bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling the heterogeneity of sodium and calcium homeostasis between cortical and hippocampal astrocytes and its impact on bioenergetics
Authors: Thapaliya Pawan , Pape Nils , Rose Christine R. , Ullah Ghanim
Published: January 2023

Emerging evidence indicates that neuronal activity-evoked changes in sodium concentration in astrocytes Naarepresent a special form of excitability, which is tightly linked to all other major ions in the astrocyte and extracellular space, as well as to bioenergetics, neurotransmitter uptake, and neurovascular coupling. Recently, one of us reported that Naatransients in the neocortex have a significantly higher amplitude than those in the hippocampus. Based on the extensive data from that study, here we develop a detailed biophysical model to further understand the origin of this heterogeneity and how it affects bioenergetics in the astrocytes. In addition to closely fitting the observed experimental Naachanges under different conditions, our model shows that the heterogeneity in Naasignaling leads to substantial differences in the dynamics of astrocytic Ca2+signals in the two brain regions, and leaves cortical astrocytes more susceptible to Na+and Ca2+overload under metabolic stress. The model also predicts that activity-evoked Naatransients result in significantly larger ATP consumption in cortical astrocytes than in the hippocampus. The difference in ATP consumption is mainly due to the different expression levels of NMDA receptors in the two regions. We confirm predictions from our model experimentally by fluorescence-based measurement of glutamate-induced changes in ATP levels in neocortical and hippocampal astrocytes in the absence and presence of the NMDA receptor's antagonist (2R)-amino-5-phosphonovaleric acid.
Long-term consequences of reduced availability and compensatory supplementation of sialylated HMOs on cognitive capabilities
Authors: Pisa Edoardo , Traversa Alice , Caputo Viviana , Ottomana Angela Maria , Hauser Jonas , Macrì Simone
Published: January 2023

Breast milk (BM) is the optimal source of nutrition for mammals’ early life. It exerts multiple benefits, including the development of cognitive capabilities and protection against several diseases like obesity and infection of the respiratory tract. However, which components of BM are involved in individual development has remained elusive. Sialylated human milk oligosaccharides (HMOs) may constitute a valid candidate, whereby they represent the principal source of sialic acid and act as building blocks for brain development. We hypothesize that the reduced availability of two HMOs, sialyl(alpha2,6)lactose (6′SL) and sialyl(alpha2,3)lactose (3′SL), may impair attention, cognitive flexibility, and memory in a preclinical model and that the exogenous supplementation of these compounds may contrast the observed deficits. We evaluated cognitive capabilities in a preclinical model exposed to maternal milk containing reduced concentrations of 6′SL and 3′SL during lactation. To modulate their concentrations, we utilized a preclinical model characterized by the absence of genes that synthesize 3′SL and 6′SL (B6.129-St3gal4tm1.1Jxm and St6gal1tm2Jxm, double genetic deletion), producing milk lacking 3′SL and 6′SL. Then, to ensure exposure to 3′SL–6′SL-poor milk in early life, we adopted a cross-fostering protocol. The outcomes assessed in adulthood were different types of memory, attention and information processing, some of which are part of executive functions. Then, in the second study, we evaluated the long-term compensatory potential of the exogenous oral supplementation of 3′SL and 6′SL during lactation. In the first study, exposure to HMO-poor milk resulted in reduced memory and attention. Specifically, it resulted in impaired working memory in the T-maze test, in reduced spatial memory in the Barnes maze, and in impaired attentional capabilities in the Attentional set-shifting task. In the second part of the study, we did not observe any difference between experimental groups. We hypothesize that the experimental procedures utilized for the exogenous supplementation may have impacted our ability to observe the cognitive read-out in vivo. This study suggests that early life dietary sialylated HMOs play a crucial role in the development of cognitive functions. Future studies are needed to clarify if an exogenous supplementation of these oligosaccharides may compensate for these affected phenotypes.
Treatment of membranous nephropathy: Perspectives on current and future therapies
Authors: Shah Monarch , DeLaat Andrew , Cavanaugh Corey
Published: January 2023

Primary membranous nephropathy remains one of the most frequent causes of nephrotic syndrome in adults. It is an autoimmune disorder in which auto-antibodies target antigens at the podocytes cell membrane–basement membrane interface. Our understanding of membranous nephropathy has expanded dramatically as of late. After the initial discovery of the phospholipase A2 receptor auto-antibody in 2009, eight more antigens have been discovered. These discoveries have led to refinement in our understanding of the pathogenesis, diagnosis, and natural history of primary membranous nephropathy. Now, many experts advocate for redefining primary membranous nephropathy based on antigen, potentially shedding the primary and secondary nomenclature. Recently, therapies for primary membranous have also expanded. Immunosuppressive therapies like cyclophosphamide and rituximab, which primarily target B-cells, remain the cornerstone of therapy. However, there is still significant room for improvement, as many as 30-40% do not respond to this therapy according to recent trials. Additionally, drugs targeting complement, and other novel therapies are also under investigation. In this review we will discuss the available therapies for primary membranous nephropathy in light of recent clinic trials like GEMRITUX, MENTOR, RI-CYCLO, and STARMEN, as well as management strategies. While the last 10 years have seen a boom in our mechanistic understanding of this ever-diversifying disease, we are likely to see a similar boom in the therapeutic options in the years to come.
Clustering and prediction of disease progression trajectories in Huntington's disease: An analysis of Enroll-HD data using a machine learning approach
Authors: Ko Jinnie , Furby Hannah , Ma Xiaoye , Long Jeffrey D. , Lu Xiao-Yu , Slowiejko Diana , Gandhy Rita
Published: January 2023

Introduction

Huntington's disease (HD) is a rare neurodegenerative disease characterized by cognitive, behavioral and motor symptoms that progressively worsen with time. Cognitive and behavioral signs of HD are generally present in the years prior to a diagnosis; however, manifest HD is typically assessed by genetic confirmation and/or the presence of unequivocal motor symptoms. Nevertheless, there is a large variation in symptom severity and rate of progression among individuals with HD.

Methods

In this retrospective study, longitudinal natural history of disease progression was modeled in individuals with manifest HD from the global, observational Enroll-HD study (NCT01574053). Unsupervised machine learning (k-means; km3d) was used to jointly model clinical and functional disease measures simultaneously over time, based on one-dimensional clustering concordance such that individuals with manifest HD (N = 4,961) were grouped into three clusters: rapid (Cluster A; 25.3%), moderate (Cluster B; 45.5%) and slow (Cluster C; 29.2%) progressors. Features that were considered predictive of disease trajectory were then identified using a supervised machine learning method (XGBoost).

Results

The cytosine adenine guanine-age product score (a product of age and polyglutamine repeat length) at enrollment was the top predicting feature for cluster assignment, followed by years since symptom onset, medical history of apathy, body mass index at enrollment and age at enrollment.

Conclusions

These results are useful for understanding factors that affect the global rate of decline in HD. Further work is needed to develop prognostic models of HD progression as these could help clinicians with individualized clinical care planning and disease management.
Decreased degree centrality values as a potential neuroimaging biomarker for migraine: A resting-state functional magnetic resonance imaging study and support vector machine analysis
Authors: Wang Qian , Gao Yujun , Zhang Yuandong , Wang Xi , Li Xuying , Lin Hang , Xiong Ling , Huang Chunyan
Published: January 2023

Objective

Misdiagnosis and missed diagnosis of migraine are common in clinical practice. Currently, the pathophysiological mechanism of migraine is not completely known, and its imaging pathological mechanism has rarely been reported. In this study, functional magnetic resonance imaging (fMRI) technology combined with a support vector machine (SVM) was employed to study the imaging pathological mechanism of migraine to improve the diagnostic accuracy of migraine.

Methods

We randomly recruited 28 migraine patients from Taihe Hospital. In addition, 27 healthy controls were randomly recruited through advertisements. All patients had undergone the Migraine Disability Assessment (MIDAS), Headache Impact Test – 6 (HIT-6), and 15 min magnetic resonance scanning. We ran DPABI (RRID: SCR_010501) on MATLAB (RRID: SCR_001622) to preprocess the data and used REST (RRID: SCR_009641) to calculate the degree centrality (DC) value of the brain region and SVM (RRID: SCR_010243) to classify the data.

Results

Compared with the healthy controls (HCs), the DC value of bilateral inferior temporal gyrus (ITG) in patients with migraine was significantly lower and that of left ITG showed a positive linear correlation with MIDAS scores. The SVM results showed that the DC value of left ITG has the potential to be a diagnostic biomarker for imaging, with the highest diagnostic accuracy, sensitivity, and specificity for patients with migraine of 81.82, 85.71, and 77.78%, respectively.

Conclusion

Our findings demonstrate abnormal DC values in the bilateral ITG among patients with migraine, and the present results provide insights into the neural mechanism of migraines. The abnormal DC values can be used as a potential neuroimaging biomarker for the diagnosis of migraine.
Parent artery occlusion for ruptured aneurysms in moyamoya vessels or on collaterals
Authors: Zhou Zibo , Xu Kan , Yu Jinlu
Published: January 2023

Background

Aneurysms in moyamoya vessels or on collaterals are difficult to treat. Parent artery occlusion (PAO) via endovascular treatment (EVT) is often the last resort, but the safety and efficacy of this approach need to be evaluated.

Materials and methods

A retrospective study was performed on patients admitted to our hospital who were diagnosed with unilateral or bilateral moyamoya disease (MMD) associated with ruptured aneurysms in moyamoya vessels or on collaterals. These aneurysms were treated with PAO, and the clinical outcome was recorded.

Results

Eleven patients were aged 54.7 ± 10.4 years, and six patients were male (54.5%, 6/11). The aneurysms in 11 patients were single and ruptured, and the average size was 2.7 ± 0.6 mm. Three (27.3%, 3/11) aneurysms were located at the distal anterior choroidal artery, 3 (27.3%, 3/11) were at the distal lenticulostriate artery, 3 (27.3%, 3/11) were at the P2–3 segment of the posterior cerebral artery, 1 (9.1%, 1/11) was at the P4–5 segment of the posterior cerebral artery, and 1 was at the transdural location of the middle meningeal artery. Among the 11 aneurysms, PAO by coiling was performed on 7 (63.6%, 7/11), and Onyx casting was performed on 4 (36.4%, 4/11). Of 11 patients, 2 (18.2%, 2/11) suffered intraoperative hemorrhagic complications. During follow-up, all patients had good outcomes with a modified Rankin scale score of 0–2.

Conclusion

As a last resort, the application of PAO with coiling or casting Onyx for ruptured aneurysms in moyamoya vessels or on collaterals may be safe with an acceptable clinical outcome. However, patients with MMD may not always achieve expected health outcomes, and PAO for the aneurysm can bring only temporary relief.
Triglyceride glucose index and poor sleep patterns in non-diabetic adults: Evidence from NHANES 2005–2016
Authors: Liu Chi-Feng , Chien Li-Wei
Published: January 2023

Introduction

Sleep disorders are commonly encountered in modern populations. This cross-sectional study aimed to investigate the associations between triglyceride glucose (TyG) index and poor sleep patterns in non-diabetic adults.

Methods

Data of non-diabetic adults aged 20–70 years were extracted from the US National Health and Nutrition Examination Survey database 2005–2016. Pregnant women, individuals with diabetes and cancer history, and individuals lacking complete data on sleep patterns or parameters for calculating TyG index were excluded. Poor sleep pattern was defined as having two or more following conditions: (1) abnormal sleep duration, defined as less than 7 h or longer than 9 h; (2) self-reported trouble sleeping; and (3) physician-confirmed sleep disorders. Associations between poor sleep patterns, TyG index, and an additional index incorporating body mass index (BMI), TyGBMI, and other study variables were determined by univariable and multivariable logistic regression analysis.

Results

Among 9,390 included participants, 1,422 had poor sleep patterns and 7,968 did not. The individuals with poor sleep patterns had a higher mean TyG index, were older, had higher BMI, and had higher proportions of hypertension and history of CVD than those without poor sleep pattern (all p < 0.001). Multivariable analysis showed no significant association between poor sleep pattern and TyG index. However, among the components of poor sleep pattern, TyG index in the highest quartile (Q4) was significantly associated with trouble sleeping [adjusted OR (aOR): 1.46, 95%CI: 1.04–2.03) as compared with the lowest TyG quartile (Q1). In addition, TyG-BMI in Q4 was indepently associated with increased likelihood for poor sleep patterns (aOR: 2.18, 95%CI: 1.61–2.95), trouble sleeping (aOR: 1.76, 95%CI: 1.30–2.39), abnormal sleep duration (aOR: 1.41, 95%CI: 1.12–1.78), and sleep disorders (aOR: 3.11, 95%CI: 2.08–4.64) as compared to Q1.

Discussion

Among US adults without diabetes, elevated TyG index is correlated with self-reported trouble sleeping, independent of BMI. Future studies should build upon this preliminary work and examine these associations longitudinally and through treatment trials.
Extrachromosomal circular DNA in cancer drug resistance and its potential clinical implications
Authors: Luo Juanjuan , Li Ying , Zhang Tangxuan , Xv Tianhan , Chen Chao , Li Mengting , Qiu Qixiang , Song Yusheng , Wan Shaogui
Published: January 2023

Chemotherapy is widely used to treat patients with cancer. However, resistance to chemotherapeutic drugs remains a major clinical concern. The mechanisms of cancer drug resistance are extremely complex and involve such factors such as genomic instability, DNA repair, and chromothripsis. A recently emerging area of interest is extrachromosomal circular DNA (eccDNA), which forms owing to genomic instability and chromothripsis. eccDNA exists widely in physiologically healthy individuals but also arises during tumorigenesis and/or treatment as a drug resistance mechanism. In this review, we summarize the recent progress in research regarding the role of eccDNA in the development of cancer drug resistance as well as the mechanisms thereof. Furthermore, we discuss the clinical applications of eccDNA and propose some novel strategies for characterizing drug-resistant biomarkers and developing potential targeted cancer therapies.
Combining prognostic nutritional index (PNI) and controlling nutritional status (CONUT) score as a valuable prognostic factor for overall survival in patients with stage I–III colorectal cancer
Authors: Kim Harin , Shin Dong-Min , Lee Jae-Hoon , Cho Eun-Suk , Lee Hye Sun , Shin Su-Jin , Park Eun Jung , Baik Seung Hyuk , Lee Kang Young , Kang Jeonghyun
Published: January 2023

Background and aims

This study compared the prognostic significance of various nutritional and inflammatory indicators such as neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio and platelet-to-lymphocyte ratio, prognostic nutritional index, and controlling nutritional status score. In addition, we aimed to establish a more accurate prognostic indicator.

Methods

We retrospectively evaluated 1112 patients with stage I–III colorectal cancer between January 2004 and April 2014. The controlling nutritional status scores were classified as low (0–1), intermediate (2–4), and high (5–12) scores. The cut-off values for prognostic nutritional index and inflammatory markers were calculated using the X-tile program. P-CONUT, a combination of prognostic nutritional index and the controlling nutritional status score, was suggested. The integrated areas under the curve were then compared.

Results

The multivariable analysis showed that prognostic nutritional index was an independent prognostic factor for overall survival, whereas the controlling nutritional status score, neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and platelet-to-lymphocyte ratio were not. The patients were divided into three P-CONUT groups as follows: G1, controlling nutritional status (0–4) and high prognostic nutritional index; G2, controlling nutritional status (0–4) and low prognostic nutritional index; and G3, controlling nutritional status (5–12) and low prognostic nutritional index. There were significant survival differences between the P-CONUT groups (5-year overall survival of G1, G2, and G3 were 91.7%, 81.2%, and 64.1%, respectively; p < 0.0001). The integrated areas under the curve of P-CONUT (0.610, CI: 0.578–0.642) was superior to those of the controlling nutritional status score alone (bootstrap integrated areas under the curve mean difference=0.050; 95% CI=0.022–0.079) and prognostic nutritional index alone (bootstrap integrated areas under the curve mean difference=0.012; 95% CI=0.001–0.025).

Conclusion

Prognostic effect of P-CONUT may be better than inflammatory markers such as neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio and platelet-to-lymphocyte ratio. Thus, it could be used as a reliable nutritional risk stratification tool in patients with colorectal cancer.
Prioritization of patients for germline testing based on tumor profiling of hematopoietic malignancies
Authors: Godley Lucy A.
Published: January 2023

Germline predisposition to hematopoietic malignancies is more common than previously appreciated, with several clinical guidelines advocating for cancer risk testing in an expanding pool of patients. As molecular profiling of tumor cells becomes a standard practice for prognostication and defining options for targeted therapies, recognition that germline variants are present in all cells and can be identified by such testing becomes paramount. Although not to be substituted for proper germline cancer risk testing, tumor-based profiling can help prioritize DNA variants likely to be of germline origin, especially when they are present on sequential samples and persist into remission. Performing germline genetic testing as early during patient work-up as possible allows time to plan allogeneic stem cell transplantation using appropriate donors and optimize post-transplant prophylaxis. Health care providers need to be attentive to the differences between molecular profiling of tumor cells and germline genetic testing regarding ideal sample types, platform designs, capabilities, and limitations, to allow testing data to be interpreted as comprehensively as possible. The myriad of mutation types and growing number of genes involved in germline predisposition to hematopoietic malignancies makes reliance on detection of deleterious alleles using tumor-based testing alone very difficult and makes understanding how to ensure adequate testing of appropriate patients paramount.
DNA repair deficiency as circulating biomarker in prostate cancer
Authors: Catalano Martina , Generali Daniele , Gatti Marta , Riboli Barbara , Paganini Leda , Nesi Gabriella , Roviello Giandomenico
Published: January 2023

Deleterious aberrations in DNA repair genes are actionable in approximately 25% of metastatic castration-resistant prostate cancers (mCRPC) patients. Homology recombination repair (HRR) is the DNA damage repair (DDR) mechanism most frequently altered in prostate cancer; of note BRCA2 is the most frequently altered DDR gene in this tumor. Poly ADP-ribose polymerase inhibitors showed antitumor activity with a improvement in overall survival in mCRPC carrying somatic and/or germline alterations of HHR. Germline mutations are tested on peripheral blood samples using DNA extracted from peripheral blood leukocytes, while the somatic alterations are assessed by extracting DNA from a tumor tissue sample. However, each of these genetic tests have some limitations: the somatic tests are related to the sample availability and tumor heterogeneity, while the germline testing are mainly related to the inability to detect somatic HRR mutations. Therefore, the liquid biopsy, a non-invasive and easily repeatable test compared to tissue test, could identified somatic mutation detected on the circulating tumor DNA (ctDNA) extracted from a plasma. This approach should better represent the heterogeneity of the tumor compared to the primary biopsy and maybe helpful in monitoring the onset of potential mutations involved in treatment resistance. Furthermore, ctDNA may inform about timing and potential cooperation of multiple driver genes aberration guiding the treatment options in patients with mCRPC. However, the clinical use of ctDNA test in prostate cancer compared to blood and tissue testing are currently very limited. In this review, we summarize the current therapeutic indications in prostate cancer patients with DDR deficiency, the recommendation for germline and somatic-genomic testing in advanced PC and the advantages of the use liquid biopsy in clinical routine for mCRPC.
First-line programmed death-1 inhibitor treatment for locoregionally advanced or metastatic cutaneous squamous cell carcinoma – A real-world experience from Israel
Authors: Averbuch Itamar , Salman Saeed , Shtamper Noa , Doweck Ilana , Popovtzer Aron , Markel Gal , Hendler Daniel , Finkel Inbar , Moore Assaf , Fenig Eyal , Taha Tarek , Mhameed Kamel , Kurman Noga , Billan Salem
Published: January 2023

Objective

Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer worldwide. It is usually treated surgically, with very high cure rates. However, in 3%-7% of cases, cSCC metastasizes to lymph nodes or distant organs. Many of the affected patients are elderly with comorbidities who are not candidates for standard-of-care curative-intent treatment with surgery and/or radio-/chemotherapy. Immune checkpoint inhibitors, which target programmed cell death protein 1 (PD-1) pathways, have recently emerged as a potent therapeutic option. The present report presents the Israeli experience with PD-1 inhibitors for the treatment of loco-regionally advanced or metastatic cSCC in a diverse and elderly population, with or without the addition of radiotherapy.

Material and methods

The databases of two university medical centers were retrospectively searched for patients with cSCC treated with the PD-1 inhibitors cemiplimab or pembrolizumab between January 2019 and May 2022. Data on baseline, disease-related, treatment-related, and outcome parameters were collected and analyzed.

Results

The cohort included 102 patients of a median age 78.5 years. Evaluable response data were available for 93. The overall response rate was 80.6%: complete response in 42 patients (45.2%) and partial response in 33 (35.5%). Stable disease was recorded in 7 (7.5%) and progressive disease in 11 (11.8%). Median progression-free survival was 29.5 months. Radiotherapy was administered to the target lesion during PD-1 treatment in 22.5% of patients. mPFS was not significantly different in patients who treated with RT than patients how did not (NR vs 18.4 months, HR=0.93, 95%CI: 0.39 - 2.17, p<0.859). Any-grade toxicity was recorded in 57 patients (55%), including grade ‗3 in 25, of whom 5 (5% of cohort) died. Compared to toxicity-free patients, patients with drug toxicity had better progression-free survival (18.4 months vs not reached, HR=0.33, 95% CI: 0.13-0.82, p=0.012) and higher overall response rate (87% vs 71.8%, p=0.06).

Conclusion

This retrospective real-world study showed that PD-1 inhibitors were effective in the treatment of locally advanced or metastatic cSCC and appeared to be amenable for use in elderly or fragile patients with comorbidities. However, the high toxicity warrants consideration against other modalities. Induction or consolidation radiotherapy may improve the results. These findings need to be corroborated in a prospective trial.
Development and validation of an advanced ex vivo brain slice invasion assay to model glioblastoma cell invasion into the complex brain microenvironment
Authors: Decotret Lisa R. , Shi Rocky , Thomas Kiersten N. , Hsu Manchi , Pallen Catherine J. , Bennewith Kevin L.
Published: January 2023

Organotypic cultures of murine brain slices are well-established tools in neuroscience research, including electrophysiology studies, modeling neurodegeneration, and cancer research. Here, we present an optimized ex vivo brain slice invasion assay that models glioblastoma multiforme (GBM) cell invasion into organotypic brain slices. Using this model, human GBM spheroids can be implanted with precision onto murine brain slices and cultured ex vivo to allow tumour cell invasion into the brain tissue. Traditional top-down confocal microscopy allows for imaging of GBM cell migration along the top of the brain slice, but there is limited resolution of tumour cell invasion into the slice. Our novel imaging and quantification technique involves embedding stained brain slices into an agar block, re-sectioning the slice in the Z-direction onto slides, and then using confocal microscopy to image cellular invasion into the brain tissue. This imaging technique allows for the visualization of invasive structures beneath the spheroid that would otherwise go undetected using traditional microscopy approaches. Our ImageJ macro (BraInZ) allows for the quantification of GBM brain slice invasion in the Z-direction. Importantly, we note striking differences in the modes of motility observed when GBM cells invade into Matrigel in vitro versus into brain tissue ex vivo highlighting the importance of incorporating the brain microenvironment when studying GBM invasion. In summary, our version of the ex vivo brain slice invasion assay improves upon previously published models by more clearly differentiating between migration along the top of the brain slice versus invasion into the slice.
Refining empiric subgroups of pediatric sepsis using machine-learning techniques on observational data
Authors: Qin Yidi , Caldino Bohn Rebecca I. , Sriram Aditya , Kernan Kate F. , Carcillo Joseph A. , Kim Soyeon , Park Hyun Jung
Published: January 2023

Sepsis contributes to 1 of every 5 deaths globally with 3 million per year occurring in children. To improve clinical outcomes in pediatric sepsis, it is critical to avoid “one-size-fits-all” approaches and to employ a precision medicine approach. To advance a precision medicine approach to pediatric sepsis treatments, this review provides a summary of two phenotyping strategies, empiric and machine-learning-based phenotyping based on multifaceted data underlying the complex pediatric sepsis pathobiology. Although empiric and machine-learning-based phenotypes help clinicians accelerate the diagnosis and treatments, neither empiric nor machine-learning-based phenotypes fully encapsulate all aspects of pediatric sepsis heterogeneity. To facilitate accurate delineations of pediatric sepsis phenotypes for precision medicine approach, methodological steps and challenges are further highlighted.
Cytochrome P450 3A4 suppression by epimedium and active compound kaempferol leads to synergistic anti-inflammatory effect with corticosteroid
Authors: Li Ke , Yu Xiu-Hua , Maskey Anish R. , Musa Ibrahim , Wang Zhen-Zheng , Garcia Victor , Guo Austin , Yang Nan , Srivastava Kamal , Dunkin David , Li Jun-Xiong , Guo Longgang , Cheng Yung-Chi , Yuan Haoliang , Tiwari Raj , Li Xiu-Min
Published: January 2023

Introduction: Cytochrome P450 (CYP) 3A4 is a major drug metabolizing enzyme for corticosteroids (CS). Epimedium has been used for asthma and variety of inflammatory conditions with or without CS. It is unknown whether epimedium has an effect on CYP 3A4 and how it interacts with CS. We sought to determine the effects of epimedium on CYP3A4 and whether it affects the anti-inflammatory function of CS and identify the active compound responsible for this effect.

Methods: The effect of epimedium on CYP3A4 activity was evaluated using the Vivid CYP high-throughput screening kit. CYP3A4 mRNA expression was determined in human hepatocyte carcinoma (HepG2) cells with or without epimedium, dexamethasone, rifampin, and ketoconazole. TNF-α levels were determined following co-culture of epimedium with dexamethasone in a murine macrophage cell line (Raw 264.7). Active compound (s) derived from epimedium were tested on IL-8 and TNF-α production with or without corticosteroid, on CYP3A4 function and binding affinity.

Results: Epimedium inhibited CYP3A4 activity in a dose-dependent manner. Dexamethasone enhanced the expression of CYP3A4 mRNA, while epimedium inhibited the expression of CYP3A4 mRNA and further suppressed dexamethasone enhancement of CYP3A4 mRNA expression in HepG2 cells (p < 0.05). Epimedium and dexamethasone synergistically suppressed TNF-α production by RAW cells (p < 0.001). Eleven epimedium compounds were screened by TCMSP. Among the compounds identified and tested only kaempferol significantly inhibited IL-8 production in a dose dependent manner without any cell cytotoxicity (p < 0.01). Kaempferol in combination with dexamethasone showed complete elimination of TNF-α production (p < 0.001). Furthermore, kaempferol showed a dose dependent inhibition of CYP3A4 activity. Computer docking analysis showed that kaempferol significantly inhibited the catalytic activity of CYP3A4 with a binding affinity of −44.73kJ/mol.

Discussion: Inhibition of CYP3A4 function by epimedium and its active compound kaempferol leads to enhancement of CS anti-inflammatory effect.
Proton-pump inhibitor use amongst patients with severe hypomagnesemia
Authors: Seah Sherry , Tan Yen Kheng , Teh Kevin , Loh Wann Jia , Tan Pei Ting , Goh Leng Chuan , Malakar Roy Debajyoti , Aw Tar Choon , Lau Chin Shern , Dhalliwal Trishpal , Kui Swee Leng , Kam Jia Wen , Khoo Joan , Tay Tunn Lin , Tan Eberta , Au Vanessa , Soh Shui Boon , Zhang Meifen , King Thomas F. , Gani Linsey , Puar Troy H.
Published: January 2023

Introduction: Long-term proton pump inhibitor (PPI) use has been associated with hypomagnesemia. It is unknown how frequently PPI use is implicated in patients with severe hypomagnesemia, and its clinical course or risk factors.

Methods: All patients with severe hypomagnesemia from 2013 to 2016 in a tertiary center were assessed for likelihood of PPI-related hypomagnesemia using Naranjo algorithm, and we described the clinical course. The clinical characteristics of each case of PPI-related severe hypomagnesemia was compared with three controls on long-term PPI without hypomagnesemia, to assess for risk factors of developing severe hypomagnesemia.

Results: Amongst 53,149 patients with serum magnesium measurements, 360 patients had severe hypomagnesemia (<0.4 mmol/L). 189 of 360 (52.5%) patients had at least possible PPI-related hypomagnesemia (128 possible, 59 probable, two definite). 49 of 189 (24.7%) patients had no other etiology for hypomagnesemia. PPI was stopped in 43 (22.8%) patients. Seventy (37.0%) patients had no indication for long-term PPI use. Hypomagnesemia resolved in most patients after supplementation, but recurrence was higher in patients who continued PPI, 69.7% versus 35.7%, p = 0.009. On multivariate analysis, risk factors for hypomagnesemia were female gender (OR 1.73; 95% CI: 1.17–2.57), diabetes mellitus (OR, 4.62; 95% CI: 3.05–7.00), low BMI (OR, 0.90; 95% CI: 0.86–0.94), high-dose PPI (OR, 1.96; 95% CI: 1.29–2.98), renal impairment (OR, 3.85; 95% CI: 2.58–5.75), and diuretic use (OR, 1.68; 95% CI: 1.09–2.61).

Conclusion: In patients with severe hypomagnesemia, clinicians should consider the possibility of PPI-related hypomagnesemia and re-examine the indication for continued PPI use, or consider a lower dose.
A pharmacist-led medication review service with a deprescribing focus guided by implementation science
Authors: Alaa Eddine Nada , Schreiber James , El-Yazbi Ahmed F. , Shmaytilli Haya , Amin Mohamed Ezzat Khamis
Published: January 2023

Background: Little research addressed deprescribing-focused medication optimization interventions while utilizing implementation science. This study aimed to develop a pharmacist-led medication review service with a deprescribing focus in a care facility serving patients of low income receiving medications for free in Lebanon followed by an assessment of the recommendations’ acceptance by prescribing physicians. As a secondary aim, the study evaluates the impact of this intervention on satisfaction compared to satisfaction associated with receiving routine care.

Methods: The Consolidated Framework for Implementation Research (CFIR) was used to address implementation barriers and facilitators by mapping its constructs to the intervention implementation determinants at the study site. After filling medications and receiving routine pharmacy service at the facility, patients 65 years or older and taking 5 or more medications, were assigned into two groups. Both groups of patients received the intervention. Patient satisfaction was assessed right after receiving the intervention (intervention group) or just before the intervention (control group). The intervention consisted of an assessment of patient medication profiles before addressing recommendations with attending physicians at the facility. Patient satisfaction with the service was assessed using a validated translated version of the Medication Management Patient Satisfaction Survey (MMPSS). Descriptive statistics provided data on drug-related problems, the nature and the number of recommendations as well as physicians’ responses to recommendations. Independent sample t-tests were used to assess the intervention’s impact on patient satisfaction.

Results: Of 157 patients meeting the inclusion criteria, 143 patients were enrolled: 72 in the control group and 71 in the experimental group. Of 143 patients, 83% presented drug-related problems (DRPs). Further, 66% of the screened DRPs met the STOPP/START criteria (77%, and 23% respectively). The intervention pharmacist provided 221 recommendations to physicians, of which 52% were to discontinue one or more medications. Patients in the intervention group showed significantly higher satisfaction compared to the ones in the control group (p < 0.001, effect size = 1.75). Of those recommendations, 30% were accepted by the physicians.

Conclusion: Patients showed significantly higher satisfaction with the intervention they received compared to routine care. Future work should assess how specific CFIR constructs contribute to the outcomes of deprescribing-focused interventions.
Autophagy and necroptosis in cisplatin-induced acute kidney injury: Recent advances regarding their role and therapeutic potential
Authors: Alassaf Noha , Attia Hala
Published: January 2023

Cisplatin (CP) is a broad-spectrum antineoplastic agent, used to treat many different types of malignancies due to its high efficacy and low cost. However, its use is largely limited by acute kidney injury (AKI), which, if left untreated, may progress to cause irreversible chronic renal dysfunction. Despite substantial research, the exact mechanisms of CP-induced AKI are still so far unclear and effective therapies are lacking and desperately needed. In recent years, necroptosis, a novel subtype of regulated necrosis, and autophagy, a form of homeostatic housekeeping mechanism have witnessed a burgeoning interest owing to their potential to regulate and alleviate CP-induced AKI. In this review, we elucidate in detail the molecular mechanisms and potential roles of both autophagy and necroptosis in CP-induced AKI. We also explore the potential of targeting these pathways to overcome CP-induced AKI according to recent advances.
Salt processing: A unique and classic technology for Chinese medicine processing
Authors: Hou Ajiao , Lv Jiahao , Zhang Shihao , Zhang Jiaxu , Yang Liu , Jiang Hai , Kuang Haixue
Published: January 2023

Traditional Chinese medicine (TCM) processing is the summary of long-term clinical experience, processing can change the property, taste and meridian of TCM, achieve the purpose of reducing toxicity and increasing efficiency, to ensure the safety of clinical medication. This paper summarizes the research advance of salt processing in recent years from the aspects of the types of excipients, salt processing methods, salt processing purpose and the influence of salt process on the chemical composition, pharmacodynamic effect and in vivo behavior of TCM, and analyzes and discusses the shortcomings of the current research, so as to provide ideas for the further research and development of salt processing of TCM. The literatures were classified and summarized by consulting the scientific database (such as SciFinder Scholar, CNKI, Google Scholar, Baidu Scholar, etc.), Chinese herbal classics and Chinese Pharmacopoeia and so on. The results show that salt processing is helpful to introduce drugs into the kidney channel and enhance the effect of nourishing Yin and falling fire. The pharmacological effect, chemical composition and in vivo behavior of TCM will change after salt processing. In the future, we should strengthen the research on standardizing the dosage of excipients, the quality standard after processing, the relationship between the change of chemical composition after salt processing and the enhancement of pharmacological efficacy, so as to deeply explain the principle of salt processing, and further improve and optimize the salt making process. By combing the influence of the of salt processing of TCM and analyzed the current problems, we hope to provide guidance for the in-depth study of the salt processing mechanism of TCM and the inheritance and innovation of TCM processing technology.
The MHD graphene−CMC−water nanofluid past a stretchable wall with Joule heating and velocity slip impact: Coolant application
Authors: Rashid I. , Zubair T. , Asjad M. I. , Irshad S. , Eldin S. M.
Published: January 2023

The heat transport mechanism has an engrossing application in effective heat management for the automobile industry and the biomedical industry. The analysis of the MHD graphene−carboxymethyl cellulose (CMC) solution−water nanofluid past a stretchable wall with Joule heating and velocity slip impact is performed in this regard. A graphene-based nanofluid is considered. The dynamic model is used to simplify the complicated ordinary differential equations into non-dimensional forms, which are then evaluated analytically. Numerical data and graphs are produced to analyze the consequences of a physical entity with the aid of Maple 17. Moreover, the velocity field is decreased, while the magnitude of the magnetic parameter is increased. A decrease in θ(η) is observed as a result of an increase in ϕ. It is noted that a rise in the magnetic parameter causes a fall in the temperature distribution. It is perceived that −f′′(0) is decreased with an augmentation in βs, and an opposite trend is shown for ϕ. The velocity profile is the growing function of Mgn, βs, and Kve, with the reversed mode shown in case of ϕ. The temperature profile is the declining function of Pr, Ecrt, ϕ, and χ, with a contradictory trend observed for Mgn and βs. The flow regime is displayed against the viscoelastic parameter.
Cardiovascular risk assessment in periodontitis patients and controls using the European Systematic COronary Risk Evaluation (SCORE) model. A pilot study.
Authors: Kosho Madeline X. F. , Verhelst Alexander R. E. , Teeuw Wijnand J. , Gerdes Victor E. A. , Loos Bruno G.
Published: January 2023

Aim: To investigate the use of the European SCORE model in a dental setting by exploring the frequency of a ‘high’ and ‘very high’ 10-year CVD mortality risk in patients with and without periodontitis. The secondary aim was to investigate the association of SCORE with various periodontitis parameters adjusting for remaining potential confounders.

Material and methods: In this study, we recruited periodontitis patients and non-periodontitis controls, all aged ≥40 years. We determined the 10-year CVD mortality risk per individual with the European Systematic Coronary Risk Evaluation (SCORE) model by using certain patient characteristics and biochemical analyses from blood by finger stick sampling.

Results: In total, 105 periodontitis patients (61 localized, 44 generalized stage III/IV) and 88 non-periodontitis controls were included (mean age: 54.4 years). The frequency of a ‘high’ and ‘very high’ 10-year CVD mortality risk was 43.8% in all periodontitis patients and 30.7% in controls (p = .061). In total, 29.5% generalized periodontitis patients had a ‘very high’ 10-year CVD mortality risk, compared to 16.4% in localized periodontitis patients and 9.1% in controls (p = .003). After adjustment for potential confounders, the total periodontitis group (OR 3.31; 95% CI 1.35–8.13), generalized periodontitis group (OR 5.32; 95% CI 1.90–14.90), lower number of teeth (OR .83; 95% CI .73–1.00) and higher number of teeth with radiographic bone loss ≥33% (OR 1.06; 95% CI 1.00–1.12) were associated with a “very high” SCORE category. In addition, various biochemical risk markers for CVD were more frequently elevated in periodontitis compared to controls (e.g., total cholesterol, triglycerides, C-reactive protein).

Conclusion: The periodontitis group as well as the control group had a sizable frequency of a ‘high’ and ‘very high’ 10-year CVD mortality risk. The presence and extent of periodontitis, lower number of teeth and higher number of teeth with bone loss ≥33% are significant risk indicators for a ‘very high’ 10-year CVD mortality risk. Therefore, SCORE in a dental setting can be a very useful tool to employ for primary and secondary prevention of CVD, especially among the dental attenders who have periodontitis.
Autonomic nervous system and cardiac neuro-signaling pathway modulation in cardiovascular disorders and Alzheimer’s disease
Authors: Elia Andrea , Fossati Silvia
Published: January 2023

The heart is a functional syncytium controlled by a delicate and sophisticated balance ensured by the tight coordination of its several cell subpopulations. Accordingly, cardiomyocytes together with the surrounding microenvironment participate in the heart tissue homeostasis. In the right atrium, the sinoatrial nodal cells regulate the cardiac impulse propagation through cardiomyocytes, thus ensuring the maintenance of the electric network in the heart tissue. Notably, the central nervous system (CNS) modulates the cardiac rhythm through the two limbs of the autonomic nervous system (ANS): the parasympathetic and sympathetic compartments. The autonomic nervous system exerts non-voluntary effects on different peripheral organs. The main neuromodulator of the Sympathetic Nervous System (SNS) is norepinephrine, while the principal neurotransmitter of the Parasympathetic Nervous System (PNS) is acetylcholine. Through these two main neurohormones, the ANS can gradually regulate cardiac, vascular, visceral, and glandular functions by turning on one of its two branches (adrenergic and/or cholinergic), which exert opposite effects on targeted organs. Besides these neuromodulators, the cardiac nervous system is ruled by specific neuropeptides (neurotrophic factors) that help to preserve innervation homeostasis through the myocardial layers (from epicardium to endocardium). Interestingly, the dysregulation of this neuro-signaling pathway may expose the cardiac tissue to severe disorders of different etiology and nature. Specifically, a maladaptive remodeling of the cardiac nervous system may culminate in a progressive loss of neurotrophins, thus leading to severe myocardial denervation, as observed in different cardiometabolic and neurodegenerative diseases (myocardial infarction, heart failure, Alzheimer’s disease). This review analyzes the current knowledge on the pathophysiological processes involved in cardiac nervous system impairment from the perspectives of both cardiac disorders and a widely diffused and devastating neurodegenerative disorder, Alzheimer’s disease, proposing a relationship between neurodegeneration, loss of neurotrophic factors, and cardiac nervous system impairment. This overview is conducive to a more comprehensive understanding of the process of cardiac neuro-signaling dysfunction, while bringing to light potential therapeutic scenarios to correct or delay the adverse cardiovascular remodeling, thus improving the cardiac prognosis and quality of life in patients with heart or neurodegenerative disorders.
A smart IoMT based architecture for E-healthcare patient monitoring system using artificial intelligence algorithms
Authors: A Ahila , Dahan Fadl , Alroobaea Roobaea , Alghamdi Wael. Y. , Mustafa Khaja Mohammed  , Hajjej Fahima , Deema mohammed alsekait  , Raahemifar Kaamran
Published: January 2023

Generally, cloud computing is integrated with wireless sensor network to enable the monitoring systems and it improves the quality of service. The sensed patient data are monitored with biosensors without considering the patient datatype and this minimizes the work of hospitals and physicians. Wearable sensor devices and the Internet of Medical Things (IoMT) have changed the health service, resulting in faster monitoring, prediction, diagnosis, and treatment. Nevertheless, there have been difficulties that need to be resolved by the use of AI methods. The primary goal of this study is to introduce an AI-powered, IoMT telemedicine infrastructure for E-healthcare. In this paper, initially the data collection from the patient body is made using the sensed devices and the information are transmitted through the gateway/Wi-Fi and is stored in IoMT cloud repository. The stored information is then acquired, preprocessed to refine the collected data. The features from preprocessed data are extracted by means of high dimensional Linear Discriminant analysis (LDA) and the best optimal features are selected using reconfigured multi-objective cuckoo search algorithm (CSA). The prediction of abnormal/normal data is made by using Hybrid ResNet 18 and GoogleNet classifier (HRGC). The decision is then made whether to send alert to hospitals/healthcare personnel or not. If the expected results are satisfactory, the participant information is saved in the internet for later use. At last, the performance analysis is carried so as to validate the efficiency of proposed mechanism.