bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparable Outcomes in Acquired Severe Aplastic Anemia Patients With Haploidentical Donor or Matched Related Donor Transplantation: A Retrospective Single-Center Experience
Authors: Wang QingYun , Ren HanYun , Liang ZeYin , Liu Wei , Yin Yue , Wang QingYa , Wang Qian , Sun YuHua , Xu WeiLin , Qiu ZhiXiang , Ou JinPing , Han Na , Wang Jing , Dong YuJun , Li Yuan
Published: January 2022

Clinical data of patients with severe aplastic anemia (SAA) were retrospectively analyzed to evaluate the outcomes of haploidentical hematopoietic stem cell transplantation (HID-HSCT) with matched related sibling hematopoietic stem cell transplantation (MSD-HSCT) in complications and survivals. Thirty consecutive patients were enrolled in the study with a median follow-up of 50 months (range 4, 141), and the median age of the patients was 21 years (range 3, 49). All the patients achieved myeloid engraftment in the two cohorts. The cumulative incidences of platelet engraftment were 95.5 and 100% in HID cohort and MSD cohort, respectively. The median time for neutrophil and platelet recovery was 11 (range 9, 19) and 15 (range 10, 25) days in HID cohort, and 12 (range 10, 19) and 14 (range 8, 25) days in MSD cohort. The cumulative incidences of grade II–IV and grade III–IV acute graft vs. host disease (aGvHD) in HID cohort and in MSD cohort were 18.9 vs. 14.3% (p = 0.77) and 10.5 vs. 0% (p = 0.42), respectively. The cumulative incidences of chronic graft vs. host disease (cGvHD) was 22.7% in HID cohort and 25.5% in MSD cohort (p = 0.868). The 5-year overall survival (OS) rates and 5-year failure-free survival (FFS) rates in HID cohort and MSD cohort were 85.1 vs. 87.5% (p = 0.858), 80.3 vs. 87.5% (p = 0.635), respectively. The median time to achieve engraftment, cumulative incidence of aGvHD and cGvHD, and the 5-year OS and FFS rates were not significantly different between the two cohorts. We suggest that HID-HSCT might be a safety and effective option for SAA patients without a matched donor.
Case Report: Unusual Presentations of Loss-of-Function Mutations of the Calcium-Sensing Receptor
Authors: Palmieri Serena , Grassi Giorgia , Guarnieri Vito , Chiodini Iacopo , Arosio Maura , Eller-Vainicher Cristina
Published: January 2022

Background

In recent years, heterozygous loss-of-function mutations of the Calcium Sensing Receptor gene (CaSR) were implicated in different hypercalcemic syndromes besides familial hypocalciuric hypercalcemia (FHH), including neonatal severe primary hyperparathyroidism (NSHPT) and primary hyperparathyroidism (PHPT).

Cases presentation

Here we describe two unusual presentations of heterozygous inactivating CaSR mutations. Case 1: a case of NSHPT due to a de novo, p.(ArgR185Gln) CaSR mutation and successfully treated with cinacalcet monotherapy for 8 years until definitive surgical resolution. Case 2: a 37 years-old woman with PHPT complicated with hypercalcemia and nephrocalcinosis with a novel heterozygous p.(Pro393Arg) CaSR mutation and cured with parathyroidectomy.

Conclusions

These cases reinforce the fact that the clinical spectrum of inactivating mutations of the CaSR has widened and, although carrying a mutation suggestive of FHH, some patients may have different clinical phenotypes and complications requiring individualized therapies.
Key Multimodal Fundus Imaging Findings to Recognize Multifocal Choroiditis in Patients With Pathological Myopia
Authors: Gallego-Pinazo Roberto , Hernández Sara , Dolz-Marco Rosa
Published: January 2022

Myopia represents a major socioeconomic burden with an increasing prevalence worldwide. Pathologic myopia refers to myopic patients with structural changes in the posterior pole including different patterns of chorioretinal atrophy, choroidal neovascularization (CNV) and vitreomacular tractional diseases. Multifocal choroiditis (MFC) is one of the most frequent noninfectious posterior uveitis, and epidemiologically typically affects young myopic females. Acute and chronic chorioretinal atrophic changes are the hallmark feature of MFC, with CNV developing in almost one third of cases. Thus, differentiation of inflammatory lesions due to MFC or neurodenegerative lesions due to pathologic myopic is key in order to establish a particular prognosis, follow-up schedule, and therapeutic approach. The aim of the present manuscript is to summarize and illustrate the main multimodal imaging features of these diseases.
Oceanic Crustal Fluid Single Cell Genomics Complements Metagenomic and Metatranscriptomic Surveys With Orders of Magnitude Less Sample Volume
Authors: D’Angelo Timothy , Goordial Jacqueline , Poulton Nicole J. , Seyler Lauren , Huber Julie A. , Stepanauskas Ramunas , Orcutt Beth N.
Published: January 2022

Fluids circulating through oceanic crust play important roles in global biogeochemical cycling mediated by their microbial inhabitants, but studying these sites is challenged by sampling logistics and low biomass. Borehole observatories installed at the North Pond study site on the western flank of the Mid-Atlantic Ridge have enabled investigation of the microbial biosphere in cold, oxygenated basaltic oceanic crust. Here we test a methodology that applies redox-sensitive fluorescent molecules for flow cytometric sorting of cells for single cell genomic sequencing from small volumes of low biomass (approximately 103 cells ml–1) crustal fluid. We compare the resulting genomic data to a recently published paired metagenomic and metatranscriptomic analysis from the same site. Even with low coverage genome sequencing, sorting cells from less than one milliliter of crustal fluid results in similar interpretation of dominant taxa and functional profiles as compared to ‘omics analysis that typically filter orders of magnitude more fluid volume. The diverse community dominated by Gammaproteobacteria, Bacteroidetes, Desulfobacterota, Alphaproteobacteria, and Zetaproteobacteria, had evidence of autotrophy and heterotrophy, a variety of nitrogen and sulfur cycling metabolisms, and motility. Together, results indicate fluorescence activated cell sorting methodology is a powerful addition to the toolbox for the study of low biomass systems or at sites where only small sample volumes are available for analysis.
KAT2A Promotes Hepatitis B Virus Transcription and Replication Through Epigenetic Regulation of cccDNA Minichromosome
Authors: Qin Yi-Ping , Yu Hai-Bo , Yuan Si-Yu , Yang Zhen , Ren Fang , Wang Qing , Li Fan , Ren Ji-Hua , Cheng Sheng-Tao , Zhou Yu-Jiao , He Xin , Zhou Hong-Zhong , Zhang Yuan , Tan Ming , Yang Min-Li , Zhang Da-Peng , Wen Xu , Dong Mei-Ling , Zhang Hui , Liu Jing , Li Zhi-Hong , Chen Yao , Huang Ai-Long , Chen Wei-Xian , Chen Juan
Published: January 2022

Hepatitis B virus (HBV) infection remains a major health problem worldwide. Sufficient maintenance of the HBV covalently closed circular DNA (cccDNA), which serves as a template for HBV transcription, is responsible for the failure of antiviral therapies. While accumulating evidence suggests that cccDNA transcription is regulated by epigenetic machinery, particularly the acetylation and methylation of cccDNA-bound histone 3 (H3) and histone 4 (H4), the potential contributions of histone succinylation and related host factors remain obscured. Here, by screening a series of succinyltransferases and desuccinylases, we identified KAT2A as an important host factor of HBV transcription and replication. By using HBV-infected cells and mouse models with HBV infection, KAT2A was found to affect the transcriptional activity of cccDNA but did not affect cccDNA production. Mechanism studies showed that KAT2A is mainly located in the nucleus and could bind to cccDNA through interaction with HBV core protein (HBc). Moreover, we confirmed histone H3K79 succinylation (H3K79succ) as a histone modification on cccDNA minichromosome by using the cccDNA ChIP-Seq approach. Importantly, KAT2A silencing specifically reduced the level of cccDNA-bound succinylated H3K79. In conclusion, KAT2A promotes HBV transcription and replication through epigenetic machinery, and our findings may provide new insight into the treatment of HBV infection.
Curcumin Inhibits Membrane-Damaging Pore-Forming Function of the β-Barrel Pore-Forming Toxin Vibrio cholerae Cytolysin
Authors: Singh Mahendra , Rupesh N. , Pandit Shashi Bhushan , Chattopadhyay Kausik
Published: January 2022

Vibrio cholerae cytolysin (VCC) is a β-barrel pore-forming toxin (β-PFT). Upon encountering the target cells, VCC forms heptameric β-barrel pores and permeabilizes the cell membranes. Structure-function mechanisms of VCC have been extensively studied in the past. However, the existence of any natural inhibitor for VCC has not been reported yet. In the present study, we show that curcumin can compromise the membrane-damaging activity of VCC. Curcumin is known to modulate a wide variety of biological processes and functions. However, the application of curcumin in the physiological scenario often gets limited due to its extremely poor solubility in the aqueous environment. Interestingly, we find that VCC can associate with the insoluble fraction of curcumin in the aqueous medium and thus gets separated from the solution phase. This, in turn, reduces the availability of VCC to attack the target membranes and thus blocks the membrane-damaging action of the toxin. We also observe that the soluble aqueous extract of curcumin, generated by the heat treatment, compromises the pore-forming activity of VCC. Interestingly, in the presence of such soluble extract of curcumin, VCC binds to the target membranes and forms the oligomeric assembly. However, such oligomers appear to be non-functional, devoid of the pore-forming activity. The ability of curcumin to bind to VCC and neutralize its membrane-damaging activity suggests that curcumin has the potential to act as an inhibitor of this potent bacterial β-PFT.
An Iterative Method for Predicting Essential Proteins Based on Multifeature Fusion and Linear Neighborhood Similarity
Authors: Zhu Xianyou , Zhu Yaocan , Tan Yihong , Chen Zhiping , Wang Lei
Published: January 2022

Growing evidence have demonstrated that many biological processes are inseparable from the participation of key proteins. In this paper, a novel iterative method called linear neighborhood similarity-based protein multifeatures fusion (LNSPF) is proposed to identify potential key proteins based on multifeature fusion. In LNSPF, an original protein-protein interaction (PPI) network will be constructed first based on known protein-protein interaction data downloaded from benchmark databases, based on which, topological features will be further extracted. Next, gene expression data of proteins will be adopted to transfer the original PPI network to a weighted PPI network based on the linear neighborhood similarity. After that, subcellular localization and homologous information of proteins will be integrated to extract functional features for proteins, and based on both functional and topological features obtained above. And then, an iterative method will be designed and carried out to predict potential key proteins. At last, for evaluating the predictive performance of LNSPF, extensive experiments have been done, and compare results between LNPSF and 15 state-of-the-art competitive methods have demonstrated that LNSPF can achieve satisfactory recognition accuracy, which is markedly better than that achieved by each competing method.
Evaluation of Optimal Control Approaches for Predicting Active Knee-Ankle-Foot-Orthosis Motion for Individuals With Spinal Cord Injury
Authors: Febrer-Nafría Míriam , Fregly Benjamin J. , Font-Llagunes Josep M.
Published: January 2022

Gait restoration of individuals with spinal cord injury can be partially achieved using active orthoses or exoskeletons. To improve the walking ability of each patient as much as possible, it is important to personalize the parameters that define the device actuation. This study investigates whether using an optimal control-based predictive simulation approach to personalize pre-defined knee trajectory parameters for an active knee-ankle-foot orthosis (KAFO) used by spinal cord injured (SCI) subjects could potentially be an alternative to the current trial-and-error approach. We aimed to find the knee angle trajectory that produced an improved orthosis-assisted gait pattern compared to the one with passive support (locked knee). We collected experimental data from a healthy subject assisted by crutches and KAFOs (with locked knee and with knee flexion assistance) and from an SCI subject assisted by crutches and KAFOs (with locked knee). First, we compared different cost functions and chose the one that produced results closest to experimental locked knee walking for the healthy subject (angular coordinates mean RMSE was 5.74°). For this subject, we predicted crutch-orthosis-assisted walking imposing a pre-defined knee angle trajectory for different maximum knee flexion parameter values, and results were evaluated against experimental data using that same pre-defined knee flexion trajectories in the real device. Finally, using the selected cost function, gait cycles for different knee flexion assistance were predicted for an SCI subject. We evaluated changes in four clinically relevant parameters: foot clearance, stride length, cadence, and hip flexion ROM. Simulations for different values of maximum knee flexion showed variations of these parameters that were consistent with experimental data for the healthy subject (e.g., foot clearance increased/decreased similarly in experimental and predicted motions) and were reasonable for the SCI subject (e.g., maximum parameter values were found for moderate knee flexion). Although more research is needed before this method can be applied to choose optimal active orthosis controller parameters for specific subjects, these findings suggest that optimal control prediction of crutch-orthosis-assisted walking using biomechanical models might be used in place of the trial-and-error method to select the best maximum knee flexion angle during gait for a specific SCI subject.
Exosomal microRNAs as Potential Biomarkers and Therapeutic Agents for Acute Ischemic Stroke: New Expectations
Authors: Xu Yingzhi , Hu Yue , Xu Shixin , Liu Fengzhi , Gao Ying
Published: January 2022

The morbidity and mortality rates of ischemic stroke (IS) are very high, and IS constitutes one of the main causes of disability and death worldwide. The pathogenesis of ischemic stroke includes excitotoxicity, calcium overload, oxygen radical injury, inflammatory reactions, necrosis/apoptosis, destruction of the blood-brain barrier (BBB), and other pathologic processes. Recent studies have shown that exosomes are critical to the pathogenesis, diagnosis, and treatment of cerebral infarctions resulting from ischemic stroke; and there is growing interest in the role of exosomes and exosomal miRNAs in the diagnosis and treatment of IS. Exosomes from central nervous system cells can be found in cerebrospinal fluid and peripheral bodily fluids, and exosomal contents have been reported to change with disease occurrence. Exosomes are small membranous extracellular vesicles (EVs), 30–150 nm in diameter, that are released from the cell membrane into the depressions that arise from the membranes of multivesicular bodies. Exosomes carry lipids, proteins, mRNAs, and microRNAs (miRNAs) and transport information to target cells. This exosomal transfer of functional mRNAs/miRNAs and proteins ultimately affects transcription and translation within recipient cells. Exosomes are EVs with a double-membrane structure that protects them from ribonucleases in the blood, allowing exosomal miRNAs to be more stable and to avoid degradation. New evidence shows that exosomes derived from neural cells, endothelial cells, and various stem cells create a fertile environment that supports the proliferation and growth of neural cells and endothelial cells, inhibits apoptosis and inflammatory responses, and promotes angiogenesis. In the present review, we discuss how circulating exosomes—and exosomal miRNAs in particular—may provide novel strategies for the early diagnosis and treatment of ischemic stroke via their potential as non-invasive biomarkers and drug carriers.
Fractional Anisotropy and Troponin T Parallel Structural Nerve Damage at the Upper Extremities in a Group of Patients With Prediabetes and Type 2 Diabetes – A Study Using 3T Magnetic Resonance Neurography
Authors: Jende Johann M. E. , Kender Zoltan , Morgenstern Jakob , Renn Pascal , Mooshage Christoph , Juerchott Alexander , Kopf Stefan , Nawroth Peter P. , Bendszus Martin , Kurz Felix T.
Published: January 2022

Background

Recent studies have found that troponin T parallels the structural and functional decay of peripheral nerves at the level of the lower limbs in patients with type 2 diabetes (T2D). The aim of this study was to determine whether this finding can also be reproduced at the level of the upper limbs.

Methods

Ten patients with fasting glucose levels >100 mg/dl (five with prediabetes and five with T2D) underwent magnetic resonance neurography of the right upper arm comprising T2-weighted and diffusion weighted sequences. The fractional anisotropy (FA), an indicator for the structural integrity of peripheral nerves, was calculated in an automated approach for the median, ulnar, and radial nerve. All participants underwent additional clinical, serological, and electrophysiological assessments.

Results

High sensitivity Troponin T (hsTNT) and HbA1c were negatively correlated with the average FA of the median, ulnar and radial nerve (r = −0.84; p = 0.002 and r = −0.68; p = 0.032). Both FA and hsTNT further showed correlations with items of the Michigan Hand Outcome Questionnaire (r = −0.76; p = 0.010 and r = 0.87; p = 0.001, respectively). A negative correlation was found for hsTNT and HbA1c with the total Purdue Pegboard Test Score (r = −0.87; p = 0.001 and r = −0.68; p = 0.031).

Conclusion

This study is the first to find that hsTNT and HbA1c are associated with functional and structural parameters of the nerves at the level of the upper limbs in patients with impaired glucose tolerance and T2D. Our results support the hypothesis that hyperglycemia-related microangiopathy, represented by elevated hsTNT levels, is a contributor to nerve damage in diabetic polyneuropathy.
Systematic Phenotyping and Characterization of the 3xTg-AD Mouse Model of Alzheimer’s Disease
Authors: Javonillo Dominic I. , Tran Kristine M. , Phan Jimmy , Hingco Edna , Kramár Enikö A. , da Cunha Celia , Forner Stefania , Kawauchi Shimako , Milinkeviciute Giedre , Gomez-Arboledas Angela , Neumann Jonathan , Banh Crystal E. , Huynh Michelle , Matheos Dina P. , Rezaie Narges , Alcantara Joshua A. , Mortazavi Ali , Wood Marcelo A. , Tenner Andrea J. , MacGregor Grant R. , Green Kim N. , LaFerla Frank M.
Published: January 2022

Animal models of disease are valuable resources for investigating pathogenic mechanisms and potential therapeutic interventions. However, for complex disorders such as Alzheimer’s disease (AD), the generation and availability of innumerous distinct animal models present unique challenges to AD researchers and hinder the success of useful therapies. Here, we conducted an in-depth analysis of the 3xTg-AD mouse model of AD across its lifespan to better inform the field of the various pathologies that appear at specific ages, and comment on drift that has occurred in the development of pathology in this line since its development 20 years ago. This modern characterization of the 3xTg-AD model includes an assessment of impairments in long-term potentiation followed by quantification of amyloid beta (Aβ) plaque burden and neurofibrillary tau tangles, biochemical levels of Aβ and tau protein, and neuropathological markers such as gliosis and accumulation of dystrophic neurites. We also present a novel comparison of the 3xTg-AD model with the 5xFAD model using the same deep-phenotyping characterization pipeline and show plasma NfL is strongly driven by plaque burden. The results from these analyses are freely available via the AD Knowledge Portal (https://modeladexplorer.org/). Our work demonstrates the utility of a characterization pipeline that generates robust and standardized information relevant to investigating and comparing disease etiologies of current and future models of AD.
Ischemic Infarction of Pituitary Apoplexy: A Retrospective Study of 46 Cases From a Single Tertiary Center
Authors: Zhu Qiang , Liang Yuchao , Fan Ziwen , Liu Yukun , Zhou Chunyao , Zhang Hong , Li Tianshi , Zhou Yanpeng , Yang Jianing , Wang Yinyan , Wang Lei
Published: January 2022

Objective

Ischemic infarction of pituitary apoplexy (PA) is a rare type of pituitary apoplexy. This study aims to characterize ischemic PA via clinical presentations, imaging data, histopathological manifestations, and focus on the management and prognosis of the disease.

Methods

This study retrospectively identified 46 patients with ischemic PA confirmed using histopathology at a single institution from January 2013 to December 2020. The clinical presentations, imaging data, laboratory examination, management, and outcomes were collected. We then summarized the clinical presentations, imaging features, intraoperative findings, and histopathological manifestations, and compared the outcomes based on the timing of surgical intervention.

Results

Headache was the most common initial symptom (95.65%, 44/46), followed by visual disturbance (89.13%, 41/46), and nausea and vomiting (58.70%, 27/46). 91.3% of the patients had at least one pituitary dysfunction, with hypogonadism being the most common endocrine dysfunction (84.78%, 39/46). Cortisol dysfunction occurred in 24 (52.17%) patients and thyroid dysfunction occurred in 17 (36.96%). Typical rim enhancement and thickening of the sphenoid sinus on MRI were seen in 35 (85.37%) and 26 (56.52%) patients, respectively. Except for one patient with asymptomatic apoplexy, the remaining patients underwent early (≤ 1 week, 12 patients) and delayed (> 1 week, 33 patients) transsphenoidal surgery. Total tumor resection was achieved in 27 patients and subtotal tumor resection in 19 patients. At surgery, cottage cheese–like necrosis was observed in 50% (23/46) of the patients. At the last follow-up of 5.5 ± 2.7 years, 92.68% (38/41) of the patients had gained a significant improvement in visual disturbance regardless of surgical timing, and 65% of the patients were still receiving long-term hormone replacement therapy.

Conclusion

Patients with ischemic PA can be accurately diagnosed by typical imaging characteristics preoperatively. The timing of surgical intervention does not significantly affect the resolution of neurological and endocrinological dysfunctions. Preoperative endocrine dysfunctions are common and usually appear to be poor after surgical intervention.
Brain-Type Glycogen Phosphorylase Is Crucial for Astrocytic Glycogen Accumulation in Chronic Social Defeat Stress-Induced Depression in Mice
Authors: Zhu Yuanyuan , Fan Ze , Zhao Qiuying , Li Jiaqi , Cai Guohong , Wang Rui , Liang Yi , Lu Naining , Kang Junjun , Luo Danlei , Tao Huiren , Li Yan , Huang Jing , Wu Shengxi
Published: January 2022

Astrocytic glycogen plays an important role in brain energy metabolism. However, the contribution of glycogen metabolism to stress-induced depression remains unclear. Chronic social defeat stress was used to induce depression-like behaviors in mice, assessed with behavioral tests. Glycogen concentration in the medial prefrontal cortex (mPFC) and the expression of key enzymes of the glycogen metabolism were investigated using Western blots, immunofluorescent staining, electron microscopy, and biochemical assays. Stereotaxic surgery and viral-mediated gene transfer were applied to knockdown or overexpress brain-type glycogen phosphorylase (PYGB) in the mPFC. The glycogen content increased in the mPFC after stress. Glycogenolytic dysfunction due to inactivation of PYGB was responsible for glycogen accumulation. Behavioral tests on astrocyte-specific PYGB overexpression mice showed that augmenting astrocytic PYGB reduces susceptibility to depression when compared with stress-susceptible mice. Conversely, PYGB genetic down-regulation in the mPFC was sufficient to induce glycogen accumulation and depression-like behaviors. Furthermore, PYGB overexpression in the mPFC decreases susceptibility to depression, at least partially by rescuing glycogen phosphorylase activity to maintain glycogen metabolism homeostasis during stress. These findings indicate that (1) glycogen accumulation occurs in mice following stress and (2) glycogenolysis reprogramming leads to glycogen accumulation in astrocytes and PYGB contributes to stress-induced depression-like behaviors. Pharmacological tools acting on glycogenolysis might constitute a promising therapy for depression.
High Value-Added Application of Two Renewable Sources as Healthy Food: The Nutritional Properties, Chemical Compositions, Antioxidant, and Antiinflammatory Activities of the Stalks of Rheum officinale Baill. and Rheum tanguticum Maxim. ex Regel
Authors: Dai Li-Xia , Miao Xiaolou , Yang Xiao-Rong , Zuo Li-Ping , Lan Zhi-Hui , Li Bing , Shang Xiao-Fei , Yan Feng-Yuan , Guo Xiao , Wang Yu , Zhang Ji-Yu
Published: January 2022

Rhubarb plants (Rheum officinale and R. tanguticum) have edible stalks. In this work, we aimed to compare the nutritional properties, chemical compositions, and bioactivities of R. officinale (SRO) and R. tanguticum (SRT) stalks and to analyze the composition–function relationship. Results showed that the two stalks were good sources of fiber, as well as minerals. They contained abundant essential amino acids and essential fatty acids to regulate the immunity and prevent some chronic diseases; the contents of polyunsaturated fatty acids were 2,244.32 mg/100 g and 2,844.69 mg/100 g, respectively. The antioxidant activity were also proved. Metabolomics showed that SRO and SRT contained abundant phenolic acids. Due to the higher concentrations of flavones, SRT has better antiinflammatory activities than SRO by inhibiting NF-κB signaling pathway. Rhubarb stalks exhibited good safety in acute toxicity and cytotoxicity tests. This work indicated that the two stalks have nutritional value, safety, and bioactivities, and could be used as sources of nutritional ingredients for regulating the immunity of body in food industry.
A Smartphone App-Based Lifestyle Change Program for Prediabetes (D'LITE Study) in a Multiethnic Asian Population: A Randomized Controlled Trial
Authors: Lim Su Lin , Ong Kai Wen , Johal Jolyn , Han Chad Yixian , Yap Qai Ven , Chan Yiong Huak , Zhang Zhi Peng , Chandra Cheryl Christine , Thiagarajah Anandan Gerard , Khoo Chin Meng
Published: January 2022

Introduction

Landmark studies have established that lifestyle interventions focused on weight loss, diet modification and physical activity can prevent diabetes progression. However, the effectiveness of mobile health application among Asians with prediabetes remains largely unexamined. We aimed to assess whether a smartphone app-based lifestyle intervention program would lead to weight loss, normoglycemia and improved metabolic indices in a multiethnic Asian population with prediabetes.

Research Design and Methods

This multicentre prediabetes RCT is part of the Diabetes Lifestyle Intervention using Technology Empowerment (D'LITE) trial. Adults (n = 148) with prediabetes and BMI ≥ 23 kg/m2 were randomly allocated either to the intervention group (n = 72) empowered by self-monitoring features of the Nutritionist Buddy Diabetes app with in-app dietitian coaching for 6 months, or the control group (n = 76) receiving standard diet counseling at baseline. Primary outcome was defined as change in body weight at 6 months, while secondary outcomes included glycemic control and other metabolic indices analyzed using Generalized Linear Mixed Model analysis with intention-to-treat approach.

Results

Intervention group achieved a significantly greater weight loss of 4.2 vs. 1.3 kg [mean difference of −3.1 kg (95% CI −4.5 to −1.7), p < 0.001], and a 4.3-fold increased likelihood of achieving ≥ 5% weight loss, as compared to the control group at 6 months. The likelihood of achieving normoglycemia (defined as HbA1c < 5.7%) was 2.1 times higher in intervention group than in the control group (p < 0.018). Changes to blood pressure, total and LDL cholesterol were not statistically significant.

Conclusion

An app-based lifestyle program led to clinically significant weight loss and improved glycemia, and can potentially augment current standard care in the prevention of diabetes among an Asian multiethnic population.

Clinical Trial Registration

anzctr.org.au, identifier: ACTRN12617001112358.
Components of the Mediterranean Diet and Risk of COVID-19
Authors: Perez-Araluce Rafael , Martínez-González Miguel Ángel , Gea Alfredo , Carlos Silvia
Published: January 2022

Adherence to the traditional Mediterranean diet has been customarily assessed with the Mediterranean diet score (MDS or Trichopolou Index), with values of 0 or 1 assigned to each of the nine elements, and with the use of the sex-specific median as the cutoff. The value of persons whose consumption of the six beneficial items (ratio of monounsaturated to saturated fatty acids, vegetables, legumes, fruits and nuts, cereal, and fish) is at or above the median and is assigned a value of 1. Otherwise they receive 0 points. For detrimental elements (meats and dairy products) persons whose consumption is below the median are assigned a value of 1. An additional ninth point is assigned to moderate ethanol intake. We assessed the effect of each of the nine components of the MDS (replacing the fats ratio with olive oil, the main source of monounsaturated fats in the Mediterranean diet) on the risk of COVID-19 infection, symptomatic and severe COVID-19. From March to December 2020, 9,699 participants of the “Seguimiento Universidad de Navarra” (SUN) cohort answered a COVID-19 questionnaire. After excluding doctors and nurses, 5,194 participants were included in the main statistical analyses. Among them, we observed 382 cases of COVID-19 based on symptoms and clinical diagnosis; 167 of them with test confirmation. For the two COVID-19 definitions used, we found a significant decrease in risk for a higher adherence to the Mediterranean diet (OR = 0.64, 95% CI: 0.42–0.98, p for trend = 0.040; and OR = 0.44, 95% CI: 0.22–0.88, p for trend = 0.020, for test-diagnosed cases). A protective effect was also found for symptomatic COVID-19 (OR = 0.64, 95% CI: 0.41–1.00, p for trend = 0.050). Among the different individual food groups, only the consumption of whole dairy products showed a harmful direct association. The Mediterranean diet as a whole seems more important than each of its components in preventing the infection and symptoms of COVID-19.
Association Between Tumor Mutation Profile and Clinical Outcomes Among Hispanic-Latino Patients With Metastatic Colorectal Cancer
Authors: Philipovskiy Alexander , Ghafouri Reshad , Dwivedi Alok Kumar , Alvarado Luis , McCallum Richard , Maegawa Felipe , Konstantinidis Ioannis T. , Hakim Nawar , Shurmur Scott , Awasthi Sanjay , Gaur Sumit , Corral Javier
Published: January 2022

In the United States, CRC is the third most common type of cancer and the second leading cause of cancer-related death. Although the incidence of CRC among the Hispanic population has been declining, recently, a dramatic increase in CRC incidents among HL younger than 50 years of age has been reported. The incidence of early-onset CRC is more significant in HL population (45%) than in non-Hispanic Whites (27%) and African-Americans (15%). The reason for these racial disparities and the biology of CRC in the HL are not well understood. We performed this study to understand the biology of the disease in HL patients. We analyzed formalin-fixed paraffin-embedded tumor tissue samples from 52 HL patients with mCRC. We compared the results with individual patient clinical histories and outcomes. We identified commonly altered genes in HL patients (APC, TP53, KRAS, GNAS, and NOTCH). Importantly, mutation frequencies in the APC gene were significantly higher among HL patients. The combination of mutations in the APC, NOTCH, and KRAS genes in the same tumors was associated with a higher risk of progression after first-line of chemotherapy and overall survival. Our data support the notion that the molecular drivers of CRC might be different in HL patients.
MRVI1 and NTRK3 Are Potential Tumor Suppressor Genes Commonly Inactivated by DNA Methylation in Cervical Cancer
Authors: Ji Huihui , Li Kehan , Jiang Wenxiao , Li Jingwei , Zhang Jian-an , Zhu Xueqiong
Published: January 2022

The abnormally methylated tumor suppressor genes (TSGs) associated with cervical cancer are unclear. DNA methylation data, RNA-seq expression profiles, and overall survival data were downloaded from TCGA CESC database. DMGs and DEGs were obtained through CHAMP and DESeq packages, respectively. TSGs were downloaded from TSGene 2.0. Candidate hypermethylated/down-regulated TSGs were further evaluated and pyrosequencing was used to confirm their difference in methylation levels of selected TSGs in cervical cancer patients. A total of 25946 differentially methylated CpGs corresponding to 2686 hypermethylated genes and 4898 hypomethylated genes between cervical cancer and adjacent normal cervical tissues were found in this study. Besides, 693 DEGs (109 up-regulated and 584 down-regulated) were discovered in cervical cancer tissues. Then, 192 hypermethylated/down-regulated genes were obtained in cervical cancer compared to adjacent tissues. Interestingly, 26 TSGs were found in hypermethylated/down-regulated genes. Among these genes, low expression of MRVI1 and NTRK3 was associated with poor overall survival in cervical cancer. Moreover, GEO data showed that MRVI1 and NTRK3 were significantly decreased in cervical cancer tissues. The expression levels of MRVI1 and NTRK3 were negatively correlated with the methylation levels of their promoter CpG sites. Additionally, elevated methylation levels of MRVI1 and NTRK3 promoter were further verified in cervical cancer tissues by pyrosequencing experiments. Finally, the ROC results showed that the promoter methylation levels of MRVI1 and NTRK3 had the ability to discriminate cervical cancer from healthy samples. The study contributes to our understanding of the roles of MRVI1 and NTRK3 in cervical cancer.
A Comparative Study on the Accuracy and Efficacy Between Dalton and CINtec® PLUS p16/Ki-67 Dual Stain in Triaging HPV-Positive Women
Authors: Li Ying , Fu Yunfeng , Cheng Bei , Xie Xing , Wang Xinyu
Published: January 2022

Background

CINtec® PLUS p16/Ki-67 dual-stained cytology (DS) is an alternative test to cytology in triaging human papillomavirus (HPV)-positive women. Dalton p16/Ki-67 Dual Stain kit employs the similar immunocytochemical detection and operating procedures with CINtec® PLUS, but its accuracy and efficacy in triaging HPV-positive women need to be evaluated.

Methods

A total of 717 HPV-positive specimens of cervical exfoliated cells were included. Cytology, Dalton, and CINtec® PLUS were subsequently performed, and two DS tests were separately completed in each of the same specimens. The results of two DS tests were head-to-head compared, and their efficacies to identify high-grade cervical intraepithelial neoplasia (CIN) were evaluated, using histopathology of biopsy as the golden standard.

Results

The overall positive rate of two DS tests were 28.31% for Dalton and 33.89% for CINtec® PLUS (p < 0.05); both rose with the increased severity of histopathological and cytological abnormalities. Compared to CINtec® PLUS, the positive rate of Dalton was significantly lower in the normal histopathology group (p < 0.05) and lower, but not significantly, in mild abnormal histopathology and cytology NILM and LSIL groups. Two DS tests showed a good consistency (Kappa value, 0.63; 95% CI, 0.557–0.688), with 100% of consistency in the cytology HSIL group. Inconsistency occurred mainly in the cytology NILM and LSIL groups, with more Dalton negative but CINtec® PLUS positive. Compared to CINtec® PLUS, Dalton showed similar sensitivity (94.59% vs. 91.89%), but significantly higher specificity (75.29% vs. 69.26%, p = 0.013) and accuracy (76.29% vs. 70.43%, p = 0.012), with a larger area under the curve (AUC) of 0.849 (95% CI, 0.800–0.899) for identifying CIN3+. The similar results were observed when identifying CIN2+.

Conclusions

Dalton presents the lower false positive rate and better efficacy in identifying high-grade CIN than CINtec® PLUS, suggesting that Dalton may be superior to CINtec® PLUS and an alternative technique for triaging primary HPV-positive women in cervical cancer screening.
Starting at Birth: An Integrative, State-of-the-Science Framework for Optimizing Infant Neuromotor Health
Authors: Peyton Colleen , Sukal Moulton Theresa , Carroll Allison J. , Anderson Erica , Brozek Alexandra , Davis Matthew M. , Horowitz Jessica , Jayaraman Arun , O'Brien Megan , Patrick Cheryl , Pouppirt Nicole , Villamar Juan , Xu Shuai , Lieber Richard L. , Wakschlag Lauren S. , Krogh-Jespersen Sheila
Published: January 2022

Numerous conditions and circumstances place infants at risk for poor neuromotor health, yet many are unable to receive treatment until a definitive diagnosis is made, sometimes several years later. In this integrative perspective, we describe an extensive team science effort to develop a transdiagnostic approach to neuromotor health interventions designed to leverage the heightened neuroplasticity of the first year of life. We undertook the following processes: (1) conducted a review of the literature to extract common principles and strategies underlying effective neuromotor health interventions; (2) hosted a series of expert scientific exchange panels to discuss common principles, as well as practical considerations and/or lessons learned from application in the field; and (3) gathered feedback and input from diverse stakeholders including infant caregivers and healthcare providers. The resultant framework was a pragmatic, evidence-based, transdiagnostic approach to optimize neuromotor health for high-risk infants based on four principles: (a) active learning, (b) environmental enrichment, (c) caregiver engagement, and (d) strength-based approaches. In this perspective paper, we delineate these principles and their potential applications. Innovations include: engagement of multiple caregivers as critical drivers of the intervention; promoting neuromotor health in the vulnerability phase, rather than waiting to treat neuromotor disease; integrating best practices from adjacent fields; and employing a strengths-based approach. This framework holds promise for implementation as it is scalable, pragmatic, and holistically addresses both the needs of the infant and their family.
Association Between Serum Lactate and Unsatisfactory Outcomes in Critically Ill Children in the Immediate Post-operative Period of Liver Transplantation
Authors: Fernández-Sarmiento Jaime , Wilches-Cuadros María Angélica , Hernandez-Sarmiento Ricardo , Mulett Hernando , Moreno-Medina Karen , Molano Nicolás , Dominguez Julián Augusto Palomar , Acevedo Lorena , Salinas Claudia , Rivera Jairo
Published: January 2022

Objectives

Serum lactate is a useful biomarker of tissue perfusion in critically ill patients. We evaluated the behavior of serum lactate in children in the pediatric intensive care unit (PICU) immediately after liver transplantation and its association with surgical complications, graft dysfunction and 90-day mortality.

Materials and Methods

A prospective observational study carried out between November 2009 and December 2019. Multidisciplinary PICU at the University Children's Hospital, Fundación Cardioinfantil-IC, Bogotá, Colombia.

Measurements and Main Results

Patients between 1 month and 18 years of age who were in the immediate post-operative period following living-donor or cadaveric liver transplantation were included. A total of 145 patients with a median age of 14 months (IQR 8–60) met the inclusion criteria. Biliary atresia was the main diagnosis in 56.5% of the cases. A serum lactate level > 3.0 mmol/L on admission to the PICU was associated with biliary complications (AUC 0.73 95% CI 0.54–0.93; p = 0.05) and mortality (AUC 0.72 95% CI 0.63–0.8; p = 0.01). A lactate level > 2 mmol/L after 6 h in the PICU was associated with mortality (AUC 0.70 95% CI 0.54–0.83; p = 0.02). Higher lactate levels and lack of clearance were associated with the presence of tardus et parvus waveforms (p = 0.001) on liver Doppler, primary dysfunction (p < 0.001), arterial thrombosis (p < 0.001) and neurological complications (p = 0.04). There was an inverse correlation between admission lactate and the volume of fluids administered during surgery (rho = 0.36; p < 0.001). A total procedure time > 350 min, along with a vasopressor score > 7 and elevated lactate, were associated with worse outcomes (p < 0.001).

Conclusions

In post-operative pediatric liver transplant patients, the level of serum lactate is associated with post-operative surgical complications and mortality.
Case Report: Prevention of Rhabdomyolysis-Associated Acute Kidney Injury by Extracorporeal Blood Purification With Cytosorb®
Authors: Rauch Simon , Borgato Andrea , Gruber Ewald , Leggieri Carlo , Bock Matthias , Seraglio Paolo Mario Enrico
Published: January 2022

Acute kidney injury (AKI) is a severe complication of rhabdomyolysis. The pathophysiology of rhabdomyolysis-associated AKI is complex, but myoglobin related damage plays a major role. Extracorporeal removal of myoglobin is therefore an appealing target to prevent AKI, however, attempts to remove myoglobin with standard dialysis membranes have so far been disappointing. Here we report the case of a 12-year-old boy with severe trauma-related rhabdomyolysis where we successfully utilized continuous renal replacement therapy in combination with Cytosorb® to eliminate myoglobin and prevent AKI. The early use of extracorporeal myoglobin removal with Cytosorb® after severe rhabdomyolysis might be an option and should be further investigated as a tool to prevent the development of AKI.
Diosgenin From Dioscorea Nipponica Rhizoma Against Graves’ Disease—On Network Pharmacology and Experimental Evaluation
Authors: Xin Jingxin , Cheng Wencong , Yu Yongbing , Chen Juan , Zhang Xinhuan , Shao Shanshan
Published: January 2022

Dioscorea nipponica rhizoma (DNR) is commonly used for the cure of hyperthyroidism resulting from Graves’ disease (GD) or thyroid nodules. However, its therapeutic mechanism remains unclear. This study aimed to utilize network pharmacology integrated molecular docking and experimental verification to reveal the potential pharmacological mechanism of DNR against GD. First, the active componds of DNR were collected from the HERB database and a literature search was conducted. Then, according to multisource database, the predicted genes of DNR and GD were collected to generate networks. The analysis of protein–protein interaction and GO enrichment and KEGG pathway were employed to discover main mechanisms associated with therapeutic targets. Moreover, molecular docking simulation was applied in order to verify the interactions between the drug and target. Finally, our experiments validated the ameliorated effects of diosgenin, the main component of DNR, in terms of phosphorylation deactivation in IGF-1R, which in turn inhibited the phosphorylation and activation of PI3K-AKT and Rap1-MEK signaling pathways, promoting cell apoptosis and GD remission. Our present study provided a foundation for further investigation of the in-depth mechanisms of diosgenin in GD and will provide new scientific evidence for clinical application.
Spectrum-Effect Relationship Between Antioxidant and Anti-inflammatory Effects of Banxia Baizhu Tianma Decoction: An Identification Method of Active Substances With Endothelial Cell Protective Effect
Authors: Xu Nan , Li Mingchen , Wang Ping , Wang Shuling , Shi Haiyan
Published: January 2022

Banxia Baizhu Tianma decoction (BBTD), a six-herb Chinese medicine formula first described approximately 1732 AD, is commonly prescribed for Hypertension with Phlegm-dampness Stagnation (HPDS) as an adjuvant therapy in China. Obesity is an important risk factor for the increasing prevalence of hypertension year by year in China. In Traditional Chinese medicine, obesity is often differentiated as the syndrome of excessive phlegm-dampness.Vascular endothelial cell injury plays an important role in the development and occurrence of HPDS. In this study, the protective effects of 18 batches of BBTD samples from different origins on HUVEC cells were evaluated, including antioxidant and anti-inflammatory activities. Ultrahigh performance liquid chromatography (UPLC) was used to establish fingerprints, and combined with pharmacodynamic indexes, the protective components of BBTD on endothelial cells were analyzed. Antioxidant and anti-inflammatory activities were evaluated by ROS and Hs-CRP models, respectively. Hierarchical cluster analysis (HCA) and Bivariate correlation analysis (BCA) were used to investigate the potential correlation between chemical components and endothelial cell protection. The results indicated that BBTD could reduce ROS and hs-CRP levels in HUVEC cells, and the pharmacological activities in 18 batches of BBTD samples were significantly different. The results of BCA indicated that Gastrodin, Liquiritin, Hesperidin, Isoliquiritin, Hesperetin, and Isoliquiritigenin might be the active constituents to activate ROS and suppress hs-CRP as determined by spectrum-effect relationships. The antioxidant and anti-inflammatory activities of the 6 components at different concentration were verified, and the results showed that all of them had good antioxidant and anti-inflammatory activities in a concentration-dependent manner. This study showed that activity determination and spectral correlation can be used to search for active substances in Chinese medicine formula and provide data support for quality control of Traditional Chinese medicine (TCM).
Limonin, an AMPK Activator, Inhibits Hepatic Lipid Accumulation in High Fat Diet Fed Mice
Authors: Wang Si-wei , Lan Tian , Chen Hang-fei , Sheng Hao , Xu Chun-yi , Xu Li-feng , Zheng Fang , Zhang Feng
Published: January 2022

NAFLD is the most prevalent liver disease in human history. The treatment is still limited yet. In the current study, we reported that limonin inhibited hepatic lipid accumulation and fatty acid synthesis in HFD fed mice. Using AMPK inhibitor and AMPK deficient C. elegans, we revealed the effect was dependent on the activation of AMPK. We found that limonin activated AMPK through inhibition of cellular energy metabolism and increasing ADP:ATP ratio. Furthermore, the treatment of limonin induced AMPK mediated suppression of the transcriptional activity of SREBP1/2. Our study suggests that limonin may a promising therapeutic agent for the treatment of NAFLD.
Deletion of Smooth Muscle Lethal Giant Larvae 1 Promotes Neointimal Hyperplasia in Mice
Authors: Zhang Ya , Yuan Peidong , Ma Xiaoping , Deng Qiming , Gao Jiangang , Yang Jianmin , Zhang Tianran , Zhang Cheng , Zhang Wencheng
Published: January 2022

Vascular smooth muscle cell (VSMC) proliferation and migration contribute to neointimal hyperplasia after injury, which causes vascular remodeling related to arteriosclerosis, hypertension, and restenosis. Lethal giant larvae 1 (LGL1) is a highly conserved protein and plays an important role in cell polarity and tumor suppression. However, whether LGL1 affects neointimal hyperplasia is still unknown. In this study, we used smooth muscle-specific LGL1 knockout (LGL1SMKO) mice generated by cross-breeding LGL1flox/flox mice with α-SMA-Cre mice. LGL1 expression was significantly decreased during both carotid artery ligation in vivo and PDGF-BB stimulation in vitro. LGL1 overexpression inhibited the proliferation and migration of VSMCs. Mechanistically, LGL1 could bind with signal transducer and activator of transcription 3 (STAT3) and promote its degradation via the proteasomal pathway. In the carotid artery ligation animal model, smooth muscle-specific deletion of LGL1 accelerated neointimal hyperplasia, which was attenuated by the STAT3 inhibitor SH-4-54. In conclusion, LGL1 may inhibit neointimal hyperplasia by repressing VSMC proliferation and migration via promoting STAT3 proteasomal degradation.