , Che Xu
Published: November 2021

Background

Nivolumab and pembrolizumab disrupt the programmed cell death-1 immune checkpoint and display promising efficacy and safety results in advanced hepatocellular carcinoma (HCC). However, the benefits remain limited. The preliminary results of lenvatinib (LEN) combined with immune checkpoint inhibitors (ICIs) reveal that the combinations were well-tolerated and encouraging. This study aimed to analyze the safety and efficacy of LEN plus ICIs in a real-world cohort of patients with advanced HCC.

Method

Between June 4, 2017, and June 30, 2019, 16 patients received LEN plus nivolumab, and 13 patients were treated with LEN plus pembrolizumab, with the confirmed advanced HCC retrospectively analyzed. The clinical parameters, as well as the outcomes, were assessed.

Results

All the patients had Barcelona Clinical Liver Cancer Stage C. LEN with ICIs was used as systemic second-, third-, and fourth-line treatments in seven (24.1%), 14 (48.3%), and eight (27.6%) patients, respectively. At the time of data cutoff, six patients (37.5%) were still receiving LEN with nivolumab, while another six patients (46.2%) were still receiving LEN with pembrolizumab. An objective response was recorded in seven patients (25.9%), while the best overall responses were from one complete response and six partial responses. The 6- and 12-month over survival (OS) rates were 62.6% and 53.7%, respectively. Furthermore, the 6- and 12-month progression-free survival (PFS) rates were 43.5% and 31.8%, respectively. In the subgroup analyses, the 6- and 12-month OS and PFS rates for patients treated with LEN plus nivolumab were 62.5% and 52.1%, respectively, and 43.8% and 30.0%, respectively. The 6- and 12-month OS and PFS rates for patients treated with LEN plus pembrolizumab were 51.3% and 51.3%, respectively, and 49.2% and 49.2%, respectively. A total of 11 (31%) deaths were reported in this study, four of which were attributed to grade 5 adverse events presented as fatal treatment-related hepatitis.

Conclusion

The combination of LEN and ICIs is a promising new strategy for the treatment of HCC patients. However, high-grade hepatic toxicity was observed and further evaluation of this combination is still required.
The Surgeon’s Proficiency Affected Survival Outcomes of Minimally Invasive Surgery for Early-Stage Cervical Cancer: A Retrospective Study of 851 Patients
Authors: Yang Ying , Huang Yue , Li Zhengyu
Published: November 2021

Purpose

To compare the clinical outcomes of patients with early-stage cervical cancer who underwent minimally invasive surgery (MIS) by surgeons in different phases and evaluate whether the proficiency of surgeons affects the survival outcomes.

Materials and Methods

A total of 851 patients with early-stage cervical cancer who underwent radical hysterectomy between January 2008 and June 2018 (every year from January to June) at a tertiary hospital were retrospectively analyzed. We categorized patients into four phases according to their sequence (phase one, 1-10 cases; phase two: 11-20 cases; phase three: 21-30 cases; phase four: > 30 cases). Demographics and clinical and pathological data were collected and analyzed.

Results

There were no statistical differences between the open surgery and MIS groups regarding three- and five-year overall survival (OS) and disease-free survival (DFS). The OS and DFS of patients in the MIS group in phase one were significantly lower than those in later phases and those in the open surgery group after adjustment (OS, P = 0.009; HR, 2.896; 95%CI, 1.303-6.435; DFS, P = 0.009; HR, 2.712; 95%CI, 1.289-5.706). Survival outcomes were not statistically significant when comparing different surgeons.

Conclusion

The phase one cases of MIS had lower OS and DFS than those in later phases and those in the open surgery group. Thus, we suggest that the proficiency of surgeons is associated with survival outcomes of MIS. Favorable outcomes can be obtained after a certain number of MIS cases.
Opioid Therapy in Cancer Patients and Survivors at Risk of Addiction, Misuse or Complex Dependency
Authors: Pergolizzi Joseph V. , Magnusson Peter , Christo Paul J. , LeQuang Jo Ann , Breve Frank , Mitchell Kailyn , Varrassi Giustino
Published: November 2021

A clinical conundrum can occur when a patient with active opioid use disorder (OUD) or at elevated risk for the condition presents with cancer and related painful symptoms. Despite earlier beliefs that cancer patients were relatively unaffected by opioid misuse, it appears that cancer patients have similar risks as the general population for OUD but are more likely to need and take opioids. Treating such patients requires an individualized approach, informed consent, and a shared decision-making model. Tools exist to help stratify patients for risk of OUD. While improved clinician education in pain control is needed, patients too need to be better informed about the risks and benefits of opioids. Patients may fear pain more than OUD, but opioids are not always the most effective pain reliever for a given patient and some patients do not tolerate or want to take opioids. The association of OUD with mental health disorders (dual diagnosis) can also complicate delivery of care as patients with mental health issues may be less adherent to treatment and may use opioids for “chemical coping” as much as for pain control.
Cannabinoid Receptor 1 Expression in Human Dorsal Root Ganglia and CB13-Induced Bidirectional Modulation of Sensory Neuron Activity
Authors: Ford Zachary K. , Reker Ashlie N. , Chen Sisi , Kadakia Feni , Bunk Alexander , Davidson Steve
Published: November 2021

Cannabinoid receptors have been identified as potential targets for analgesia from studies on animal physiology and behavior, and from human clinical trials. Here, we sought to improve translational understanding of the mechanisms of cannabinoid-mediated peripheral analgesia. Human lumbar dorsal root ganglia were rapidly recovered from organ donors to perform physiological and anatomical investigations into the potential for cannabinoids to mediate analgesia at the level of the peripheral nervous system. Anatomical characterization of in situ gene expression and immunoreactivity showed that 61 and 53% of human sensory neurons express the CB1 gene and receptor, respectively. Calcium influx evoked by the algogen capsaicin was measured by Fura-2AM in dissociated human sensory neurons pre-exposed to the inflammatory mediator prostaglandin E2 (PGE2) alone or together with CB13 (1 μM), a cannabinoid agonist with limited blood–brain barrier permeability. Both a higher proportion of neurons and a greater magnitude of response to capsaicin were observed after exposure to CB13, indicating cannabinoid-mediated sensitization. In contrast, membrane properties measured by patch-clamp electrophysiology demonstrated that CB13 suppressed excitability and reduced action potential discharge in PGE2-pre-incubated sensory neurons, suggesting the suppression of sensitization. This bidirectional modulation of sensory neuron activity suggests that cannabinoids may suppress overall membrane excitability while simultaneously enhancing responsivity to TRPV1-mediated stimuli. We conclude that peripherally restricted cannabinoids may have both pro- and anti-nociceptive effects in human sensory neurons.
Risk and Preventive Factors for SUDI: Need We Adjust the Current Prevention Advice in a Low-Incidence Country
Authors: Kanits Floortje , L'Hoir Monique P. , Boere-Boonekamp Magda M. , Engelberts Adèle C. , Feskens Edith J. M.
Published: November 2021

Background: The incidence of Sudden Unexpected Death in Infancy (SUDI) is low in the Netherlands, with an incidence rate of 0.18 per 1,000 live births. Therefore, prevention advice may receive less attention, potentially leading to increasing incidence rates. It is currently unknown whether the risks for SUDI changed in the Netherlands, and if other risk factors might be present. The aim of this study was to examine the current risks and preventive factors for SUDI in Dutch infants, in order to determine if it is necessary to adapt the prevention advice toward the current needs.

Methods: A case-control study was conducted comparing SUDI cases aged <12 months from 2014–2020 in the Netherlands (n = 47), to a Dutch national survey control group from 2017 including infants <12 months of age (n = 1,192).

Results: Elevated risks for several well-known factors were observed, namely: duvet use (aOR = 8.6), mother smoked during pregnancy (aOR = 9.7), or after pregnancy (aOR = 5.4) and the prone sleeping position (aOR = 4.6). Reduced risks were observed for the well-known factors: room-sharing (aOR = 0.3), sleep sack use (aOR = 0.3), breastfeeding (aOR = 0.3), and the use of a pacifier (aOR = 0.4). For infants <4 months, the risk for SUDI was higher when bed-sharing (aOR = 3.3), and lower when room-sharing (aOR = 0.2) compared to older infants. For older infants, the sleep sack was found to be more protective (aOR = 0.2). A high risk for SUDI when bed-sharing was found when mother smoked, smoked during pregnancy, or if the infant did not receive any breastfeeding (respectively aOR = 17.7, aOR = 10.8, aOR = 9.2).

Conclusions: Internationally known factors related to the sudden unexpected death of infants were also found in this study. Relatively new findings are related to specific groups of infants, in which the strengths of these risk factors differed. In a low-incidence country like the Netherlands, renewed attention to the current prevention advice is needed. Furthermore, additional attention for prevention measures in low educated groups, and additional advice specifically targeting high-risk groups is recommended.
Taxus wallichiana var. chinensis (Pilg.) Florin Aqueous Extract Suppresses the Proliferation and Metastasis in Lung Carcinoma via JAK/STAT3 Signaling Pathway
Authors: Sun Leitao , Ding Shuning , Luo Qi , Wang Peipei , Yang Xiao , Wu Linqin , Chen Yangfan , Zheng Xueer , Zhang Hang , Yuan Li , Ruan Shanming , Xie Changsheng
Published: November 2021

As one of the most common neoplasms globally, lung cancer (LC) is the leading cause of cancer-related mortality. Recurrence and metastasis negatively influencing therapeutic efficacy and overall survival demand new strategies in LC treatment. The advantages of TCM are increasingly highlighted. In this study, we obtained the major chemical components and their ratios in the aqueous extract of Taxus wallichiana var. chinensis (Pilg.) Florin (AETW) by UPLC-Q/TOF-MS/MS detection. The CCK-8 assay revealed that AETW could selectively inhibit the growth of A549 and HCC827 cells in a dose-dependent manner with little effect on normal human lung cells. Moreover, both in vitro and in vivo experiments showed that AETW was able to suppress the capacities of cell migration and invasion and downregulate the EMT and the JAK/STAT3 signaling pathway. To further probe into the molecular mechanism, the overexpression of STAT3 was performed into LC cells with AETW treatment, which counteracted the inhibitory effect on malignant behaviors of A549 and HCC827 cells with the decline in the expressions of p-JAK and p-STAT3. Taken together, we propose that AETW may inhibit the proliferation and metastasis by inactivating the JAK/STAT3 axis.
Intranasal Delivery of Nerve Growth Factor in Neurodegenerative Diseases and Neurotrauma
Authors: Manni Luigi , Conti Giorgio , Chiaretti Antonio , Soligo Marzia
Published: November 2021

Since the 1980s, the development of a pharmacology based on nerve growth factor (NGF) has been postulated for the therapy of Alzheimer’s disease (AD). This hypothesis was based on the rescuing effect of the neurotrophin on the cholinergic phenotype of the basal forebrain neurons, primarily compromised during the development of AD. Subsequently, the use of NGF was put forward to treat a broader spectrum of neurological conditions affecting the central nervous system, such as Parkinson’s disease, degenerative retinopathies, severe brain traumas and neurodevelopmental dysfunctions. While supported by solid rational assumptions, the progress of a pharmacology founded on these hypotheses has been hampered by the difficulty of conveying NGF towards the brain parenchyma without resorting to invasive and risky delivery methods. At the end of the last century, it was shown that NGF administered intranasally to the olfactory epithelium was able to spread into the brain parenchyma. Notably, after such delivery, pharmacologically relevant concentration of exogenous NGF was found in brain areas located at considerable distances from the injection site along the rostral-caudal axis. These observations paved the way for preclinical characterization and clinical trials on the efficacy of intranasal NGF for the treatment of neurodegenerative diseases and of the consequences of brain trauma. In this review, a summary of the preclinical and clinical studies published to date will be attempted, as well as a discussion about the mechanisms underlying the efficacy and the possible development of the pharmacology based on intranasal conveyance of NGF to the brain.
Antinociceptive and Antipruritic Effects of HSK21542, a Peripherally-Restricted Kappa Opioid Receptor Agonist, in Animal Models of Pain and Itch
Authors: Wang Xin , Gou Xiaoli , Yu Xiaojuan , Bai Dongdong , Tan Bowei , Cao Pingfeng , Qian Meilin , Zheng Xiaoxiao , Wang Hairong , Tang Pingming , Zhang Chen , Ye Fei , Ni Jia
Published: November 2021

Kappa opioid receptor (KOR) agonists have been promising therapeutic candidates, owing to their potential for relieving pain and treating intractable pruritus. Although lacking morphine-like central nervous system (CNS) effects, KOR agonists do elicit sedation, dysphoria and diuresis which seriously impede their development. Peripherally-restricted KOR agonists have a poor ability to penetrate into the CNS system, so that CNS-related adverse effects can be ameliorated or even abolished. However, the only approved peripherally-restricted KOR agonist CR845 remains some frequent CNS adverse events. In the present study, we aim to address pharmacological profiles of HSK21542, with an expectation to provide a safe and effective alternative for patients who are suffering from pain and pruritus. The in vitro experimental results showed that HSK21542 was a selective and potent KOR agonist with higher potency than CR845, and had a brain/plasma concentration ratio of 0.001, indicating its peripheral selectivity. In animal models of pain, HSK21542 significantly inhibited acetic acid-, hindpaw incision- or chronic constriction injury-induced pain-related behaviors, and the efficacy was comparable to CR845 at 15 min post-dosing. HSK21542 had a long-lasting analgesic potency with a median effective dose of 1.48 mg/kg at 24 h post-drug in writhing test. Meanwhile, the antinociceptive activity of HSK21542 was effectively reversed by a KOR antagonist nor-binaltorphimine. In addition, HSK21542 had powerful antipruritic activities in compound 48/80-induced itch model. On the other hand, HSK21542 had a weak ability to produce central antinociceptive effects in a hot-plate test and fewer effects on the locomotor activity of mice. HSK21542 didn’t affect the respiratory rate of mice. Therefore, HSK21542 might be a safe and effective KOR agonist and promising candidate for treating pain and pruritus.
Drought Stress Influences the Growth and Physiological Characteristics of Solanum rostratum Dunal Seedlings From Different Geographical Populations in China
Authors: Yu Hailun , Zhao Xueyong , Huang Wenda , Zhan Jin , He Yuanzheng
Published: November 2021

Extensive studies have shown that the success of invasive plants in large environmental gradients can be partly attributed to related factors, including phenotypic plasticity and rapid evolution. To enhance their ability to compete and invade, invasive plants often show higher morphological and physiological plasticity to adapt to different habitat conditions. In the past two decades, invasive species have expanded to some new habitats in North and Northwest China, including arid oasis agricultural zones, which are disturbed by human activities, and the ecosystem itself is very fragile. To evaluate the ecological adaptability of invasive plants widely distributed in North and Northwest China, we studied the physiological response and tolerance mechanism of different geographical populations of Solanum rostratum Dunal to different drought-stress gradients in extremely arid regions (Xinjiang population) and semi-arid regions (Inner Mongolia population). The results showed that with the aggravation of drought stress, S. rostratum from different geographical populations adopted different physiological mechanisms to drought stress. Xinjiang population was mostly affected by root/shoot ratio and chlorophyll fluorescence characteristics, showing higher plasticity in the net and total photosynthetic rates, while the Inner Mongolia population mainly relied on the accumulation of osmotic adjustment substances, higher leaf dry matter content, and increased malondialdehyde to cope with drought stress. Based on these results, we concluded that the physiological responses of S. rostratum invading different habitats in northern China to drought stress were significantly different. The drought resistance of the Xinjiang population was higher than that of the Inner Mongolia population. In general, S. rostratum can be widely adapted to both harsh and mild habitats through phenotypic plasticity, threatening agricultural production and ecological environment security in northern China.