bluuebunny/crossref_metadata_2025 huggingface dataset:
Concepts of Neuroinflammation and Their Relationship With Impaired Mitochondrial Functions in Bipolar Disorder
Authors: Cyrino Luiz Arthur Rangel , Delwing-de Lima Daniela , Ullmann Oliver Matheus , Maia Thayná Patachini
Published: February 2021

Bipolar disorder (BD) is a chronic psychiatric disease, characterized by frequent behavioral episodes of depression and mania, and neurologically by dysregulated neurotransmission, neuroplasticity, growth factor signaling, and metabolism, as well as oxidative stress, and neuronal apoptosis, contributing to chronic neuroinflammation. These abnormalities result from complex interactions between multiple susceptibility genes and environmental factors such as stress. The neurocellular abnormalities of BD can result in gross morphological changes, such as reduced prefrontal and hippocampal volume, and circuit reorganization resulting in cognitive and emotional deficits. The term “neuroprogression” is used to denote the progressive changes from early to late stages, as BD severity and loss of treatment response correlate with the number of past episodes. In addition to circuit and cellular abnormalities, BD is associated with dysfunctional mitochondria, leading to severe metabolic disruption in high energy-demanding neurons and glia. Indeed, mitochondrial dysfunction involving electron transport chain (ETC) disruption is considered the primary cause of chronic oxidative stress in BD. The ensuing damage to membrane lipids, proteins, and DNA further perpetuates oxidative stress and neuroinflammation, creating a perpetuating pathogenic cycle. A deeper understanding of BD pathophysiology and identification of associated biomarkers of neuroinflammation are needed to facilitate early diagnosis and treatment of this debilitating disorder.
COVID-19 Pandemic Impact on Care for Stroke in Australia: Emerging Evidence From the Australian Stroke Clinical Registry
Authors: Cadilhac Dominique A. , Kim Joosup , Tod Emma K. , Morrison Julie L. , Breen Sibilah J. , Jaques Katherine , Grimley Rohan , Jones Brett , Cloud Geoffrey C. , Kleinig Timothy , Hillier Susan , Castley Helen , Lindley Richard I. , Lannin Natasha A. , Middleton Sandy , Yan Bernard , Hill Kelvin , Clissold Benjamin B. , Mitchell Peter J. , Anderson Craig S. , Faux Steven G. , Campbell Bruce C. V. ,   The AuSCR COVID-19 Reporting Consortium Group
Published: February 2021

We present information on acute stroke care for the first wave of the COVID-19 pandemic in Australia using data from the Australian Stroke Clinical Registry (AuSCR). The first case of COVID-19 in Australia was recorded in late January 2020 and national restrictions to control the virus commenced in March. To account for seasonal effects of stroke admissions, patient-level data from the registry from January to June 2020 were compared to the same period in 2019 (historical-control) from 61 public hospitals. We compared periods using descriptive statistics and performed interrupted time series analyses. Perceptions of stroke clinicians were obtained from 53/72 (74%) hospitals participating in the AuSCR (80% nurses) via a voluntary, electronic feedback survey. Survey data were summarized to provide contextual information for the registry-based analysis. Data from the registry covered locations that had 91% of Australian COVID-19 cases to the end of June 2020. For the historical-control period, 9,308 episodes of care were compared with the pandemic period (8,992 episodes). Patient characteristics were similar for each cohort (median age: 75 years; 56% male; ischemic stroke 69%). Treatment in stroke units decreased progressively during the pandemic period (control: 76% pandemic: 70%, p < 0.001). Clinical staff reported fewer resources available for stroke including 10% reporting reduced stroke unit beds. Several time-based metrics were unchanged whereas door-to-needle times were longer during the peak pandemic period (March-April, 2020; 82 min, control: 74 min, p = 0.012). Our data emphasize the need to maintain appropriate acute stroke care during times of national emergency such as pandemic management.
Wernicke Encephalopathy in COVID-19 Patients: Report of Three Cases
Authors: Branco de Oliveira Marcus Vinicius , Bernabé Daniel Galera , Irikura Sergio , Irikura Rodrigo Batista , Fontanelli Antônio Mendes , Gonçalves Marcus Vinícius Magno
Published: February 2021

Encephalopathy has been frequently reported in patients with acute respiratory distress syndrome (ARDS) related to COVID-19, and its etiology remains undetermined. These patients display hypercatabolic state, weight loss, use of diuretics, and dialytic therapy, which represent risk factors for thiamine depletion. The diagnosis of Wernicke encephalopathy (WE) is challenging and based on risk factors for the depletion of thiamine. We reported three cases of patients with COVID-19-related WE treated with intravenous thiamine. All patients responded with immediate neurologic improvement, and two of them had accelerated ventilatory weaning. The cases reported suggest that thiamine deficiency could represent relevant etiology of COVID-19-related encephalopathy.
Nerve Ultrasound Comparison Between Transthyretin Familial Amyloid Polyneuropathy and Chronic Inflammatory Demyelinating Polyneuropathy
Authors: Du Kang , Xu Ke , Cheng Si , Lv He , Zhang Wei , Wang Zhaoxia , Yuan Yun , Meng Lingchao
Published: February 2021

Backgrounds: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is frequently misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP) because of similar phenotypes in the two diseases. This study was intended to identify the role of nerve ultrasonography in evaluating TTR-FAP and CIDP.

Methods: Eighteen patients with TTR-FAP, 13 patients with CIDP, and 14 healthy controls (HC) were enrolled in this study. Consecutive ultrasonography scanning was performed in six pairs of nerves of bilateral limbs with 30 sites. The cross-sectional areas (CSAs) and CSA variability data of different groups were calculated and compared.

Results: Both TTR-FAP and CIDP showed larger CSAs at most sites of both upper and lower limbs than in HC groups. CIDP patients had larger CSAs than TTR-FAP patients at 8/15 of these sites, especially at U1-3, Sci2 sites (p < 0.01). However, the CSAs at above sites were not a credible index to differentiate TTR-FAP from CIDP with a low area under the curve (<0.8). The CSA variability of median nerves was significantly higher in CIDP than in TTR-FAP and HC groups, with high sensitivity (0.692) and specificity (0.833) to differentiate CIDP from TTR-FAP. The CSA variability of ulnar nerves was not significantly different between the three groups. For the TTR-FAP group, mean CSAs at each site were not correlated with different Coutinho stages, modified polyneuropathy disability, course of sensory motor peripheral neuropathy, Neuropathy Impairment Score, or Norfolk Quality of life-diabetic neuropathy score. The mean compound muscle action potential of ulnar nerves was negatively correlated with the mean CSAs of ulnar nerves.

Interpretation: TTR-FAP patients had milder nerve enlargement with less variability in CSAs of median nerves than those with CIDP, suggesting that nerve ultrasound can be a potential useful auxiliary tool to help differentiate the two neuropathies.
Relation of Decreased Functional Connectivity Between Left Thalamus and Left Inferior Frontal Gyrus to Emotion Changes Following Acute Sleep Deprivation
Authors: Li Bo-zhi , Cao Ya , Zhang Ying , Chen Yang , Gao Yu-hong , Peng Jia-xi , Shao Yong-cong , Zhang Xi
Published: February 2021

Objective: The thalamus is a key node for sleep-wake pathway gate switching during acute sleep deprivation (ASD), and studies have shown that it plays a certain role in emotion changes. However, there are no studies on the association between the thalamus and emotion changes in ASD. In this study, we used resting-state functional magnetic resonance imaging (R-fMRI) to explore whether changes in the functional connections between the thalamus and other brain regions are related to emotion changes and further explored the function of the thalamus under total ASD conditions.

Method: Thirty healthy, right-handed adult men underwent emotional assessment according to the Profile of Mood States Scale and R-fMRI scans before and after ASD. The correlations between changes in functional connectivity between the thalamus and other brain regions and emotion changes were then studied.

Results: Positive emotions and psychomotor performance were reduced, and negative emotions were increased following ASD. The functional connections between the left thalamus and left middle temporal gyrus, left inferior frontal gyrus, right thalamus, right inferior temporal gyrus, left middle temporal pole gyrus, right calcarine, left cuneus, left rectus and left medial superior frontal gyrus were significantly altered. Decreased functional connectivity between left thalamus and left inferior frontal gyrus related to emotion changes following ASD.

Conclusion: This study finds that functional changes in the thalamus are associated with emotion changes during ASD, suggesting that the left thalamus probably plays an essential role in emotion changes under ASD conditions.
Electroencephalographic Correlate of Mexican Spanish Emotional Speech Processing in Autism Spectrum Disorder: To a Social Story and Robot-Based Intervention
Authors: Duville Mathilde Marie , Alonso-Valerdi Luz Maria , Ibarra-Zarate David I.
Published: February 2021

Socio-emotional impairments are key symptoms of Autism Spectrum Disorders. This work proposes to analyze the neuronal activity related to the discrimination of emotional prosodies in autistic children (aged 9 to 11-year-old) as follows. Firstly, a database for single words uttered in Mexican Spanish by males, females, and children will be created. Then, optimal acoustic features for emotion characterization will be extracted, followed of a cubic kernel function Support Vector Machine (SVM) in order to validate the speech corpus. As a result, human-specific acoustic properties of emotional voice signals will be identified. Secondly, those identified acoustic properties will be modified to synthesize the recorded human emotional voices. Thirdly, both human and synthesized utterances will be used to study the electroencephalographic correlate of affective prosody processing in typically developed and autistic children. Finally, and on the basis of the outcomes, synthesized voice-enhanced environments will be created to develop an intervention based on social-robot and Social StoryTM for autistic children to improve affective prosodies discrimination. This protocol has been registered at BioMed Central under the following number: ISRCTN18117434.
The Interrelation Between Peripersonal Action Space and Interpersonal Social Space: Psychophysiological Evidence and Clinical Implications
Authors: Coello Yann , Cartaud Alice
Published: February 2021

The peripersonal space is an adaptive and flexible interface between the body and the environment that fulfills a dual-motor function: preparing the body for voluntary object-oriented actions to interact with incentive stimuli and preparing the body for defensive responses when facing potentially harmful stimuli. In this position article, we provide arguments for the sensorimotor rooting of the peripersonal space representation and highlight the variables that contribute to its flexible and adaptive characteristics. We also demonstrate that peripersonal space represents a mediation zone between the body and the environment contributing to not only the control of goal-directed actions but also the organization of social life. The whole of the data presented and discussed led us to the proposal of a new theoretical framework linking the peripersonal action space and the interpersonal social space and we highlight how this theoretical framework can account for social behaviors in populations with socio-emotional deficits.
Dissociation Between Insulin Resistance and Abnormalities in Lipoprotein Particle Concentrations and Sizes in Normal-Weight Chinese Adults
Authors: Tranæs Kaare , Ding Cherlyn , Chooi Yu Chung , Chan Zhiling , Choo John , Leow Melvin K.-S. , Magkos Faidon
Published: February 2021

Insulin resistance in obesity coincides with abnormalities in lipid profile and lipoprotein subclass distribution and size even before abnormalities in glucose homeostasis manifest. We aimed to assess this relationship in the absence of obesity. Insulin sensitivity (3-h intravenous glucose tolerance test and minimal modeling) and lipoprotein particle concentrations and sizes (proton nuclear magnetic resonance spectroscopy) were evaluated in 15 insulin-resistant and 15 insulin-sensitive lean Asians of Chinese descent with normal glucose tolerance, matched on age, sex, and body mass index. Despite a ~50% lower insulin sensitivity index (Si) in insulin-resistant than in insulin-sensitive subjects, which was accompanied by significantly greater acute insulin response to glucose (AIRg) and fasting insulin concentration but not different fasting glucose concentration, there were no significant differences between groups in the blood lipid profile (p ≥ 0.44) or the lipoprotein subclass concentrations (p ≥ 0.30) and particle sizes (p ≥ 0.43). We conclude that, contrary to observations in subjects with obesity, insulin resistance is not accompanied by unfavorable changes in the plasma lipid profile and lipoprotein particle concentrations and sizes in lean Asians with normal glucose tolerance. Therefore, insulin resistance at the level of glucose metabolism is mechanistically or temporally dissociated from lipid and lipoprotein metabolism.

Trial Registration:clinicaltrials.gov, NCT03264001.
Exploration of the Prognostic and Immunotherapeutic Value of B and T Lymphocyte Attenuator in Skin Cutaneous Melanoma
Authors: Dong Xubin , Song Jingjing , Chen Buran , Qi Yufeng , Jiang Wenjie , Li Huihui , Zheng Danni , Wang Yinghao , Zhang Xiaohua , Liu Haiguang
Published: February 2021

B and T lymphocyte attenuator (BTLA) is a newly identified immune checkpoint molecular belonging to the CD28 immunoglobulin superfamily. However, the expression and clinical value of BTLA in skin cutaneous melanoma (SKCM) has not been widely characterized. We found that BTLA levels were upregulated in metastatic melanoma compared to normal skin tissues and primary melanoma. Higher BTLA was also correlated with improved prognosis in SKCM based on several datasets. The multivariate Cox regression model revealed that BTLA was an independent survival indicator in metastatic melanoma. Tumor microenvironment analysis indicated BTLA was positively associated with the infiltrating levels of different immune cells and the activity of the anti-cancer immunity cycle. Importantly, BTLA accurately predicted the outcome of melanoma patients treated with MAGE-A3 blocker or first-line anti-PD-1. The present findings disclose that BTLA is a reliable biomarker for prognosis and immunotherapeutic response and might contribute to developing novel SKCM immunological treatment strategies.
A Prognostic Nomogram of Colon Cancer With Liver Metastasis: A Study of the US SEER Database and a Chinese Cohort
Authors: Liu Chuan , Hu Chuan , Huang Jiale , Xiang Kanghui , Li Zhi , Qu Jinglei , Chen Ying , Yang Bowen , Qu Xiujuan , Liu Yunpeng , Zhang Guangwei , Wen Ti
Published: February 2021

Background

Among colon cancer patients, liver metastasis is a commonly deadly phenomenon, but there are few prognostic models for these patients.

Methods

The clinicopathologic data of colon cancer with liver metastasis (CCLM) patients were downloaded from the Surveillance, Epidemiology and End Results (SEER) database. All patients were randomly divided into training and internal validation sets based on the ratio of 7:3. A prognostic nomogram was established with Cox analysis in the training set, which was validated by two independent validation sets.

Results

A total of 5,700 CCLM patients were included. Age, race, tumor size, tumor site, histological type, grade, AJCC N status, carcinoembryonic antigen (CEA), lung metastasis, bone metastasis, surgery, and chemotherapy were independently associated with the overall survival (OS) of CCLM in the training set, which were used to establish a nomogram. The AUCs of 1-, 2- and 3-year were higher than or equal to 0.700 in the training, internal validation, and external validation sets, indicating the favorable effects of our nomogram. Besides, whether in overall or subgroup analysis, the risk score calculated by this nomogram can divide CCLM patients into high-, middle- and low-risk groups, which suggested that the nomogram can significantly determine patients with different prognosis and is suitable for different patients.

Conclusion

Higher age, the race of black, larger tumor size, higher grade, histological type of mucinous adenocarcinoma and signet ring cell carcinoma, higher N stage, RCC, lung metastasis, bone metastasis, without surgery, without chemotherapy, and elevated CEA were independently associated with poor prognosis of CCLM patients. A nomogram incorporating the above variables could accurately predict the prognosis of CCLM.
Case Report and Supporting Documentation: Acute Kidney Injury Manifested as Oliguria Is Reduced by Intravenous Magnesium Before Cisplatin
Authors: Money Mary Elizabeth , Hamroun Aghiles , Shu Yan , Matthews Carolyn , Ahmed Eltayeb Sara , Ciarimboli Giuliano , Metz Christine Noel
Published: February 2021

After more than four decades of post-approval, cisplatin is still an important treatment for numerous cancers. However, acute kidney injury (AKI), defined as significant impairment of renal filtration as discussed below, is the major limiting side effect of cisplatin, occurring in approximately 30% of patients (25–33% after the first course). Cisplatin also damages the kidneys’ ability to reabsorb magnesium in 40–100% of patients, with collateral health risks due to subsequent hypomagnesemia. Multiple methods and drugs have been proposed for preventing cisplatin-induced AKI, including saline infusion with or without mannitol, which has not always prevented AKI and has been found to activate a cellular stress response in renal tubular cells. While numerous reports and trials, as well as the National Comprehensive Cancer Network (NCCN), support premedication with magnesium and hydration, this practice has not been universally accepted. Many clinics administer intravenous magnesium (IV) only after identification of hypomagnesemia post-cisplatin treatment, thus placing patients at risk for AKI and chronic renal loss of magnesium. We present the following case report and additional supporting evidence identifying the immediate effect of IV magnesium prior to intraperitoneal cisplatin for cycle 4 because of documented hypomagnesemia resulting in normalization of oliguria, which had been experienced for the first three cycles. The patient subsequently requested and received IV magnesium before cisplatin for the next two cycles with continuation of normal urinary output. The effect of pretreatment with IV magnesium on urine output following cisplatin has not been previously reported and further supports pre-cisplatin administration. In addition, two recent meta-analyses of clinical trials and pre-clinical research are reviewed that demonstrate effectiveness of magnesium pretreatment to preventing AKI without reducing its chemotherapeutic efficacy. This case report with additional evidence supports the adoption of administration of 1–3 g IV magnesium before cisplatin as best practice to prevent cisplatin induced AKI and hypomagnesemia regardless of patient baseline serum magnesium levels.
Anticancer Properties of the Antipsychotic Drug Chlorpromazine and Its Synergism With Temozolomide in Restraining Human Glioblastoma Proliferation In Vitro
Authors: Matteoni Silvia , Matarrese Paola , Ascione Barbara , Buccarelli Mariachiara , Ricci-Vitiani Lucia , Pallini Roberto , Villani Veronica , Pace Andrea , Paggi Marco G. , Abbruzzese Claudia
Published: February 2021

The extremely poor prognosis of patients affected by glioblastoma (GBM, grade IV glioma) prompts the search for new and more effective therapies. In this regard, drug repurposing or repositioning can represent a safe, swift, and inexpensive way to bring novel pharmacological approaches from bench to bedside. Chlorpromazine, a medication used since six decades for the therapy of psychiatric disorders, shows in vitro several features that make it eligible for repositioning in cancer therapy. Using six GBM cell lines, three of which growing as patient-derived neurospheres and displaying stem-like properties, we found that chlorpromazine was able to inhibit viability in an apoptosis-independent way, induce hyperdiploidy, reduce cloning efficiency as well as neurosphere formation and downregulate the expression of stemness genes in all these cell lines. Notably, chlorpromazine synergized with temozolomide, the first-line therapeutic in GBM patients, in hindering GBM cell viability, and both drugs strongly cooperated in reducing cloning efficiency and inducing cell death in vitro for all the GBM cell lines assayed. These results prompted us to start a Phase II clinical trial on GBM patients (EudraCT # 2019-001988-75; ClinicalTrials.gov Identifier: NCT04224441) by adding chlorpromazine to temozolomide in the adjuvant phase of the standard first-line therapeutic protocol.
Cyclooxygenase-2 Inhibitor: A Potential Combination Strategy With Immunotherapy in Cancer
Authors: Pu Dan , Yin Liyuan , Huang Lin , Qin Changlong , Zhou Yuwen , Wu Qiang , Li Yan , Zhou Qinghua , Li Lu
Published: February 2021

The clinical application of immunotherapy is the milestone of cancer treatment. However, some patients have bad reaction. Cyclooxygenase-2 (COX-2) is frequently expressed in multiple cancer cells and is associated with poor prognosis. It is the key enzyme of prostaglandin E2 (PGE2) that has been proved to promote the development, proliferation and metastasis of tumor cells. Recent studies further find the PGE2 in tumor microenvironment (TME) actively triggers tumor immune evasion via many ways, leading to poor response of immunotherapy. COX-2 inhibitor is suggested to restrain the immunosuppression of PGE2 and may enhance or reverse the response of immune checkpoint inhibitors (ICIs). This review provides insight into the mechanism of COX-2/PGE2 signal in immunosuppressive TME and summarizes the clinical application and trials in cancer treatment.
Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia
Authors: Brethon Benoît , Lainey Elodie , Caye-Eude Aurélie , Grain Audrey , Fenneteau Odile , Yakouben Karima , Roupret-Serzec Julie , Le Mouel Lou , Cavé Hélène , Baruchel André
Published: February 2021

Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents’ agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Case Report: A Novel de novo Mutation in DNM1L Presenting With Developmental Delay, Ataxia, and Peripheral Neuropathy
Authors: Wei Yanping , Qian Min
Published: February 2021

DNM1L encodes dynamin-related protein 1 (Drp1), which is a member of the dynamin superfamily of GTPases and mediates mitochondrial and peroxisomal fission. In humans, several de novo heterozygous missense mutations in DNM1L have been reported, which were characterized by devastating courses with refractory epilepsy, myoclonus, and brain atrophy on MRI. We describe a 4.5-year-old male child harboring a novel de novo mutation in DNM1L presenting a phenotype of developmental delay, ataxia, and peripheral neuropathy. The clinical features, magnetic resonance imaging findings, and genetic results were summarized. Meanwhile, all the cases of DNM1L mutations reported were reviewed. DNM1L variants may need to be considered in phenotypes that include global developmental delay, peripheral neuropathy, and ataxia.
Gestational Age-Specific Complete Blood Count Signatures in Necrotizing Enterocolitis
Authors: Pantalone Julia M. , Liu Silvia , Olaloye Oluwabunmi O. , Prochaska Erica C. , Yanowitz Toby , Riley Melissa M. , Buland Justin R. , Brozanski Beverly S. , Good Misty , Konnikova Liza
Published: February 2021

Objective: Necrotizing enterocolitis (NEC) is characterized by peripheral cell abnormalities, yet few studies have analyzed the complete blood count (CBC) specifically by gestational age (GA). Our objective was to describe GA-specific immune abnormalities in NEC through a comprehensive analysis of the CBC differential.

Methods: Using a cohort of 246 infants (177 cases, 69 controls) admitted to neonatal intensive care units at a single institution, we retrospectively analyzed CBCs around illness onset in NEC cases compared with controls. Cases included surgical NEC (S-NEC, 34.5%) and medical NEC (M-NEC, 65.5%). Infants were divided into those born at GA <33 and ≥33 weeks. Differences in CBC values were described as absolute and percent changes at NEC onset from baseline and at antibiotic completion after NEC. We used machine learning algorithms based on the CBC at NEC to generate predictive models for diagnosis.

Results: At NEC onset, there was an acute drop in monocytes and lymphocytes along with a rise in bands in S-NEC infants born <33 weeks compared with M-NEC. In comparison, both M-NEC and S-NEC ≥33 weeks had a percent drop in neutrophils at diagnosis compared with controls. At antibiotic completion, monocytes in S-NEC <33 weeks significantly rose compared with M-NEC, yet for S-NEC ≥33 weeks, bands significantly dropped compared with M-NEC. Predictive modeling was able to accurately predict S-NEC from M-NEC and controls.

Conclusion: There are discrete leukocyte patterns in NEC based on GA. The CBC at diagnosis may be useful in identifying patients who will require surgery.
Hemostatic Challenges in Pediatric Critical Care Medicine—Hemostatic Balance in VAD
Authors: Ghbeis Muhammad Bakr , Vander Pluym Christina J. , Thiagarajan Ravi Ram
Published: February 2021

Ventricular assist devices (VAD) are used more in children. Safe and effective anticoagulation is required for successful management of children supported with ventricular assist devices. Developmental hemostasis, device hemocompatibility, plastic to body ratio, surgical variable techniques, lack of knowledge on pharmacokinetics of anticoagulants, and wide variability in anticoagulation protocols have all contributed to increased incidence of bleeding and thromboembolic complications. New collaborative learning networks, such as the ACTION network, provide opportunities to define best practices, optimize, and reduce anticoagulation related adverse events. ACTION was established Dec 2017. It consists of expert clinicians in heart failure, as well as researchers, parents, and patients, with goals to improve outcomes, share data, improve education and standard practice for children with heart failure (1, n.d). Changes in pediatric VAD anticoagulation strategy from using mainly heparin to DTI such as bivalirudin have helped reduce bleeding and clotting complications.
The Effect of Plasma Rich in Growth Factors on Microglial Migration, Macroglial Gliosis and Proliferation, and Neuronal Survival
Authors: Ruzafa Noelia , Pereiro Xandra , Fonollosa Alex , Araiz Javier , Acera Arantxa , Vecino Elena
Published: February 2021

Plasma rich in growth factors (PRGF) is a subtype of platelet-rich plasma that has being employed in the clinic due to its capacity to accelerate tissue regeneration. Autologous PRGF has been used in ophthalmology to repair a range of retinal pathologies with some efficiency. In the present study, we have explored the role of PRGF and its effect on microglial motility, as well as its possible pro-inflammatory effects. Organotypic cultures from adult pig retinas were used to test the effect of the PRGF obtained from human as well as pig blood. Microglial migration, as well as gliosis, proliferation and the survival of retinal ganglion cells (RGCs) were analyzed by immunohistochemistry. The cytokines present in these PRGFs were analyzed by multiplex ELISA. In addition, we set out to determine if blocking some of the inflammatory components of PRGF alter its effect on microglial migration. In organotypic cultures, PRGF induces microglial migration to the outer nuclear layers as a sign of inflammation. This phenomenon could be due to the presence of several cytokines in PRGF that were quantified here, such as the major pro-inflammatory cytokines IL-1β, IL-6 and TNFα. Heterologous PRGF (human) and longer periods of cultured (3 days) induced more microglia migration than autologous porcine PRGF. Moreover, the migratory effect of microglia was partially mitigated by: 1) heat inactivation of the PRGF; 2) the presence of dexamethasone; or 3) anti-cytokine factors. Furthermore, PRGF seems not to affect gliosis, proliferation or RGC survival in organotypic cultures of adult porcine retinas. PRGF can trigger an inflammatory response as witnessed by the activation of microglial migration in the retina. This can be prevented by using autologous PRGF or if this is not possible due to autoimmune diseases, by mitigating its inflammatory effect. In addition, PRGF does not increase either the proliferation rate of microglial cells or the survival of neurons. We cannot discard the possible positive effect of microglial cells on retinal function. Further studies should be performed to warrant the use of PRGF on the nervous system.
The Role of Nrf2 in the PM-Induced Vascular Injury Under Real Ambient Particulate Matter Exposure in C57/B6 Mice
Authors: Gao Mengyu , Ma Yuanyuan , Luo Jing , Li Daochuan , Jiang Menghui , Jiang Qixiao , Pi Jingbo , Chen Rui , Chen Wen , Zhang Rong , Zheng Yuxin , Cui Lianhua
Published: February 2021

Short-and long-term exposure to particulate matter (PM) has been associated with cardiovascular disease (CVD). It is well recognized that oxidative stress is a potential major mechanism in PM-induced vascular injuries, in which the nuclear factor E2-related factor 2 (Nrf2) signaling pathway plays a critical role. In the current study, a Nrf2 knockout mouse model was used in combination with an individual ventilated cage (IVC)-based real-ambient PM exposure system to assess the potential vascular injury and the potential role of Nrf2 in the angiotensin II (Ang II)-associated vascular injury. After 6-or 11-week exposure to PM, the histopathology assay revealed that PM exposure resulted in the thickening of the walls of vascular. After 6 weeks exposure to PM, the ELISA assay revealed that PM exposure resulted in the elevated plasma concentration of Ang II. The expression levels of genes of interest were then further investigated with quantitative real-time PCR. Notably, the results showed that Angiotensinogen (AGT), Angiotensin converting enzyme (ACE) and Angiotensin type I receptor (AT1R) were involved in PM-induced pathological changes. Western blotting for ACE showed similar results. Moreover, the extent of vascular thickening and the Ang II elevation was most prominent in the Nrf2 gene knockout PM exposure group (KOE). Furthermore, the expression of Nrf2 downstream relevant genes (HO1, Nqo1, Gclc, Gsta4) were significantly enhanced in the wildtype PM exposure group (WTE), while those were remarkably suppressed in the Nrf2 gene knockout groups. The ELISA result of monocyte chemoattractant protein-1 (MCP-1) serum levels in the KOE group was significantly higher in relation to that in the Nrf2 knockout control group (KOC). In summary, PM exposure is associated with thickening of vascular wall, while Nrf2 knockout may further enhance this effect. A potential mechanistic contributor of such effects is the activation of ACE/ANGII/AT1R axis, in which Nrf2 played a regulatory role.
Discovering Potential RNA Dependent RNA Polymerase Inhibitors as Prospective Drugs Against COVID-19: An in silico Approach
Authors: Saha Satabdi , Nandi Rajat , Vishwakarma Poonam , Prakash Amresh , Kumar Diwakar
Published: February 2021

COVID-19, caused by Severe Acute Respiratory Syndrome Corona Virus 2, is declared a Global Pandemic by WHO in early 2020. In the present situation, though more than 180 vaccine candidates with some already approved for emergency use, are currently in development against SARS-CoV-2, their safety and efficacy data is still in a very preliminary stage to recognize them as a new treatment, which demands an utmost emergency for the development of an alternative anti-COVID-19 drug sine qua non for a COVID-19 free world. Since RNA-dependent RNA polymerase (RdRp) is an essential protein involved in replicating the virus, it can be held as a potential drug target. We were keen to explore the plant-based product against RdRp and analyze its inhibitory potential to treat COVID-19. A unique collection of 248 plant compounds were selected based on their antiviral activity published in previous literature and were subjected to molecular docking analysis against the catalytic sub-unit of RdRp. The docking study was followed by a pharmacokinetics analysis and molecular dynamics simulation study of the selected best-docked compounds. Tellimagrandin I, SaikosaponinB2, Hesperidin and (-)-Epigallocatechin Gallate were the most prominent ones that showed strong binding affinity toward RdRp. All the compounds mentioned showed satisfactory pharmacokinetics properties and remained stabilized at their respective binding sites during the Molecular dynamics simulation. Additionally, we calculated the free-binding energy/the binding properties of RdRp-ligand complexes with the connection of MM/GBSA. Interestingly, we observe that SaikosaponinB2 gives the best binding affinity (∆Gbinding = −42.43 kcal/mol) in the MM/GBSA assay. Whereas, least activity is observed for Hesperidin (∆Gbinding = −22.72 kcal/mol). Overall our study unveiled the feasibility of the SaikosaponinB2 to serve as potential molecules for developing an effective therapy against COVID-19 by inhibiting one of its most crucial replication proteins, RdRp.
The Biological Significance and Implications of Planar Cell Polarity for Nephrology
Authors: Papakrivopoulou Eugenia , Jafree Daniyal J. , Dean Charlotte H. , Long David A.
Published: February 2021

The orientation of cells in two-dimensional and three-dimensional space underpins how the kidney develops and responds to disease. The process by which cells orientate themselves within the plane of a tissue is termed planar cell polarity. In this Review, we discuss how planar cell polarity and the proteins that underpin it govern kidney organogenesis and pathology. The importance of planar cell polarity and its constituent proteins in multiple facets of kidney development is emphasised, including ureteric bud branching, tubular morphogenesis and nephron maturation. An overview is given of the relevance of planar cell polarity and its proteins for inherited human renal diseases, including congenital malformations with unknown aetiology and polycystic kidney disease. Finally, recent work is described outlining the influence of planar cell polarity proteins on glomerular diseases and highlight how this fundamental pathway could yield a new treatment paradigm for nephrology.
Differences in Daytime Activity Levels and Daytime Sleep Between Night and Day Duty: An Observational Study in Italian Orthopedic Nurses
Authors: Roveda Eliana , Castelli Lucia , Galasso Letizia , Mulè Antonino , Cè Emiliano , Condemi Vincenzo , Banfi Giuseppe , Montaruli Angela , Esposito Fabio
Published: February 2021

Working nonstandard work schedules is often associated with increased sedentary behavior and risk of sleep disorders. Night shift workers are prone to accumulating sleep debt, which they recover by sleeping during the day. The effect on daytime activity levels is unknown. The present study aims to objectively assess whether daytime sleep could affect daytime activity levels of shift worker nurses, resulting in an accumulation of their activity debt differently between working and rest periods. The study population (N = 37; mean age 41.7 ± 9.1 years) was composed of orthopedic nurses working on a rotating schedule, including either a night shift (NS) or only day/afternoon shift (DS). Actigraph monitoring lasted both on the working and the rest period. For the NS nurses, the working period recorded higher daytime activity levels than the rest period, while daytime sleep during the working and rest periods was similar. Conversely, DS nurses showed higher daytime activity levels and shorter daytime sleep during the working period. NS nurses were less active than DS nurses during the working period, probably because NS tended to have a longer daytime sleep. During the rest period, daytime activity levels for both groups were decreased. For NS nurses, sleep recorded the better sleep parameters during the rest period, while sleep parameters did not show significant differences between the working and the rest periods in DS. During the working period, NS nurses slept worse than the DS nurses. Both groups tended to accumulate a debt in daytime activity levels during the rest period. While daytime sleep may be an excellent way to counteract sleep debt and increase sleep duration over 24 h period, on the other hand, it makes nurses less active.
Effects of Plyometric Jump Training on Physical Fitness in Amateur and Professional Volleyball: A Meta-Analysis
Authors: Ramirez-Campillo Rodrigo , García-de-Alcaraz Antonio , Chaabene Helmi , Moran Jason , Negra Yassine , Granacher Urs
Published: February 2021

We aimed to examine the effects of plyometric jump training (PJT) on measures of physical fitness in amateur and professional volleyball players. A systematic electronic literature search was carried out in the databases PubMed, MEDLINE, Web of Science, and SCOPUS. Controlled studies including pre-to-post intervention tests of physical fitness and involving healthy volleyball players regardless of age and sex were considered. A random-effects model was used to calculate effect sizes (ES) between intervention and control groups. Moderator analyses considered programme duration, training frequency, total number of training sessions and jumps, participants' sex, age, and expertise level. The Physiotherapy Evidence Database scale was used to assess the methodological quality of the included studies. Eighteen moderate-to-high quality (median of 5 PEDro points) studies were eligible, comprising a total of 746 athletes. None of the included studies reported injuries related to the PJT intervention. The main findings showed small-to-moderate effects (p< 0.05) of PJT on linear sprint speed (ES = 0.70), squat jump (ES = 0.56), countermovement jump (CMJ) (ES = 0.80), CMJ with arm swing (ES = 0.63), drop jump (ES = 0.81), and spike jump height (ES = 0.84). Sub-analyses of moderator factors included 48 data sets. Only age had a significant effect on CMJ performance. Participants aged ≥16 years achieved greater improvements in CMJ performance compared to <16 years old (ES = 1.28 and 0.38, respectively;p= 0.022). No significant differences (p= 0.422) were identified between amateur (ES = 0.62) and professional volleyball players (ES = 1.01). In conclusion, PJT seems safe and is effective in improving measures of physical fitness in amateur and professional volleyball players, considering studies performed in both male and female.
Identification of Copy Number Variation Among Nonsyndromic Cleft Lip and or Without Cleft Palate With Hypodontia: A Genome-Wide Association Study
Authors: Ghazali Norliana , Abd Rahman Normastura , Ahmad Azlina , Sulong Sarina , Kannan Thirumulu Ponnuraj
Published: February 2021

Nonsyndromic cleft lip and or without cleft palate (NSCL/P) with the hypodontia is a common developmental abnormality in humans and animals. This study identified the genetic aberration involved in both NSCL/P and hypodontia pathogenesis. A cross-sectional study using genome-wide study copy number variation-targeted CytoScan 750K array carried out on salivary samples from 61 NSCL/P and 20 noncleft with and without hypodontia Malay subjects aged 7–13 years old. Copy number variations (CNVs) of SKI and fragile histidine triad (FHIT) were identified in NSCL/P and noncleft children using quantitative polymerase chain reaction (qPCR) as a validation analysis. Copy number calculated (CNC) for each gene determined with Applied Biosystems CopyCaller Software v2.0. The six significant CNVs included gains (12q14.3, 15q26.3, 1p36.32, and 1p36.33) and losses (3p14.2 and 4q13.2) in NSCL/P with hypodontia patients compared with the NSCL/P only. The genes located in these regions encoded LEMD3, IGF1R, TP73, SKI, FHIT, and UGT2β15. There were a significant gain and loss of both SKI and FHIT copy number in NSCL/P with hypodontia compared with the noncleft group (p < 0.05). The results supported that CNVs significantly furnish to the development of NSCL/P with hypodontia.
Health Effects of Alternate Day Fasting Versus Pair-Fed Caloric Restriction in Diet-Induced Obese C57Bl/6J Male Mice
Authors: Henderson Chloe G. , Turner Damian L. , Swoap Steven J.
Published: February 2021

Alternate day fasting (ADF) induces weight loss and improves various markers of health in rodents and humans. However, it is unclear whether the benefits of ADF are derived from the lower caloric intake of ADF or from the 24-h fasting period. Therefore, this study directly compared selected markers for health – such as glucose control, body weight, liver triglycerides, T cell frequencies, and others – in high-fat (60% calories from fat) diet-induced obese mice subjected to either ADF or caloric restriction (CR). Obese mice were randomly assigned to one of four groups: (1) ADF: remained on the high-fat diet, but fed on alternate days (n= 5), (2) PF: remained on the high-fat diet, but pair-fed to the ADF group (n= 5), (3) LF: moved to a chowad libitumdiet (n= 5; 17% calories from fat), and (4) HF: remained on the high-fatad libitumdiet (n= 5). An additional group of non-obese mice maintained on a chow diet since weaning were used as controls (CON:n= 5). After 10 weeks, ADF, PF, and LF mice ate fewer kcals, had a lower body mass, had smaller epididymal fat pads, improved glucose tolerance, and had a lower hepatic triglyceride content relative to HF mice (p< 0.05), but none reached that of CON mice in these measures. T cell frequencies of the spleen, blood, and mesenteric lymph nodes were reduced in ADF, PF, and HF compared to the CON group. Importantly, there were no significant differences between the ADF and PF groups in any of the measurements made in the current study. These data suggest that ADF, PF, and LF diets each lead to improved markers of health relative to high-fat diet-induced obese mice, and that the caloric restriction associated with ADF is the major factor for the noted improvements.
OpenEP: A Cross-Platform Electroanatomic Mapping Data Format and Analysis Platform for Electrophysiology Research
Authors: Williams Steven E. , Roney Caroline H. , Connolly Adam , Sim Iain , Whitaker John , O’Hare Daniel , Kotadia Irum , O’Neill Louisa , Corrado Cesare , Bishop Martin , Niederer Steven A. , Wright Matt , O’Neill Mark , Linton Nick W. F.
Published: February 2021

Background

Electroanatomic mapping systems are used to support electrophysiology research. Data exported from these systems is stored in proprietary formats which are challenging to access and storage-space inefficient. No previous work has made available an open-source platform for parsing and interrogating this data in a standardized format. We therefore sought to develop a standardized, open-source data structure and associated computer code to store electroanatomic mapping data in a space-efficient and easily accessible manner.

Methods

A data structure was defined capturing the available anatomic and electrical data. OpenEP, implemented in MATLAB, was developed to parse and interrogate this data. Functions are provided for analysis of chamber geometry, activation mapping, conduction velocity mapping, voltage mapping, ablation sites, and electrograms as well as visualization and input/output functions. Performance benchmarking for data import and storage was performed. Data import and analysis validation was performed for chamber geometry, activation mapping, voltage mapping and ablation representation. Finally, systematic analysis of electrophysiology literature was performed to determine the suitability of OpenEP for contemporary electrophysiology research.

Results

The average time to parse clinical datasets was 400 ± 162 s per patient. OpenEP data was two orders of magnitude smaller than compressed clinical data (OpenEP: 20.5 ± 8.7 Mb, vs clinical: 1.46 ± 0.77 Gb). OpenEP-derived geometry metrics were correlated with the same clinical metrics (Area: R2 = 0.7726, P < 0.0001; Volume: R2 = 0.5179, P < 0.0001). Investigating the cause of systematic bias in these correlations revealed OpenEP to outperform the clinical platform in recovering accurate values. Both activation and voltage mapping data created with OpenEP were correlated with clinical values (mean voltage R2 = 0.8708, P < 0.001; local activation time R2 = 0.8892, P < 0.0001). OpenEP provides the processing necessary for 87 of 92 qualitatively assessed analysis techniques (95%) and 119 of 136 quantitatively assessed analysis techniques (88%) in a contemporary cohort of mapping studies.

Conclusions

We present the OpenEP framework for evaluating electroanatomic mapping data. OpenEP provides the core functionality necessary to conduct electroanatomic mapping research. We demonstrate that OpenEP is both space-efficient and accurately representative of the original data. We show that OpenEP captures the majority of data required for contemporary electroanatomic mapping-based electrophysiology research and propose a roadmap for future development.