bluuebunny/crossref_metadata_2025 huggingface dataset:
Case Report: A 91-Year-Old Patient With Non-Small Cell Lung Cancer Harboring MET Y1003S Point Mutation
Authors: Gao Beili , Zeng Ran
Published: January 2022

Background

The Y1003S point mutation in exon 14 of mesenchymal-epithelial transition (MET) is a rare mutation that can lead to oncogenic transformation. Few data are available on the characteristics of this mutation. This report presents an elderly patient with non-small cell lung cancer (NSCLC) and a Y1003S mutation in MET detected by next-generation sequencing (NGS).

Case Report

In October 2020, a 91-year-old male was admitted to the Department of Respiratory and Critical Care Medicine, Ruijin Hospital because of an increased carcinoembryonic antigen. Imaging revealed highly suspicious lesions in the right upper lobe of the lung, right apex, and left upper lobe with traction of the adjacent pleura. The patient was histologically confirmed as having adenocarcinoma and the MET Y1003S mutation was detected by the NGS subsequently. After evaluation, the patient started crizotinib treatment in December 2020. In the first assessment of tumor response, a chest CT scan in January 2021 showed a partial response. The patient experienced a pulmonary embolism and an abnormal liver function during the treatment and recovered after symptomatic treatment. He maintained a partial response in the last available assessment in July 2021, with the right upper lung lesion being 26 × 9 mm.

Conclusion

The MET Y1003S mutation was detected in this case, and the patient achieved a partial response using crizotinib. This case highlighted the role of NGS in detecting a rare mutation. Successful remission of complications in such an elderly patient necessitates careful and timely management.
Establishment and Validation of a Non-Invasive Diagnostic Nomogram to Identify Spontaneous Bacterial Peritonitis in Patients With Decompensated Cirrhosis
Authors: Xiang Shoushu , Tan Juntao , Tan Chao , Xu Qian , Wen Yuanjiu , Wang Tiantian , Yang Chen , Zhao Wenlong
Published: January 2022

Background

Spontaneous bacterial peritonitis (SBP) is a common and life-threatening infection in patients with decompensated cirrhosis (DC), and it is accompanied with high mortality and morbidity. However, early diagnosis of spontaneous bacterial peritonitis (SBP) is not possible because of the lack of typical symptoms or the low patient compliance and positivity rate of the ascites puncture test. We aimed to establish and validate a non-invasive diagnostic nomogram to identify SBP in patients with DC.

Method

Data were collected from 4,607 patients with DC from July 2015 to December 2019 in two tertiary hospitals in Chongqing, China (A and B). Patients with DC were divided into the SBP group (995 cases) and the non-SBP group (3,612 cases) depending on whether the patients had SBP during hospitalization. About 70% (2,685 cases) of patients in hospital A were randomly selected as the traindata, and the remaining 30% (1,152 cases) were used as the internal validation set. Patients in hospital B (770 cases) were used as the external validation set. The univariate analysis and least absolute shrinkage and selection operator (LASSO) regression were used to screen variables, and logistic regression was used to determine independent predictors to construct a nomogram to identify patients with SBP. Area under curve (AUC), calibration curve, and dynamic component analysis (DCA) were carried out to determine the effectiveness of the nomogram.

Result

The nomogram was composed of seven variables, namely, mean red blood cell hemoglobin concentration (odds ratio [OR] = 1.010, 95% CI: 1.004–1.016), prothrombin time (OR = 1.038, 95% CI: 1.015–1.063), lymphocyte percentage (OR = 0.955, 95% CI: 0.943–0.967), prealbumin (OR = 0.990, 95% CI: 0.987–0.993), total bilirubin (OR = 1.003 95% CI: 1.002–1.004), abnormal C-reactive protein (CRP) level (OR = 1.395, 95% CI: 1.107–1.755), and abnormal procalcitonin levels (OR = 1.975 95% CI: 1.522–2.556). Good discrimination of the model was observed in the internal and external validation sets (AUC = 0.800 and 0.745, respectively). The calibration curve result indicated that the nomogram was well-calibrated. The DCA curve of the nomogram presented good clinical application ability.

Conclusion

This study identified the independent risk factors of SBP in patients with DC and used them to construct a nomogram, which may provide clinical reference information for the diagnosis of SBP in patients with DC.
Case Report: A Pathogenic Missense Variant of WT1 Cosegregates With Proteinuria in a Six-Generation Chinese Family With IgA Nephropathy
Authors: Li Qianqian , Zhu Li , Shi Sufang , Xu Damin , Lv Jicheng , Zhang Hong
Published: January 2022

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide. In addition to hematuria, proteinuria is observed in a considerable proportion of patients with IgAN and has proven to be a strong risk factor for disease progression. Although the exact pathogenesis of IgAN is still unclear, genetic factors are widely considered to play a role in its occurrence and development. Here, we investigated a large IgAN-associated pedigree of 47 members belonging to six generations. Two members of the family who presented with proteinuria and hematuria were diagnosed with IgAN through renal biopsy. Four other members also exhibited proteinuria or hematuria but without renal biopsy. Using whole-exome sequencing, we identified a likely pathogenic variant in WT1 (c.1397C>T; p.Ser466Phe) that cosegregated with proteinuria in the affected family members. In addition, another pathogenic variant in NPHS1 (c.3478C>T; p.Arg1160Ter) was identified; however, it did not cosegregate with abnormal proteinuria. Compared to individuals in the pedigree with only one heterozygous WT1 variant (c.1397C>T; p.Ser466Phe), the proband and her younger brother carried an additional WT1 variant (c.1433-10G>A) and presented with a more severe phenotype and rapid progression to end-stage kidney disease. Our findings suggest the WT1 missense variant (c.1397C>T; p.Ser466Phe)-induced primary podocyte injury might contribute to the proteinuria phenotype and IgAN progression in this pedigree.
Emerging Trends and Hot Spots of Electrical Impedance Tomography Applications in Clinical Lung Monitoring
Authors: Li Zhe , Qin Shaojie , Chen Chen , Mei Shuya , Yao Yulong , Zhao Zhanqi , Li Wen , Deng Yuxiao , Gao Yuan
Published: January 2022

Objective

This study explores the emerging trends and hot topics concerning applications on electrical impedance tomography (EIT) in clinical lung monitoring.

Methods

Publications on EIT applications in clinical lung monitoring in 2001–2021 were extracted from the Web of Science Core Collection (WoSCC). The search strategy was “electrical impedance tomography” and “lung.” CiteSpace, a VOS viewer was used to study the citation characteristics, cooperation, and keyword co-occurrence. Moreover, co-cited reference clustering, structural variation analysis (SVA), and future research trends were presented.

Results

Six hundred and thirty-six publications were included for the final analysis. The global annual publications on clinical lung monitoring gradually increased in the last two decades. Germany contributes 32.2% of total global publications. University Medical Center Schleswig-Holstein (84 publications, cited frequency 2,205), Physiological Measurement (105 publications, cited frequency 2,056), and Inéz Frerichs (116 articles, cited frequency 3,609) were the institution, journal, and author with the largest number of article citations in the research field. “Electrical impedance tomography” (occurrences, 304), “mechanical ventilation” (occurrences, 99), and “acute respiratory distress syndrome” (occurrences, 67) were the top most three frequent keywords, “noninvasive monitoring” (Avg, pub, year: 2008.17), and “extracorporeal membrane oxygenation” (Avg, pub, year: 2019.60) were the earliest and latest keywords. The keywords “electrical impedance tomography” (strength 7.88) and co-cited reference “Frerichs I, 2017, THORAX” (strength 47.45) had the highest burst value. “Driving pressure,” “respiratory failure,” and “titration” are the three keywords still maintaining a high brush value until now. The largest and smallest cluster of the co-cited references are “obstructive lung diseases” (#0, size: 97) and “lung perfusion” (#20, size: 5). Co-cited reference “Frerichs I, 2017, THORAX” (modularity change rate: 98.49) has the highest structural variability. Categories with most and least interdisciplinary crossing are “ENGINEERING” and “CRITICAL CARE MEDICINE.”

Conclusions

EIT is a valuable technology for clinical lung monitoring, gradually converting from imaging techniques to the clinic. Research hot spots may continue monitoring techniques, the ventilation distribution of acute respiratory distress syndrome (ARDS), and respiratory therapy strategies. More diversified lung function monitoring studies, such as lung perfusion and interdisciplinary crossing, are potentially emerging research trends.
Characteristics and Prognostic Factors of Pulmonary Fibrosis After COVID-19 Pneumonia
Authors: Cocconcelli Elisabetta , Bernardinello Nicol , Giraudo Chiara , Castelli Gioele , Giorgino Adelaide , Leoni Davide , Petrarulo Simone , Ferrari Anna , Saetta Marina , Cattelan Annamaria , Spagnolo Paolo , Balestro Elisabetta
Published: January 2022

Background

Few is known about the long-term pulmonary sequelae after COVID-19 infection. Hence, the aim of this study is to characterize patients with persisting pulmonary sequelae at follow-up after hospitalization. We also aimed to explore clinical and radiological predictors of pulmonary fibrosis following COVID-19.

Methods

Two hundred and 20 consecutive patients were evaluated at 3–6 months after discharge with high-resolution computed tomography (HRCT) and categorized as recovered (REC) or not recovered (NOT-REC). Both HRCTs at hospitalization (HRCT0), when available, and HRCT1 during follow-up were analyzed semiquantitatively as follows: ground-glass opacities (alveolar score, AS), consolidations (CONS), and reticulations (interstitial score, IS).

Results

A total of 175/220 (80%) patients showed disease resolution at their initial radiological evaluation following discharge. NOT-REC patients (45/220; 20%) were mostly older men [66 (35–85) years vs. 56 (19–87); p = 0.03] with a longer in-hospital stay [16 (0–75) vs. 8 (1–52) days; p < 0.0001], and lower P/F at admission [233 (40–424) vs. 318 (33–543); p = 0.04]. Moreover, NOT-REC patients presented, at hospital admission, higher ALV [14 (0.0–62.0) vs. 4.4 (0.0–44.0); p = 0.0005], CONS [1.9 (0.0–26.0) vs. 0.4 (0.0–18.0); p = 0.0064], and IS [11.5 (0.0– 29.0) vs. 0.0 (0.0–22.0); p < 0.0001] compared to REC patients. On multivariate analysis, the presence of CONS and IS at HRCT0 was independent predictors of radiological sequelae at follow-up [OR 14.87 (95% CI: 1.25–175.8; p = 0.03) and 28.9 (95% CI: 2.17–386.6; p = 0.01, respectively)].

Conclusions

In our population, only twenty percent of patients showed persistent lung abnormalities at 6 months after hospitalization for COVID-19 pneumonia. These patients are predominantly older men with longer hospital stay. The presence of reticulations and consolidation on HRCT at hospital admission predicts the persistence of radiological abnormalities during follow-up.
AMPK and Polycystic Kidney Disease Drug Development: An Interesting Off-Target Target
Authors: Caplan Michael J.
Published: January 2022

Autosomal Dominant Polycystic Kidney Disease is a genetic disease that causes dramatic perturbations of both renal tissue architecture and of a multitude of cellular signaling pathways. The relationship between the products of the genes whose mutations cause polycystic kidney disease and these signaling pathways remains difficult to determine. It is clear, however, that cellular metabolism is dramatically altered in cells that are affected by polycystic kidney disease mutations. Adenosine monophosphate-stimulated protein kinase is a master regulator of cellular energy use and generation pathways whose activity appears to be perturbed in cells affected by polycystic kidney disease. Furthermore, modulation of this enzyme's activity may constitute a promising approach for the development of new therapeutics for polycystic kidney disease.
Removing Clinical Motion Artifacts During Ventilation Monitoring With Electrical Impedance Tomography: Introduction of Methodology and Validation With Simulation and Patient Data
Authors: Yang Lin , Qu Shuoyao , Zhang Yanwei , Zhang Ge , Wang Hang , Yang Bin , Xu Canhua , Dai Meng , Cao Xinsheng
Published: January 2022

Objective

Electrical impedance tomography (EIT) is a bedside tool for lung ventilation and perfusion assessment. However, the ability for long-term monitoring diminished due to interferences from clinical interventions and motion artifacts. The purpose of this study is to investigate the feasibility of the discrete wavelet transform (DWT) to detect and remove the common types of motion artifacts in thoracic EIT.

Methods

Baseline drifting, step-like and spike-like interferences were simulated to mimic three common types of motion artifacts. The discrete wavelet decomposition was employed to characterize those motion artifacts in different frequency levels with different wavelet coefficients, and those motion artifacts were then attenuated by suppressing the relevant wavelet coefficients. Further validation was conducted in two patients when motion artifacts were introduced through pulsating mattress and deliberate body movements. The db8 wavelet was used to decompose the contaminated signals into several sublevels.

Results

In the simulation study, it was shown that, after being processed by DWT, the signal consistency improved by 92.98% for baseline drifting, 97.83% for the step-like artifact, and 62.83% for the spike-like artifact; the signal similarity improved by 77.49% for baseline drifting, 73.47% for the step-like artifact, and 2.35% for the spike-like artifact. Results from patient data demonstrated the EIT image errors decreased by 89.24% (baseline drifting), 88.45% (step-like artifact), and 97.80% (spike-like artifact), respectively; the data correlations between EIT images without artifacts and the processed were all > 0.95.

Conclusion

This study found that DWT is a universal and effective tool to detect and remove these motion artifacts.
Highly Discriminative Genotyping of Mycobacterium abscessus Complex Using a Set of Variable Number Tandem Repeats in China
Authors: Huang Lihua , Li Haoran , Ren Weicong , Zhang Xuxia , Shang Yuanyuan , Liu Yi , Liu Aimei , Pang Yu
Published: January 2022

In this study, our aims were to comparatively analyze the power of variable number tandem repeat (VNTR) typing to discriminate isolates within subspecies and to identify a potential genetic marker for better molecular typing of Mycobacterium abscessus complex (MABC) strains. A total of 103 clinical MABC isolates were collected from a nationwide cross-sectional study in China. Eighteen VNTR loci were chosen to genotype the MABC isolates. Of the 103 clinical MABC isolates, there were 76 (73.8%) M. abscessus subsp. abscessus (MAA) and 27 (26.2%) M. abscessus subsp. massiliense (MAM) isolates. Among the patients with MAA lung diseases, the percentage of patients older than 45 years (67.1%) was significantly higher than that of patients with MAM lung diseases [33.3%, adjusted odds ratio (aOR) = 0.36, 95% CI = 0.13–0.98, p = 0.046]. Fifteen VNTR loci were designated as being “highly discriminant” in our sample, except for TR109. The total of 103 MABC isolates were fully discriminated into 103 unique patterns by an 18-locus VNTR set [Hunter–Gaston Discriminatory Index (HGDI) = 1.000], of which the inclusion of the top 12 loci yielded a comparative HGDI value (HGDI = 0.9998). Remarkably, the order of the diversity of the VNTR loci showed significant difference between the MAA and MAM isolates. TR137 and TR2, two loci with high diversity indices for the MAA isolates, only yielded poor discriminatory power for the MAM isolates; the allelic diversity (h) values were 0.0000 and 0.2621, respectively. A detailed analysis of TR137 in combination with the other 17 VNTR loci showed that the combination of TR137–TR2 could fully distinguish MAA from MAM isolates. In conclusion, our data revealed that MAA is more prone to affect elderly patients. Additionally, the population structure of the MABC isolates circulating in China has high diversity. The combined use of the TR137 and TR2 loci provides a simple criterion for the precise identification of MABC to the subspecies level.
Updated HIV-1 Consensus Sequences Change but Stay Within Similar Distance From Worldwide Samples
Authors: Linchangco Gregorio V. , Foley Brian , Leitner Thomas
Published: January 2022

HIV consensus sequences are used in various bioinformatic, evolutionary, and vaccine related research. Since the previous HIV-1 subtype and CRF consensus sequences were constructed in 2002, the number of publicly available HIV-1 sequences have grown exponentially, especially from non-EU and US countries. Here, we reconstruct 90 new HIV-1 subtype and CRF consensus sequences from 3,470 high-quality, representative, full genome sequences in the LANL HIV database. While subtypes and CRFs are unevenly spread across the world, in total 89 countries were represented. For consensus sequences that were based on at least 20 genomes, we found that on average 2.3% (range 0.8–10%) of the consensus genome site states changed from 2002 to 2021, of which about half were nucleotide state differences and the rest insertions and deletions. Interestingly, the 2021 consensus sequences were shorter than in 2002, and compared to 4,674 HIV-1 worldwide genome sequences, the 2021 consensuses were somewhat closer to the worldwide genome sequences, i.e., showing on average fewer nucleotide state differences. Some subtypes/CRFs have had limited geographical spread, and thus sampling of subtypes/CRFs is uneven, at least in part, due to the epidemiological dynamics. Thus, taken as a whole, the 2021 consensus sequences likely are good representations of the typical subtype/CRF genome nucleotide states. The new consensus sequences are available at the LANL HIV database.
Bacterial Community Composition in the Growth Process of Pleurotus eryngii and Growth-Promoting Abilities of Isolated Bacteria
Authors: Chen Liding , Yan Miao , Qian Xin , Yang Ziwei , Xu Yanfei , Wang Tianjiao , Cao Jixuan , Sun Shujing
Published: January 2022

The effects of biological factors on the vegetative growth process of mushrooms remain largely unexplored. We investigated the bacterial community in different growth stages of Pleurotus eryngii by high-throughput sequencing technology to explore the relationship between interacting bacteria and the growth and development of P. eryngii. We found significant variances in mushroom interacting association bacteria (MIAB) compositions among the samples from different growth stages, and 410 genera were identified. The bacteria in the full-bag and post-ripe stages were shifted to the biocontrol and growth-promotion ones. The mushroom growth-promoting bacteria (MGPB) were also isolated successfully and identified as B. cereus Bac1. The growth speed and density of mycelial pellets of P. eryngii, and activities of two exoenzymes (laccase and amylase), were analyzed by adding the different volumes of cell-free fermentation broth of B. cereus Bac1 to fungal culture media. The results showed that when a 5 mL cell-free fermentation broth was used, the growth speed of P. eryngii hyphae was enhanced by 1.15-fold over the control and reached 0.46 mm/h. The relative activity of laccase and amylase was increased by 26.9 and 43.83%. Our study revealed that the abundant interacting bacteria coexist with P. eryngii hyphae. Moreover, the abundance of some bacteria exhibiting a positive correlation with the growth periods of their host fungi can effectively promote the growth of the host, which will provide technical supports on the high-efficiency production of P. eryngii in factory cultivation.
RNA SARS-CoV-2 Persistence in the Lung of Severe COVID-19 Patients: A Case Series of Autopsies
Authors: Caniego-Casas Tamara , Martínez-García Laura , Alonso-Riaño Marina , Pizarro David , Carretero-Barrio Irene , Martínez-de-Castro Nilda , Ruz-Caracuel Ignacio , de Pablo Raúl , Saiz Ana , Royo Rosa Nieto , Santiago Ana , Rosas Marta , Rodríguez-Peralto José L. , Pérez-Mies Belén , Galán Juan C. , Palacios José
Published: January 2022

The exact role of viral replication in patients with severe COVID-19 has not been extensively studied, and it has only been possible to demonstrate the presence of replicative virus for more than 3 months in a few cases using different techniques. Our objective was to study the presence of RNA SARS-CoV-2 in autopsy samples of patients who died from COVID-19 long after the onset of symptoms. Secondary superimposed pulmonary infections present in these patients were also studied. We present an autopsy series of 27 COVID-19 patients with long disease duration, where pulmonary and extrapulmonary samples were obtained. In addition to histopathological analysis, viral genomic RNA (gRNA) and viral subgenomic RNA (sgRNA) were detected using RT-PCR and in situ hybridization, and viral protein was detected using immunohistochemistry. This series includes 26 adults with a median duration of 39 days from onset of symptoms to death (ranging 9–108 days), 92% of them subjected to immunomodulatory therapy, and an infant patient. We detected gRNA in the lung of all but one patient, including those with longer disease duration. SgRNA was detected in 11 out of 17 patients (64.7%) with illness duration up to 6 weeks and in 3 out of 9 patients (33.3%) with more than 6 weeks of disease progression. Viral protein was detected using immunohistochemistry and viral mRNA was detected using in situ hybridization in 3 out of 4 adult patients with illness duration of <2 weeks, but in none of the 23 adult patients with an illness duration of >2 weeks. A remarkable result was the detection of viral protein, gRNA and sgRNA in the lung cells of the pediatric patient after 95 days of illness. Additional pulmonary infections included: 9 acute bronchopneumonia, 2 aspergillosis, 2 cytomegalovirus, and 1 BK virus infection. These results suggest that in severe COVID-19, SARS-CoV-2 could persist for longer periods than expected, especially in immunocompromised populations, contributing to the persistence of chronic lung lesions. Additional infections contribute to the fatal course of the disease.
Complex Involvement of the Extracellular Matrix, Immune Effect, and Lipid Metabolism in the Development of Idiopathic Pulmonary Fibrosis
Authors: Qian Weiping , Xia Shu , Yang Xiaoyun , Yu Jiaying , Guo Bingpeng , Lin Zhengfang , Wei Rui , Mao Mengmeng , Zhang Ziyi , Zhao Gui , Bai Junye , Han Qian , Wang Zhongfang , Luo Qun
Published: January 2022

Background and objective: Idiopathic pulmonary fibrosis (IPF) is an aggressive fibrotic pulmonary disease with spatially and temporally heterogeneous alveolar lesions. There are no early diagnostic biomarkers, limiting our understanding of IPF pathogenesis.

Methods: Lung tissue from surgical lung biopsy of patients with early-stage IPF (n = 7), transplant-stage IPF (n = 2), and healthy controls (n = 6) were subjected to mRNA sequencing and verified by real-time quantitative PCR (RT-qPCR), immunohistochemistry, Western blot, and single-cell RNA sequencing (scRNA-Seq).

Results: Three hundred eighty differentially expressed transcripts (DETs) were identified in IPF that were principally involved in extracellular matrix (ECM) remodeling, lipid metabolism, and immune effect. Of these DETs, 21 (DMD, MMP7, POSTN, ECM2, MMP13, FASN, FADS1, SDR16C5, ACAT2, ACSL1, CYP1A1, UGT1A6, CXCL13, CXCL5, CXCL14, IL5RA, TNFRSF19, CSF3R, S100A9, S100A8, and S100A12) were selected and verified by RT-qPCR. Differences in DMD, FASN, and MMP7 were also confirmed at a protein level. Analysis of scRNA-Seq was used to trace their cellular origin to determine which lung cells regulated them. The principal cell sources of DMD were ciliated cells, alveolar type I/II epithelial cells (AT cells), club cells, and alveolar macrophages (AMs); MMP7 derives from AT cells, club cells, and AMs, while FASN originates from AT cells, ciliated cells, and AMs.

Conclusion: Our data revealed a comprehensive transcriptional mRNA profile of IPF and demonstrated that ECM remodeling, lipid metabolism, and immune effect were collaboratively involved in the early development of IPF.
6-Shogaol Inhibits Oxidative Stress-Induced Rat Vascular Smooth Muscle Cell Apoptosis by Regulating OXR1-p53 Axis
Authors: Liu Jing , Li Bin , Li Wenlian , Pan Taowen , Diao Yunpeng , Wang Fangjun
Published: January 2022

Apoptosis of vascular smooth muscle cells (VSMCs) is closely related to the pathogenesis of cardiovascular diseases, and oxidative stress is an important cause of VSMCs’ death. Inhibiting VSMCs apoptosis is an effective preventive strategy in slowing down the development of cardiovascular disease, especially for atherosclerosis. In this study, we found that oxidation resistance protein 1 (OXR1), a crucial participator for responding to oxidative stress, could modulate the expression of p53, the key regulator of cell apoptosis. Our results revealed that oxidative stress promoted VSMCs apoptosis by overexpression of the OXR1-p53 axis, and 6-shogaol (6S), a major biologically active compound in ginger, could effectively attenuate cell death by preventing the upregulated expression of the OXR1-p53 axis. Quantitative proteomics analysis revealed that the degradation of p53 mediated by OXR1 might be related to the enhanced assembly of SCF ubiquitin ligase complexes, which is reported to closely relate to the modification of ubiquitination or neddylation and subsequent degradation of p53.
Long-Lasting Pathological Mental Fatigue After Brain Injury–A Dysfunction in Glutamate Neurotransmission?
Authors: Rönnbäck Lars , Johansson Birgitta
Published: January 2022

Long-lasting mental or cognitive fatigue may be a disabling symptom after physically recovered skull trauma, stroke, infection, or inflammation in the central nervous system (CNS). It is difficult to go back to work and participate in familiar social activities, as typically the person is only able to remain mentally active for short periods, and if mentally exhausted, the recovery time will be disproportionally long. Mental fatigue after traumatic brain injury correlates with brain information processing speed. Information processing is energy consuming and requires widespread and specific neural signaling. Glutamate signaling is essential for information processing, including learning and memory. Low levels and the fine-tuning of extracellular glutamate are necessary to maintain a high precision in information processing. The astroglial cells are responsible for the fine-tuning of the glutamate transmission, but this capacity is attenuated by substances or conditions associated with neuro-inflammation in brain pathology. In this paper, we extend our previously presented hypothesis on the cellular mechanisms underlying mental fatigue suggesting a dysfunction in the astroglial support of the glutamate transmission. Changes in other neurotransmitters such as dopamine, serotonin, norepinephrine, GABA, and acetylcholine after brain injury are also taken into consideration.
Clearance Systems in the Brain, From Structure to Function
Authors: Liu Jiachen , Guo Yunzhi , Zhang Chengyue , Zeng Yang , Luo Yongqi , Wang Gaiqing
Published: January 2022

As the most metabolically active organ in the body, there is a recognized need for pathways that remove waste proteins and neurotoxins from the brain. Previous research has indicated potential associations between the clearance system in the brain and the pathological conditions of the central nervous system (CNS), due to its importance, which has attracted considerable attention recently. In the last decade, studies of the clearance system have been restricted to the glymphatic system. However, removal of toxic and catabolic waste by-products cannot be completed independently by the glymphatic system, while no known research or article has focused on a comprehensive overview of the structure and function of the clearance system. This thesis addresses a neglected aspect of linkage between the structural composition and main components as well as the role of neural cells throughout the clearance system, which found evidence that the components of CNS including the glymphatic system and the meningeal lymphatic system interact with a neural cell, such as astrocytes and microglia, to carry out vital clearance functions. As a result of this evidence that can contribute to a better understanding of the clearance system, suggestions were identified for further clinical intervention development of severe conditions caused by the accumulation of metabolic waste products and neurotoxins in the brain, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD).
The Multiple Sclerosis Prodrome: Evidence to Action
Authors: Tremlett Helen , Munger Kassandra L. , Makhani Naila
Published: January 2022

A growing body of work points toward the existence of a clinically symptomatic prodromal phase in multiple sclerosis (MS) that might span 5–10 years or more. A prodrome is an early set of signs or symptoms predating the onset of classical disease, which in turn predates a definitive diagnosis. Evidence for a prodromal phase in MS could have major implications for prevention, earlier recognition and treatment, as well as an improved disease course or prognosis. This Perspective provides a succinct overview of the recent advances in our understanding of the MS prodrome and current key challenges. Many of the MS prodromal features characterized thus far are non-specific and are common in the general population; no single feature alone is sufficient to identify an individual with prodromal MS. Biomarkers may increase specificity and accuracy for detecting individuals in the MS prodromal phase, but are yet to be discovered or formally validated. Progress made in the elucidation of prodromal phases in other neurological and immune-mediated diseases suggests that these barriers can be overcome. Therefore, while knowledge of a prodromal phase in MS remains nascent, how best to move from the rapidly growing evidence to research-related action is critical. Immediate implications include refining the concept of the MS continuum to include a prodromal phase. This will help inform the true “at risk” period when considering exposures that might cause MS. Major long-term implications include the earlier recognition of MS, improved prognosis, through earlier disease management, and the future possibility of MS disease prevention.
A Novel Proposal for an Index for Regional Cerebral Perfusion Pressure – A Theoretical Approach Using Fluid Dynamics
Authors: Kameyama Masashi , Momose Toshimitsu , Ishibashi Kenji , Ishii Kenji
Published: January 2022

Cerebral blood flow (CBF) / cerebral blood volume (CBV) ratio derived by [15O] H2O/ CO2 and CO positron emission tomography (PET) examination has been used as an index for cerebral perfusion pressure (CPP). CBF/CBV was demonstrated to be related mean arterial pressure (MAP) in baboons. However, this formula has not been confirmed to be proportionate to CPP. We have developed a new index for CPP using the Poiseuille equation based on a simple model. Our model suggests that CBF/CBV2 is proportionate to CPP and that it is mathematically a more accurate index than CBF/CBV. This new index needs experimental validation in the future.
Non-motor Adverse Effects Avoided by Directional Stimulation in Parkinson's Disease: A Case Report
Authors: Alonso-Frech Fernando , Fernandez-Garcia Carla , Gómez-Mayordomo Victor , Monje Mariana H. G. , Delgado-Suarez Celia , Villanueva-Iza Clara , Catalan-Alonso Maria Jose
Published: January 2022

Introduction

Deep brain stimulation (DBS) is widely used for treatment of advanced, medication-refractory Parkinson's disease (PD). However, a significant proportion of patients may suffer adverse effects; up to 10% will present one or more transient or permanent neurobehavioral events.

Patient and Methods

In our case study, a 44-year-old woman diagnosed with PD 6 years previously who was suffering from motor fluctuations, dyskinesia, and freezing of gait episodes was submitted for DBS and implanted with directional electrodes. Intraoperative local field potentials (LFPs) were recorded. After surgery, conventional monopolar revision was performed. Preoperative 3T MRI studies and postoperative 3D and X-ray data were integrated using the Guide DTI software application (Brainlab), and diffusion tensor imaging tractography traced from cortical areas to each subthalamic nucleus (STN) using Elements software (Brainlab).

Results

We observed that left STN stimulation in the ring mode significantly improved motor symptoms, but the patient presented uncontrollable mirthful laughter. Stimulation was then switched to the directional mode; laughter remained when using the more posteromedial contact (3-C+) but not 2-C+ or 4-C+ at the same parameters. Interestingly, LFP recordings showed the highest beta-band activity over contacts 4 and 2, and very scarce beta power over contact 3. The orientation of the directional leads was selected based on the 3D postoperative X-rays. Associative fibers showed the shortest distance to contact number 3.

Conclusion

Stimulation of the STN can affect motor and associative loops. The use of directional electrodes is a good option to avoid not only undesirable capsular or lemniscal effects, but also limbic/associative events. Oscillatory activity in the beta range that preferentially takes place over the somatomotor STN region and is closely related to motor improvement, provides a reliable guide for optimizing the DBS programming. The importance of the exact location of electrical stimulation to determine the non-motor symptoms such as mood, apathy, attention, and memory, as well as the usefulness of biological markers such as LFP for optimal programming, is discussed in relation to this case.
Telestroke for the Treatment of Ischemic Stroke in Western China During the COVID-19 Pandemic: A Multicenter Observational Study
Authors: Chen Ning , Wu Xintong , Zhou Muke , Yang Rongdong , Chen Daofeng , Liao Ming , Deng Yongyi , Hong Zhen , Zhou Dong , He Li
Published: January 2022

Background

Intravenous thrombolysis is still underutilized in patients with acute ischemic stroke (AIS) in China. A promising strategy for addressing this issue, especially in situations, such as the global pandemic of coronavirus disease 2019 (COVID-19), is the telestroke mode, which remains to be widely implemented in China. The present study aimed to assess the effects of telemedicine for patients with stroke in Western China, as well as the impact of the pandemic on telestroke services in 1 year after the COVID-19 outbreak.

Methods

In this 2-year multicenter observational study, we retrospectively collected data from 10 hospitals within the Sichuan Telestroke and Telethrombolysis Network. Demographic and clinical characteristics of patients with IS and those relevant to thrombolysis were compared between the pre-telestroke and post-telestroke phases, and between the periods before and after declaration of the COVID-19 pandemic.

Results

A total of 11,449 admissions with a primary diagnosis of IS were recorded during the study period. Prior to telestroke implementation, 6.7% of patients (n = 367) received intravenous thrombolysis, and the proportion increased to 7.4% (n = 443; p = 0.084) in the post-telestroke phase. The thrombolysis rate was 7.4% during the COVID-19 pandemic and in the latter half of the year when the viral spread was better controlled in China. The mean door-to-needle time (DNT) was significantly shorter after implementation of the telestroke network (63.76 ± 13.50 vs. 52.66 ± 25.49 min; p < 0.001).

Conclusions

Telemedicine is effective in improving the thrombolysis administration among patients with IS in Western China. Implementation of the telestroke network should be promoted, especially when access to care is affected by public health emergencies, such as the COVID-19 pandemic.
Association of Serum Biomarkers With Post-Thrombolytic Symptomatic Intracranial Hemorrhage in Stroke: A Comprehensive Protein Microarray Analysis From INTRECIS Study
Authors: Cui Yu , Zhao Yong , Chen Shao-Yuan , Sheng Bao-Ying , Wang Li-Hua , Meng Wei-Hong , Chen Hui-Sheng
Published: January 2022

Background

Symptomatic intracranial hemorrhage (sICH) after intravenous thrombolysis is closely related to the poor outcome of stroke.

Aims

To determine the serum biomarkers associated with sICH based on the INTRECIS study.

Methods

Enrolled patients with sICH and without any ICH were matched by propensity score matching with the ratio of 1:1. Preset 49 biomarkers were measured by protein microarray analysis. Gene Ontology and Pathway Enrichment Analysis and protein-protein interaction network (PPI) were analyzed in the identified biomarkers.

Results

Of the consecutive 358 patients, eight patients occurred with sICH, which was assigned as an sICH group, while eight matched patients without any ICH were assigned as a Non-sICH group. A total of nine biomarkers were found significantly different between groups, among which the levels of interferon (IFN)-γ and interleukin (IL)-4 were higher, while the levels of C-reactive protein (CRP), glial cell line-derived neurotrophic factor (GDNF), insulin-like growth factor-binding protein (IGFBP)-6, lymphatic vessel endothelial hyaluronan receptor (LYVE)-1, matrix metalloprotein (MMP)-2, plasminogen activator inhibitor (PAI)-1, and platelet-derived growth factor (PDGF)-AA were lower in the sICH group compared with those in the Non-sICH group.

Conclusions

Our finding indicated that baseline serum CRP, GDNF, IFN-γ, IGFBP-6, IL-4, LYVE-1, MMP-2, PAI-1, and PDGF-AA levels were associated with post-thrombolytic sICH in stroke.
Dissecting the Profile of Corneal Thickness With Keratoconus Progression Based on Anterior Segment Optical Coherence Tomography
Authors: Dong Yanling , Li Dongfang , Guo Zhen , Liu Yang , Lin Ping , Lv Bin , Lv Chuanfeng , Xie Guotong , Xie Lixin
Published: January 2022

Purpose

To characterize the corneal and epithelial thickness at different stages of keratoconus (KC), using a deep learning based corneal segmentation algorithm for anterior segment optical coherence tomography (AS-OCT).

Methods

An AS-OCT dataset was constructed in this study with 1,430 images from 715 eyes, which included 118 normal eyes, 134 mild KC, 239 moderate KC, 153 severe KC, and 71 scarring KC. A deep learning based corneal segmentation algorithm was applied to isolate the epithelial and corneal tissues from the background. Based on the segmentation results, the thickness of epithelial and corneal tissues was automatically measured in the center 6 mm area. One-way ANOVA and linear regression were performed in 20 equally divided zones to explore the trend of the thickness changes at different locations with the KC progression. The 95% confidence intervals (CI) of epithelial thickness and corneal thickness in a specific zone were calculated to reveal the difference of thickness distribution among different groups.

Results

Our data showed that the deep learning based corneal segmentation algorithm can achieve accurate tissue segmentation and the error range of measured thickness was less than 4 μm between our method and the results from clinical experts, which is approximately one image pixel. Statistical analyses revealed significant corneal thickness differences in all the divided zones (P < 0.05). The entire corneal thickness grew gradually thinner with the progression of the KC, and their trends were more pronounced around the pupil center with a slight shift toward the temporal and inferior side. Especially the epithelial thicknesses were thinner gradually from a normal eye to severe KC. Due to the formation of the corneal scarring, epithelial thickness had irregular fluctuations in the scarring KC.

Conclusion

Our study demonstrates that our deep learning method based on AS-OCT images could accurately delineate the corneal tissues and further successfully characterize the epithelial and corneal thickness changes at different stages of the KC progression.
Sleep Patterns, Genetic Susceptibility, and Incident Chronic Kidney Disease: A Prospective Study of 370 671 Participants
Authors: Zhang Haojie , Wang Bin , Chen Chi , Sun Ying , Chen Jie , Tan Xiao , Xia Fangzhen , Zhang Jihui , Lu Yingli , Wang Ningjian
Published: January 2022

Objectives

Unhealthy sleep behaviors may be potential risk factors for chronic kidney disease (CKD). We aimed to examine the associations of combined sleep patterns and genetic susceptibility with incident CKD.

Methods

This large-scale prospective cohort study included 370,671 participants without CKD at baseline (2006–2010) in UK Biobank data. Five sleep behaviors were made up of sleep duration, insomnia, snoring, chronotype, and daytime sleepiness according to questionnaire. Overall sleep patterns by summing the five scores were created. Weighted genetic risk score of kidney function was calculated. Incident CKD was recorded from death register, primary care, and hospital inpatient records. A subset of 41,130 individuals who participated both the initial assessment visit and follow-up visit (2012+) was also used.

Results

During a median follow-up of 10.6 years (about 3.9 million person-years), we documented 6,365 patients with incident CKD. In five sleep behaviors, sleep 7–8 h/day, free of insomnia and no frequent daytime sleepiness were independently associated with incident CKD, with a 12% (95%CI 7–16), 9% (3–14), 13% (9–18) lower risk, respectively. Compared to those with a sleep score of 0–1, participants with a score of 5 had a 21% (10–31%) lower risk of CKD. 17.1% of CKD in this cohort could be attributed to total poor sleep pattern. Participants with high genetic risk and intermediate or poor sleep pattern showed the highest risk of CKD (OR = 2.58, 95%CI 2.24–2.96; OR = 2.59, 95%CI 2.02–3.32, respectively), although there was no significant interaction between sleep patterns and genetic risk categories. Among individuals who participated both the initial assessment visit and follow-up visit, we found that the association between amelioration of sleep pattern and risk of CKD was significant after fully adjustment (OR = 0.60, 95%CI 0.36–0.99), compared with group of stable sleep pattern.

Conclusion

In this large prospective study, participants with a healthy sleep pattern was associated with a significant reduction of incident CKD risk no matter they had a high, intermediate, or low genetic risk.
Transcutaneous Electrical Nerve Stimulation in Rodent Models of Neuropathic Pain: A Meta-Analysis
Authors: Huang Jiapeng , Yang Chunlan , Zhao Kehong , Zhao Ziqi , Chen Yin , Wang Tingting , Qu Yun
Published: January 2022

Transcutaneous electrical nerve stimulation (TENS) is a non-invasive therapeutic intervention that is typically used for many years to treat chronic pain in patients who are refractory to pain medications. However, evidence of the efficacy of TENS treatment for neuropathic pain is lacking in humans. To further understand the efficacy of TENS under various intervention conditions and illuminate the current circumstance and future research directions, we systematically reviewed animal studies investigating the efficacy of TENS in relieving pain in neuropathic pain rodent models. We searched the Cochrane Library, EMBASE, MEDLINE (via PubMed), and Web of Science and identified 11 studies. Two meta-analyses were performed. The first meta-analysis showed that a single TENS treatment was capable of temporarily ameliorating neuropathic pain when compared to control groups with a significant effect (standardized mean difference: 1.54; 95% CI: 0.65, 2.42; p = 0.0007; I2 = 58%). Significant temporary alleviation in neuropathic pain intensity was also observed in the meta-analysis of repetitive TENS (standardized mean difference: 0.85; 95% CI: 0.31, 1.40; p = 0.002; I2 = 75%). Subgroup analysis showed no effect of the timing of the application of TENS (test for subgroup difference, p = 0.47). Leave-one-out sensitivity analyses suggested that no single study had an outsized effect on the pooled estimates, which may partly prove the robustness of these findings. Other stratified analyses were prevented by the insufficient number of included studies. Overall, current data suggest that TENS might be a promising therapy to ameliorate neuropathic pain. However, the high risk of bias in the included studies suggests that cautions must be considered when interpreting these findings and it is not reasonable to directly generalize the results obtained from animal studies to clinical practice. Future studies should pay more attention to improving the quality of study design and reporting, thereby facilitating the understanding of mechanisms underlying TENS treatment, reducing more potentially unsuccessful clinical trials, and optimizing the efficacy of TENS for people with neuropathic pain.
Neuroimmunoendocrine Link Between Chronic Kidney Disease and Olfactory Deficits
Authors: Corona Rebeca , Ordaz Benito , Robles-Osorio Ludivina , Sabath Ernesto , Morales Teresa
Published: January 2022

Chronic kidney disease (CKD) is a multifactorial pathology that progressively leads to the deterioration of metabolic functions and results from deficient glomerular filtration and electrolyte imbalance. Its economic impact on public health is challenging. Mexico has a high prevalence of CKD that is strongly associated with some of the most common metabolic disorders like diabetes and hypertension. The gradual loss of kidney functions provokes an inflammatory state and endocrine alterations affecting several systems. High serum levels of prolactin have been associated with CKD progression, inflammation, and olfactory function. Also, the nutritional status is altered due to impaired renal function. The decrease in calorie and protein intake is often accompanied by malnutrition, which can be severe at advanced stages of the disease. Nutrition and olfactory functioning are closely interconnected, and CKD patients often complain of olfactory deficits, which ultimately can lead to deficient food intake. CKD patients present a wide range of deficits in olfaction like odor discrimination, identification, and detection threshold. The chronic inflammatory status in CKD damages the olfactory epithelium leading to deficiencies in the chemical detection of odor molecules. Additionally, the decline in cognitive functioning impairs the capacity of odor differentiation. It is not clear whether peritoneal dialysis and hemodialysis improve the olfactory deficits, but renal transplants have a strong positive effect. In the present review, we discuss whether the olfactory deficiencies caused by CKD are the result of the induced inflammatory state, the hyperprolactinemia, or a combination of both.