NPM interaction with tumor suppressor p53 is a part of a complex interaction network and considerably affects cellular stress response. An impact of characteristic AML-associated NPM mutations on interaction with p53 has not been investigated yet, although consequences of NPMmut-induced p53 export to the cytoplasm are important for understanding of leukemogenic potential of these mutations. We investigated p53-NPM interaction in live HEK-293T cells by FLIM-FRET and in cell lysates by immunoprecipitation. Results were confirmed in leukemia cell lines. eGFP lifetime-photoconversion was used to follow redistribution dynamics of NPMmut and p53 in Selinexor-treated cells. We confirmed the p53-NPMwt interaction in intact cells and newly documented that this interaction is not compromised by the NPM mutation causing displacement of p53 to the cytoplasm. Importantly, the interaction was not abolished for non-oligomerizing NPM variants with truncated oligomerization domain, suggesting that oligomerization is not essential for interaction of NPM forms with p53. Inhibition of the nuclear exporter XPO1 by Selinexor caused expected nuclear relocalization of both NPMmut and p53. However, significantly different return rates of these proteins indicate nontrivial mechanism of p53 and NPMmut cellular trafficking. We suggest that the altered p53 regulation in cells expressing NPMmut offers a new target for AML therapy.

Background: To investigate the preoperative clinical and radiological factors that predict the development of a postoperative intraabdominal abscess (IAA) in patients with acute appendicitis who were treated by laparoscopic appendectomy (LA). Methods: Two hundred sixteen patients with pathologically proven acute appendicitis underwent LA between January 2013 and March 2018 in our department. Of these, 147 patients were diagnosed with complicated appendicitis (CA) (CA group), while the other 69 patients were diagnosed with simple appendicitis (SA) (SA group). We compared the perioperative clinical and radiographic factors between the two groups and investigated the predictive factors of postoperative IAA. Results: Sixteen patients developed postoperative IAA in the CA group, while no patients did in the SA group. The univariate analysis revealed that time from onset to surgery more than 3 days (p = 0.011), the preoperative CT finding of periappendiceal fluid (p = 0.003), abscess (p < 0.001), and free air (p <0.001), operation time more than 120 minutes (p = 0.023) and placement of a drainage tube (p <0.001) were significantly associated with the development of IAA. Multivariate analysis revealed that the preoperative CT finding of free air was independently associated with the development of IAA (p = 0.007, odds ratio = 5.427). Conclusions: IAA was developed predominantly in the patients with CA. Preoperative CT findings of free air was found to be an independent predictor for the development of IAA. Surgeons should be meticulous in managing the postoperative course of patients with this finding.

With the rapid growth of large language models (LLMs), there is increasing demand for memory and computation for LLMs. Recent efforts on post-training pruning of LLMs aim to reduce the model size and computation, yet the performance is still sub-optimal. In this paper, we present a plug-and-play solution for post-training pruning of LLMs. The proposed solution has two innovative components: 1) **Relative Importance and Activations** (RIA), a new pruning metric that jointly considers the weight and activations efficiently on LLMs; and 2) **Channel Permutation**, a new approach to maximally preserve important weights under N:M sparsity. The proposed two components can be readily combined to further enhance the N:M structuredly pruned LLMs. Our empirical experiments show that RIA alone can already surpass all existing post-training pruning methods on prevalent LLMs, e.g., LLaMA ranging from 7B to 65B. Furthermore, N:M structured pruning with channel permutation can even outperform the original LLaMA2 70B on zero-shot tasks, together with practical speed-up on specific hardware.

Text fields in electronic medical records (EMR) contain information on important factors that influence health outcomes, however, they are underutilized in clinical decision making due to their unstructured nature. We analyzed 6,497 inpatient surgical cases with 719,308 free text notes from Le Bonheur Children’s Hospital EMR. We used a text mining approach on preoperative notes to obtain the text-based risk score algorithm as predictive of death within 30 days of surgery. We studied the additional performance obtained by including text-based risk score as a predictor of death along with other structured data based clinical risk factors. The C-statistic of a logistic regression model with 5-fold cross-validation significantly improved from 0.76 to 0.92 when text-based risk scores were included in addition to structured data. We conclude that preoperative free text notes in EMR include significant information that can predict adverse surgery outcomes.

The traditional bored pile technology has some arduous problems, such as the sediment at the pile tip, the mud skin along the pile shaft, and the stress release due to borehole construction. The post-grouted technology at the pile tip of bored pile has emerged because of demand. The grouting migration height (GMH) is of great significance to the strengthen and reinforcement of the pile foundation. This paper derives the calculation formula of the GMH based on the theory of the column hole expansion and Herschel-Bulkley model. The influence of relevant parameters on the GMH is discussed. Aiming at the problem of the grouting migration along the pile shaft in layered soils, the iterative calculation method of the GMH is proposed. The correctness of the GMH is verified by an engineering case, which can guide the engineering practice. The result shows that the GMH increases with the increase of the grouting pressure, the pile diameter and the thickness of the mud skin, and the grouting pressure is positively correlated with the GMH. The GMH decreases with the increase of the buried depth, the consistency coefficient and the rheological index. On this basis, the correctness of the GMH is verified by an engineering case.

Fear extinction requires coordinated neural activity within the amygdala and medial prefrontal cortex (mPFC). Any behavior has a transcriptomic signature that is modified by environmental experiences, and specific genes are involved in functional plasticity and synaptic wiring during fear extinction. Here, we investigated the effects of optogenetic manipulations of prelimbic (PrL) pyramidal neurons on amygdala gene expression to analyze the specific transcriptional pathways involved in adaptive and maladaptive fear extinction. To this aim, transgenic mice were (or not) fear-conditioned and during the extinction phase they received optogenetic (or sham) stimulations over PrL pyramidal neurons. At the end of behavioral testing, electrophysiological (neural cellular excitability and Excitatory Post-Synaptic Currents) and morphological (spinogenesis) correlates were evaluated in the PrL pyramidal neurons. Furthermore, transcriptomic cell-specific RNA-analyses (differential gene expression profiling and functional enrichment analyses) were performed in amygdala pyramidal neurons. Our results show that the optogenetic activation of PrL pyramidal neurons in fear-conditioned mice induces fear extinction deficits, reflected in an increase of cellular excitability, excitatory neurotransmission, and spinogenesis of PrL pyramidal neurons, and in strong modifications of the transcriptome of amygdala pyramidal neurons. Understanding the electrophysiological, morphological and transcriptomic architecture of fear extinction may facilitate the comprehension of fear-related disorders.

The Acute Cystitis Symptom Score (ACSS) is a patient self-reporting questionnaire for the clinical diagnosis and patient-reported outcome (PRO) in women with acute uncomplicated cystitis (AC). The aim of the current study (part II) was the clinical validation of the Greek ACSS questionnaire. After linguistic validation according to internationally accepted guidelines and cognitive assessment (part I), the clinical validation was performed after ethical approval by using the Greek ACSS study version in 92 evaluable female participants including 53 patients with symptoms suspicious of AC and 39 controls. The clinical outcome using the ACSS questionnaire at different time points after the start of treatment was demonstrated as well. The age (mean±SD) of the 53 patients (44.7±17.0) and 39 controls (49.3±15.9) and their additional conditions at baseline visits, such as menstruation, premenstrual syndrome, pregnancy, menopause, diabetes mellitus, were comparable. There was, however, a significant difference (p&lt;0.001) between patients and controls at baseline visit regarding sum score of the ACSS domains, such as typical symptoms and quality of life. The clinical outcome of up to 7 days showed a fast reduction of the symptom scores and improvement of quality of life. The optimal thresholds for the patient-reported outcome of successful therapy could be established. The linguistically and clinically validated Greek ACSS questionnaire can now be used for clinical or epidemiological studies and also for patient’s self-diagnosis of AC and as a PRO measure tool.

Acute kidney injury (AKI) is a frequent and critical complication in the clinical setting. In rodents AKI can be prevented effectively through caloric restriction (CR), which has also been shown to increase lifespan in many species. In Caenorhabditis elegans (C. elegans) longevity studies revealed that a marked CR-induced reduction of endocannabinoids may be a key mechanism. Thus, we hypothesized that regulation of endocannabinoids, in particular arachidonoyl ethanolamide (AEA), might also play a role in CR-mediated protection from renal ischemia-reperfusion injury (IRI) in mammals including humans. In male C57Bl6J mice, CR significantly reduced renal IRI and led to a significant decrease of AEA. Supplementation of AEA to near-normal serum concentrations by repetitive intraperitoneal administration in CR mice, however, did not abrogate the protective effect of CR. We also analyzed serum samples taken before and after CR from patients of three different pilot trials of dietary interventions. In contrast to mice and C. elegans, we detected an increase of AEA. We conclude that endocannabinoid levels in mice are modulated by CR, but CR-mediated renal protection does not depend on this effect. Moreover, our results indicate that modulation of endocannabinoids by CR in humans may differ fundamentally from the effects in animal models.

Background There is a considerable overlap between clinical presentation of post-COVID-19 condition (PCC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) . Many of their common symptoms can be linked to dysregulation of the autonomic nervous system (dysautonomia). This study aimed to objectively assess autonomic function in patients with PCC and in patients with ME/CFS whose disease was not related to COVID-19. Methods Synchronous recordings of an electrocardiogram, continuous dynamics of blood pressure in the digital artery using the Penaz method and ultrasound pneumotachography with the spirography function were obtained with spiroarteriocardiorhythmography method in 34 patients diagnosed with ME/CFS, in whom the onset of the disease was not associated with COVID-19, 29 patients meeting PCC definition and 32 healthy controls. Heart rate variability (HRV), systolic and diastolic blood pressure variability (RV), respiration variability were assessed at rest and in tests with fixed respiratory rates. At rest, indicators of baroreflex regulation were additionally determined (baroreflex effectiveness index and baroreflex sensitivity). Results The total power, power of very low frequency, low-frequency and high-frequency of RR interval variability at rest as well as baroreflex effectiveness index in up-ramps of arterial blood pressure and baroreflex sensitivity were significantly lower both in PCC and ME/CFS patients compared to HC. Several diagnostic prediction models for ME/CFS were developed based on HRV parameters. During slow breathing HRV parameters return to normal in PCC, but not in ME/CFS. Correlation analysis revealed a close relationship of HRV, RV parameters and baroreflex sensitivity with fatigue, but not with HADS depressive/anxiety symptoms in ME/CFS and PCC. Conclusion A similar pattern of HRV and baroreflex failure with signs of a pathological acceleration of age-dependant dysautonomia was identified in ME/CFS and PCC. The clinical, diagnostic and therapeutic implications of these findings are discussed, in light of previously described relationship between inflammation, vascular pathology, atherosclerotic cardiovascular disease and autonomic dysfunction.

On March 2020 strict measures took place in Finland to limit the COVID -19 pandemic. A majority of the Finnish COVID -19 –patients have been located in the southern Finland and consequently cared for in the HUS Helsinki University Hospital. During the ongoing pandemic, HUS personnel’s psychological symptoms are followed via an electronic survey, which also delivers information on psychosocial support services. The baseline survey in June 2020 was sent to 25494 HUS employees out of whom 4804 (19%) answered; altogether 62.4% of the respondents were nursing staff and 8.9% medical doctors. While the follow-up continues for a year and a half, this report shares the sociodemographic characteristics of the respondents and the first results of psychological symptoms from the baseline survey. Out of those who were directly involved in pandemic patients` care, 43.4% reported potentially traumatic COVID-19 pandemic-related experiences vs. 21.8% among the other (p &lt; 0.001). While over a half of the personnel was symptomless, a group of respondents reported pandemic work –related traumatic events and concurrent depressive, insomnia and anxiety symptoms. This highlights the need to ensure appropriate psychosocial support services to all traumatized personnel and PTEs were present especially among nursing staff.

Post-Shoah Christology is embedded in the unique relationship of Jews and Christians, especially Jesus’ Jewishness and the Jewish roots of Christianity, as well as Christian moral failures towards Jews before and during the Shoah. Essential for contemporary Christianity, a vibrant post-Shoah Christology confronts three main challenges, each demanding a different response. The first challenge is the reality that soon there will be no more first-generation witnesses to the Final Solution. Such is an inevitable challenge that has to be faced and prepared for. Religious pluralism is the second challenge, and includes a number of related threads, yet should ultimately be embraced. The third challenge is the (inevitable?) loss of memory, passion, and urgency, a willful forgetfulness by Christians towards the importance of the Jewish-Christian relationship, and especially, Christian failure in the Shoah. This challenge demands robust refutation and ongoing struggle. Before addressing these challenges, I will first further define and highlight the need for a post-Shoah Christology and will conclude this article with three general and three concrete hopes for a viable post-Shoah Christology.

A critical challenge underpinning the adoption of Additive Manufacture (AM) as a technology is the postprocessing of manufactured components. For Selective Laser Sintering (SLS) this can involve the removal of powder from the interior of the component, often by vibrating the component to fluidise the powder to encourage drainage. In this paper we develop and validate a computational model of the flow of metal powder suitable for predicting powder removal from such AM components. The model is a continuum Eulerian multiphase model of the powder including models for the granular temperature; the effect of vibration can be included through appropriate wall boundaries for this granular temperature. We validate the individual sub-models appropriate for AM metal powders by comparison with in-house and literature experimental results, and then apply the full model to a more complex geometry typical of an AM Heat Exchanger. The model is shown to provide valuable and accurate results at a fraction of the computational cost of a particle-based model.

The influence of post-processing conditions on the magnetic properties of amorphous and nanocrystalline microwires have been thoroughly analyzed, paying attention on the influence of magnetoelastic, induced and magnetocrystalline anisotropies on the hysteresis loops of Fe-, Ni- and Co-rich microwires. We showed that magnetic properties of glass-coated microwires can be tuned by the selection of appropriate chemical composition and geometry in as-prepared state or further considerably modified by appropriate post-processing, which consists of either annealing or glass-coated removal. Furthermore, stress-annealing or Joule heating can further effectively modify the magnetic properties of amorphous magnetic microwires owing to induced magnetic anisotropy. Devitrification of microwires can be useful for either magnetic softening or magnetic hardening of the microwires. Depending on the chemical composition of the metallic nucleus and on structural features (grain size, precipitating phases) nanocrystalline microwires can exhibit either soft magnetic properties or semi-hard magnetic properties. We demonstrated that the microwires with coercivities from 1 A/m to 40 kA/m can be prepared.

Multiple lines of evidence indicate that CD8$^+$ T cells are important in the control of HIV-1 (HIV) replication. However, CD8$^+$ T cells induced by natural infection cannot eliminate the virus or reduce viral loads to acceptably low levels in most infected individuals. Understanding the basic quantitative features of CD8$^+$ T-cell responses induced during the course of HIV infection may therefore inform us about the limits that HIV vaccines, which aim to induce protective CD8$^+$ T-cell responses, must exceed. Using previously published experimental data from a cohort of HIV-infected individuals with sampling times from acute to chronic infection we defined the quantitative properties of CD8$^+$ T-cell responses to the whole HIV proteome. In contrast with a commonly held view, we found that the relative number of HIV-specific CD8$^+$ T-cell responses (response breadth) changed little over the course of infection (first 400 days post-infection), with moderate but statistically significant changes occurring only during the first 35 symptomatic days. This challenges the idea that a change in the T-cell response breadth over time is responsible for the slow speed of viral escape from CD8$^+$ T cells in the chronic infection. The breadth of HIV-specific CD8$^+$ T-cell responses was not correlated with the average viral load for our small cohort of patients. Metrics of relative immunodominance of HIV-specific CD8$^+$ T-cell responses such as Shannon entropy or the Evenness index were also not significantly correlated with the average viral load. Our mathematical-model-driven analysis suggested extremely slow expansion kinetics for the majority of HIV-specific CD8$^+$ T-cell responses and the presence of intra- and interclonal competition between multiple CD8$^+$ T-cell responses; such competition may limit the magnitude of CD8$^+$ T-cell responses, specific to different epitopes, and the overall number of T-cell responses induced by vaccination. Further understanding of mechanisms underlying interactions between the virus and virus-specific CD8$^+$ T-cell response will be instrumental in determining which T-cell-based vaccines will induce T-cell responses providing durable protection against HIV infection.

Background: Acute ischemic stroke is among the main causes of mortality worldwide; a rapid and opportune diagnosis is crucial to improve a patient's outcome. MicroRNAs are quite useful for a rapid and accurate diagnosis.Methods: We perform both structural networks approach and a meta-analysis (using a random-effect model to evaluate the heterogeneity and risk bias, according to the PRISMA statement) to analyze the feasibility to develop a microRNA-based biomarker panel for an opportune AIS diagnosis. Results: Structural networks identify a set of eight miRNAs (miR-16, miR-124-3p, miR-484, miR-15a, miR-4454, miR-107, miR-125b-5p and miR-320b) as preliminary microRNA-based biomarker panel, from these only three microRNAs are significantly associated with the main risk factors of AIS, (miR-107: hypertension, 95% CI 9.74-53.24 p<0.0001, type 2 Diabetes mellitus, 95% CI 2.18-19.26); p=0.0008; miR-16 hypertension, 95% CI 1.26-3.56 p=0.0046, smoking, 95% CI 1.07-3.54 p=0.0277; and miR-15a hypertension, 95% CI 1.26-3.56 p=0.0046; smoking, 95% CI 1.07-3.54 p=0.0277). However, the meta-analysis reveals that data is highly heterogeneous and biased; and only microRNAs isolated from plasma samples and further processed in microarrays are the most reliable to distinguish AIS patients.Conclusions: Together our results show that although there are some miRNAs that seem to be associated with AIS, we are still far to develop a miRNA-based biomarker for AIS diagnosis and it is necessary to harmonize the protocols, results and include more populations for further studies otherwise we will remain throwing punches in the dark.

The acetylcholinesterase (AChE) inhibitors are the main drugs for symptomatic treatment of neurodegenerative disorders like Alzheimer’s disease. A recently designed, synthesized and tested hybrid compound between the AChE inhibitor galantamine (GAL) and the antioxidant polyphenol curcumin (CU) showed high AChE inhibition in vitro. Here, we describe tests for acute and short-term toxicity in mice as well as antioxidant tests on brain homogenates measured the levels of malondialdehide (MDA) and glutathione (GSH). Haematological and serum biochemical analyses were also performed. In the acute toxicity tests, the novel AChE inhibitor given orally in mice showed LD50 of 49 mg/kg. The short-term administration of 2.5 and 5 mg/kg did not show toxicity. In the ex vivo tests, the GAL-CU hybrid performed better than GAL and CU themselves. In a dose of 5 mg/kg, it demonstrates 25% reduction in AChE activity, 28% and 73% increase in the levels of MDA and GSH, respectively. No significant changes in blood biochemical data were observed. The GAL-CU hybrid is a novel non-toxic AChE inhibitor with high antioxidant activity which makes it a perspective multitarget drug candidate for treatment of Alzheimer’s disease.

Infectious disease is the leading cause of mortality in children under five. This study has investigated environmental factors related to the morbidity of acute respiratory infections (ARIs), diarrhea, and growth using geographical information systems (GIS) technology. Anthropometric, address and disease prevalence data were collected through the SEEM study in Matiari, Pakistan. Publicly available map data was used to compile coordinates of healthcare facilities. A Pearson correlation coefficient (r) was used to calculate the correlation between distance from healthcare facilities and participant growth and morbidity. Other continuous variables influencing these outcomes were analyzed using a random forest regression model. In this study of 416 children, we found participants living closer to secondary hospitals had lower prevalence of ARI (r=0.154, p&lt;0.010) and diarrhea (r=0.228, p&lt;0.001) as well as participants living closer to Maternal Health Centers (MHCs): ARI (r=0.185, p&lt;0.002) and diarrhea (r=0.223, p&lt;0.001) compared to those living near primary facilities. Our random forest model showed distance to have high variable importance in the context of disease prevalence. Our results indicated that participants closer to more basic healthcare facilities reported a higher prevalence of both diarrhea and ARI than those near more urban facilities, highlighting potential public policy gaps in ameliorating rural health.

Introduction: Wound healing is a multifaceted biological process, and diabetic wounds add more complexity to it. In diabetic wounds, the combination of chloroform fractions of Achyranthes aspera L. (A.aspera) leaves with β-Glucans has not been investigated. The additive effect of these two (A.aspera + β-Glucans) would benefit the inflammatory phase of diabetic wounds, as improper treatment will lead to chronic injuries. Therefore, the goal of this research work was to assess the in-vivo wound healing and anti-inflammatory effects of a combination of chloroform fractions of A.aspera leaves and β-Glucans in a variety of wound models in STZ-induced diabetic rats. Methods: Preliminary phytochemical analyses of A.aspera were conducted to identify various phytoconstituents in the test extract. Acute and sub-acute dermal toxicity tests of A.aspera were carried out on mice and rats, respectively, to see whether there were any abnormalities. Excision and incision wound models, cotton pellet-induced granuloma models, rat paw edema and burn wounds were used to test wound healing and anti-inflammatory actions. To induce diabetes, streptozotocin (STZ) was administered intraperitoneally at a dosage of 65 mg/kg (i.p.). A.aspera (10% w/w) and β-Glucans (2% w/w) ointments were tested separately and in combination for wound healing activities. Silver sulfadiazine (1 % w/w) ointment was used to treat the positive control groups. Excision wound model rats that had been treated with basic ointment were used as negative controls, as were incision wound model rats that had not been treated. A.aspera (400 mg/kg, po) and β-Glucans (30 mg/kg, po) were tested separately and in combination for anti-inflammatory efficacy. Positive control groups were given indomethacin (10 mg/kg, po) for cotton pellet-induced granuloma and rat paw oedema models. Negative controls for both anti-inflammatory activity models were provided 2% Tween 80. The groups were made up of six rats, and the treatments were given topically and orally to assess wound healing and anti-inflammatory effects. The levels of hydroxyproline and hexosamine and the antioxidant enzymes (SOD and CAT) in the granulation tissue were measured in excision wound model. Healed excision wound skin was examined histopathologically. Results: The A.aspera and β-Glucans combination resulted in a significant percentage of wound contraction and a shorter epithelialization time (P<0.01). The combination was found to be the most effective, with the highest percentage of edema reduction (55 %; p<0.01). The combination also exhibited favourable hydroxylamine, hexosamine and anti-oxidant profiles supported by histopathology data. Conclusion: This research showed that the immunomodulatory effect of β-Glucans had significantly enhanced the wound healing, anti-inflammatory, and anti-oxidant potential of A.aspera in diabetic wounds.

Background: Whilst lack of concentration is a known symptom of anaemia, its association with post-stroke dementia is unclear. Methods: We used data from a UK regional stroke register. To be eligible, patient must have survived to discharge and had anaemia by WHO criteria. Dementia status and other prevalent co-morbidities were assessed using ICD-10 codes. Patients were followed till May 2015 (mean follow-up 3.7 years, total person years = 27,769). Hazard Ratio for incident dementia was calculated using Cox-proportional hazards model controlling for potential confounders. Fine and Gray model was additionally constructed using mortality as the competing risk. Results: A total of 7,454 stroke patients were included with mean age (SD) of 75.9(12.3) years (50.2% men). Those with anaemia were older, has higher disability and co-morbidity burden prior to stroke. We observed a large amount of variation in the dementia incidence rates over time and that the hazard ratio increased every year. The significant association between anaemia and dementia incidence was lost after controlling for pre-stroke Modified Rankin score (HR1.17(0.97,1.40)). With every 20g/dL increase in Hb was associated with a significant reduction in the risk of dementia after adjustment for age, sex, stroke factors and disability but lost significance after adjustment for vascular risk factors. Competing risk analyses showed similar results. Conclusion: Whilst we found no evidence of anaemia as a risk factor for post-stroke dementia, the findings may be limited by potential under recognition of post stroke dementia.

The physiological response to a psychological stressor broadly impacts energy metabolism. In-versely, changes in energy availability affect the physiological response to the stressor in terms of hypothalamus, pituitary adrenal axis (HPA) and sympathetic nervous system activation. Glu-cocorticoids, the endpoint of the HPA axis, are critical checkpoints in endocrine control of ener-gy homeostasis and have been linked to metabolic diseases including obesity, insulin resistance and type 2 diabetes. Glucocorticoids, through the glucocorticoid receptor, activate transcription of genes associated with glucose and lipid regulatory pathways and thereby control both physi-ological and pathophysiological systemic energy homeostasis. Here, we summarize the current knowledge of glucocorticoid functions in energy metabolism and systemic metabolic dysfunc-tion, particularly focusing on glucose and lipid metabolism. There are elements in the external environment that induce lifelong changes in the HPA axis stress response and glucocorticoid levels, the most prominent are early-life adversity, or exposure to traumatic stress. We hypothe-sise that when the HPA axis is so disturbed after early-life adversity, it will fundamentally alter hepatic gluconeogenesis, inducing hyperglycaemia, and hence crystalise the significant lifelong risk of developing either the metabolic syndrome, or type 2 diabetes. This gives a “Jekyll and Hyde” role to gluconeogenesis, providing the necessary energy in situations of acute stress, but driving towards pathophysiological consequences when the HPA axis has been altered.

Introduction: Otitis media with effusion (OME) is common in pediatric primary care consultations. Its etiology is multifactorial, although it has been proven that inflammation factors mediate and that immunity is in a phase of relative immaturity. The objective of this study was to assess the effects of the Traditional Mediterranean Diet (TMD) modulating inflammation and immunity in patients diagnosed with OME.

The aging of the global population has increased the prevalence of neurodegenerative conditions. Bacopa monnieri (BM), an herb with active compounds, such as bacosides A and B, betulinic acid, loliolide, asiatic acid, and quercetin, demonstrates the potential for brain health. Limited research has been conducted on the therapeutic applications of BM in neurodegenerative conditions. This systematic review aims to project BM's beneficial role in brain disorders. BM has anti-apoptotic and antioxidant actions and can repair damaged neurons, stimulate kinase activity, restore synaptic function, improve nerve transmission, and increase neuroprotection. The included twenty-two clinical trials demonstrated that BM can reduce Nuclear Factor-κB phosphorylation, improve emotional function, cognitive functions, anhedonia, hyperactivity, sleep routine, depression, attention deficit, learning problems, memory retention, impulsivity, and psychiatric problems. Moreover, BM can reduce the levels of pro-inflammatory biomarkers and oxidative stress. Here, we highlight that BM provides notable therapeutic benefits and can serve as a complementary approach for the care of patients with neurodegenerative conditions associated with brain disorders. This review adds to the growing interest in natural products and their potential therapeutic applications by improving our understanding of the mechanisms underlying cognitive function and neurodegeneration and informing the development of new therapeutic strategies for neurodegenerative diseases.

The large production of non-degradable petrol-based plastics has become a major global issue due to its environmental pollution. Biopolymers produced by microorganisms such as polyhydroxyalkanoates (PHAs) are gaining potential as a sustainable alternative, but the high cost associated to their industrial production has been a limiting factor. Post-transcriptional regulation is a key step to control gene expression in changing environments and has been reported to play a major role in numerous cellular processes. However, limited reports are available concerning the regulation of PHA accumulation in bacteria, and many essential regulatory factors still need to be identified. Here, we review studies where the synthesis of PHA has been reported to be regulated at the post-transcriptional level, and we analyze the RNA-mediated networks involved. Finally, we discuss the forthcoming research on riboregulation, synthetic and metabolic engineering which could lead to improved strategies for PHAs synthesis in industrial production, thereby reducing the costs currently associated with this procedure.

Acute Oak Decline (AOD) is complex syndrome affecting Britain’s keystone native oak species, (Quercus robur L. and Q. petraea L. (Matt.) Liebl.), in some cases causing mortality within five years of symptom development. The most distinguishable symptom is weeping stem lesions, from which four species of bacteria have been isolated: Brenneria goodwinii, Gibbsiella quercinecans, Lonsdalea britannica and Rahnella victoriana. We do not yet know where else these bacteria exist, and little is known about the relationship of the wider oak leaf microbiome (phyllosphere) to acute oak decline. Here we investigate whether incidental evidence from a large oak genome re-sequencing dataset could be used to detect these bacteria in oak foliage, and whether bacterial incidence co-varied with AOD status or location. Oak leaves and buds were sampled from 421 trees at five sites in England. Whole genomic DNA from these samples was shot-gun sequenced with short reads. Non-oak reads were extracted from these data and queried to microbial databases. Reads uniquely matching AOD-associated bacterial genomes were found to be present on trees from all five sites and included trees with active lesions, trees with historic lesions and trees without AOD symptoms. The abundance of the AOD-associated bacteria did not differ between tree health categories but did differ among sites. We conclude that the AOD-associated bacteria may be members of the normal oak microbiome, whose presence on a tree is not sufficient to cause AOD symptoms.

The three-armed cluster-randomized trial ARena (Sustainable reduction of antibiotic-induced antimicrobial resistance) aimed to foster appropriate antibiotic use and reduce overprescribing in German ambulatory care to counter antibiotic resistance. Multi-faceted interventions targeted primary care physicians, teams and patients. This study examined effectiveness of the implementation program. ARena was conducted in 14 primary care networks with 196 practices. All arms received data-based feedback on antibiotics prescribing and quality circles. Arms II and III received different add-on components each. Primary outcome examined is the prescribing rate for systemic antibiotics for cases with non-complicated acute infections (upper respiratory tract, bronchitis, sinusitis, tonsillitis, otitis media). Secondary outcomes refer to prescribing of quinolones and guideline-recommended antibiotics. Based on pseudonymized quarterly claims data, mixed logistic regression models examined pre-post intervention antibiotic prescribing rate changes and compared to matched standard care. A significant rate reduction (arm I 11.7%; arm II 9.9%; arm III 12.7%) and significantly lower prescribing rates were observed for all arms (20.1%, 18.9% and 23.6%) compared to matched standard care (29.4%). Fluoroquinolone prescribing was reduced in all intervention arms and rates for recommended substances generally increased. No significant post-interventional difference between intervention arms was detected. Findings indicate implementation program impact compared to standard care. Trial registration: ISRCTN, ISRCTN58150046

The aim of this study was to assess the key laboratory features displayed by coronavirus disease 2019 (COVID-19) inpatients which associated with mild, moderate, severe and fatal course of the disease and, through longitudinal follow-up, to understand the dynamics of COVID-19 pathophysiology. All SARS-CoV-2 positive patients admitted to the University Hospital in Motol between March and June 2020 were included in this study. Severe course of COVID-19 was associated with elevation of proinflammatory markers, efflux of immature granulocytes into peripheral blood, activation of CD8 T cells, which infiltrate lungs, and transient liver disease. In particular, the elevation of serum gamma-glutamyl transferase (GGT) and histological signs of cholestasis were highly specific for patients with severe disease. In contrast, patients with fatal course of COVID-19 failed to upregulate markers of inflammation, showed dyscoordination of immune response and progressed towards acute kidney failure. COVID-19 is a disease with multi-organ affinity characterized by activation of innate and cellular adaptive immunity. Biliary lesion with elevation of GGT and organ-infiltration of IL-6 producing cells are defining characteristic for patients with fulminant disease.

n our previous paper, we showed that the so-called quantum entanglement also exists in classical mechanics. The inability to measure this classical entanglement was rationalized with the definition of a classical observer which collapses all entanglement into distinguishable states. It was shown that evidence for this primary coherence is Newton’s third law. However, in reformulating a "classical entanglement theory" we assumed the existence of Newton’s second law as an operator form where a force operator was introduced through a Hilbert space of force states. In this paper, we derive all related physical quantities and laws from basic quantum principles. We not only define a force operator but also derive the classical mechanic's laws and prove the necessity of entanglement to obtain Newton’s third law.

The incidence of cancer in organ transplant patients is higher than in the non-transplanted population. The incidence increases with increasing age. The use of Fludeoxyglucose positron emission tomography/CT (PET/CT) is sensitive and specific to detect PTLD LD compared with conventional CT imaging. We analyzed the medical data of 127 patients aged over 60 years, who underwent heart transplantation in the above period, who have been practicing early CT-PET for diagnostic purposes between February 2007 and October 2018. Of 127 consecutive patients who underwent CT-PET, SUVs up than 4, were found in 84 patients of which 20 were affected by PTLDs, seven patients were affected by chronic non neoplastic inflammatory diseases, the remainder were affected by other neoplasms. The favorable effect of physical activity programs on cardiorespiratory and psychomotor function occur in all patients. In conclusion, CT-PET at the first doubts about the possibility of the development of neoplasms has allowed a diagnosis and then a treatment more quickly. Education in behavioral norms that improve the patient's quality of life is necessary.

In this experimental report the biocompatibility of elastomeric scaffold structures made via stereolithography employing table-top 3D printer (Ember, Autodesk) and commercial resin FormLabs Flexible (FormLabs) was studied. The samples were manufactured using standard printing and development protocol, which is known to inherit cytotoxicity due to remaining non-polymerized remaining monomers, despite the polymerized material being fully biocompatible. Additional steps were taken to remedy this problem: the fabricated structures were soaked in isopropanol and methanol for different conditions (temperature, duration) in order to leach out the non-polymerized monomers. Also printed structures were UV exposed to assure maximum polymerization degree of the material. Post-processed structures were seeded with myogenic stem cells and the number of live cells was evaluated as an indicator for the material biocompatibility. The straightforward post-processing protocol enhances the biocompatibility by 7 times after 7 days soaking in isopropanol and methanol and is comparable to control (glass and polystyrene) samples. This proposes the approach as a novel and simple method to be widely applicable for dramatic cytotoxicity reduction of optically 3D printed micro-/nano-scaffolds for biomedical applications.

The livelihood of most of the fishers in Indian Sundarbans is dependent on Penaeus monodon post larvae fishing. These post larvae collectors are socially backward lacking economic security. The activity of collecting Penaeus monodon post larvae for rearing in aquaculture, destroy other aquatic species. Many other juveniles of shellfish and fin fish were destroyed in the process of collection of Penaeus monodon post larvae. The removal of juveniles before they reach maturity disturbs the ecological chain by hampering breeding processes and may cause extinction of some fish species in the long run. The present study is an attempt to estimate the economic value of juveniles destroyed in the collection of (Penaeus monodon) post larvae. In total 32 species were identified in P.monodon the post larval by-catch. The economic loss is assessed based on estimating biomass by taking a length-weight relationship from published literature. Further, the paper illustrates how does a profit enterprise is linked with natural resource exploitation. The paper explores government policy and nature conservation issues for social justice and effective conservation.In conclusion, suggestions are given to reduce the burden of livelihood on natural resources to the extent of exploitation and to strengthen institution and policy-making considering socio-ecological vulnerabilities of the area.

Many neonates undergoing whole body hypothermia (WBH) following moderate to severe perinatal asphyxia suffer from renal impairment. While recent data suggest a WBH-related reno-protection, the differences in serum creatinine (Scr) patterns to reference patterns were not yet reported. We therefore aimed to document Scr trends and patterns in asphyxiated neonates undergoing WBH, and compared these to centiles reference Scr dataset of non-asphyia neonates. Using a systematic review strategy, reports on Scr trends (mean ± SD, or median and range) were collected (day 1-7) in WBH cohorts, and compared to centiles of an earlier reported reference cohort of non-asphyxia cases. Based on 13 papers on asphyxia+WBH cases, a pattern on postnatal Scr trends in asphyxia+WBH cases was constructed. Compared to the reference cohort, mean or median Scr values at birth (>90th centile) and the first two days of WBH (>75th centile) remained clinical relevantly higher in asphyxia+WBH cases, with a subsequent decline to reach at best high or high normal creatinine values (all >50th centile, but mainly >75th centile) from day 4 onwards. Such patterns are valuable to anticipate average changes in renal clearance capacity relevant for pharmacotherapy, but do not yet cover the relevant inter-patient variability observed in WBH cases.

Post-concussion syndrome, recently recognized as a complication of mild traumatic brain injury, is considered a consequence of the summative effect of multiple concussions received over lifetime. In elderlies, the main mild brain trauma mechanism is fall (low impact force). Many falls are often not reported or noticed but may generate serious medical and medico-legal consequences. Our research question was to find if a single, very mild brain trauma can induce neuro-behavioral consequences in elderlies. One database was queried (PubMed – MeSH terminology) looking for histopathological, neuro-cognitive and behavioral changes that can be generated by sub-concussional trauma in senescent rodents, in comparison with young animals. 41 published research articles were selected. 17 of them used very mild brain trauma in young and senescent animals, in the same experiment (6 rats and 11 mice). 24 articles evaluated the effect of sub-threshold brain trauma in adult animals (no control group). Five trauma models were used (blast models were excluded). Neuro-inflammatory changes were detected immediate after very mild primary impact. In young animals, observed pathology disappeared fast (after 3 to 7 days). Increased apoptosis, mild axonal injury in white matter tracts plus maladaptive astrogliosis and microglial activation was stronger in aged animals, persisted over time (8 months) and significantly altered animals’ cognition and behavior. Associated preexisting pathology (hypertension, tau protein deposits, microbleeds, reactive inflammation) was often responsible for amplification of the primary impact results. As translation of observation is the weak spot of pathology and behavior animal research, further investigation is needed before to conclude that even a single, very mild brain trauma may have medical consequences on human senescent brain.

In the evolving landscape of higher education, St. Michael's College (SMC) recognizes the significant impact of the COVID-19 pandemic on student welfare. This paper emphasizes the critical importance of addressing mental health, time management, and stress in the college environment, underlining their influence on academic success and personal growth. The call to action urges students to prioritize their well-being. Diverse cultural and religious perspectives, including Islam, emphasize the importance of a balanced mind and body. The wide-ranging literature review uncovers empirically supported strategies for mental health, time management, and stress reduction. Personal autonomy emerges as crucial in addressing these challenges. This study underscores the importance of these dimensions, calls for student action, and highlights the diversity of perspectives contributing to holistic well-being.

Migraine is one of the leading causes of disability worldwide [1,2]and patients with acute migraine frequently present to emergency departments (ED)[3]. The current literature suggests that ED treatment of migraine headache varies across institutions [4-7]. Considering this, we conducted a scoping review to summarize trends in medication prescribing patterns for acute migraine treatment in the ED setting. Trends were evaluated for factors influencing treatment choices, with particular attention placed on opioids and migraine specific therapy. This scoping review was based on the Arksey and O'Malley methodological framework[8]and included studies published between 1 January 2000 until 31 May 2020. 14 publications met the inclusion criteria. The most common classes of medication prescribed were often anti-emetics or Non-steroidal anti-inflammatory drugs (NSAID), but rates varied between studies. There was a concerning trend towards an underutilization of triptans and overutilization of opiates. The use of specific clinical goals of treatment (e.g. two-hour pain free freedom response) was also not evident. Additionally, 88% (n=8) of the 9 studies commenting on adherence to hospital or evidence-based guidelines stated that practices were non-adherent. Overall, the reviewed literature reveals treatment practices for acute migraine in the ED are heterogeneous and deviate from established international recommendations.

It is widely believed that the dramatic transformation of the spherical outflows of AGB stars into the extreme aspherical geometries seen during the planetary nebula (PN) phase is linked to binarity and driven by the associated production of fast jets and central disks/torii. The key to understanding the engines that produce these jets and the jet-shaping mechanisms lies in the study of objects in transition between the AGB and PN phases. I discuss the results of our recent studies with high-angular-resolution (with ALMA & HST) and at high-energies (with GALEX, XMM-Newton & Chandra) of several such objects, which reveal new details of close binary interactions and high-speed outflows. These include two PPNe (the Boomerang Nebula and IRAS16342-3814), and the late carbon star, V Hya. The Boomerang is notable for a massive, high-speed outflow that has cooled below the microwave background temperature, making it the coldest object in the Universe. IRAS16342 is the prime example of the class of water-fountain PPNe (very young PPNe with high-velocity H₂O masers) and shows the signature of a precessing jet. V Hya ejects high-speed bullets every 8.5 years associated with the periastron passage of a companion in an eccentric orbit. I discuss our work on AGB stars with strongly-variable high-energy (FUV, X-ray) emission, suggesting that these objects are in the early stages of binary interactions that result in the formation of accretion disks and jets.

Background: Treatment at stabilization center is an important intervention to avert the huge burden of mortality for children with complicated severe acute malnutrition (SAM). Recent reviews indicated a wide range in recovery rate (34-88%) due to several context-specific factors. This study aimed to estimate time to recovery and to determine predictors of time to recovery among children aged 6-59 month with severe acute malnutrition. Method: Retrospective cohort study was used among 375 children aged 6-59 months admitted in Jimma university medical center, from September 2015 to September 2017. Kaplan Meir estimate and survival curve was used to compare the time to recovery using log-rank test among different characteristics. Cox Proportional Hazard Model was used to identify significant predictors of time to recovery. Results: Median time of recovery for cohort of SAM children’s was 19 days (95%CI: 17.95-20.05). Independent predictors of time to recovery were: Play stimulation, vaccination status, Tuberculosis, malaria, use of amoxicillin, deworming and shock. Conclusion: The findings of this study showed that the average length of stay on treatment and median time for recovery are within the sphere standard. Psychosocial stimulation, appropriate provision of routine medication and management of medical co-morbidity are needed to promote fast recovery.

Acute kidney injury (AKI), especially if recurring represents a risk factor for future chronic kidney disease. In intensive care units, increased intraabdominal pressure is well-recognized as a significant contributor of AKI. However, the importance of transiently increased intra-abdominal pressures procedures is less commonly appreciated during laparoscopic surgery, the use of which has rapidly increased over the last few decades. Unlike the well-known autoregulation of the renal cortical circulation, medulla perfusion is modulated via partially independent regulatory mechanisms and strongly impacted by changes in venous and lymphatic pressures. In our review paper, we will provide a comprehensive overview of this evolving topic, covering a broad range from basic pathophysiology up to and including current clinical relevance. Key regulators of oxidative stress such as ischemia-reperfusion injury, the activation of inflammatory response and humoral changes interacting with procedural pneumoperitoneum formation and AKI risk will be recounted. Moreover, we present an in-depth review of the interaction of pneumoperitoneum formation with general anesthetic agents and animal models of congestive heart failure. A better understanding of the relationship between pneumoperitoneum formation and renal perfusion will support basic and clinical research, leading to improved clinical care and collaboration among specialists.

Aims: Clinical evidence indicates that innate immune cells may contribute to the onset and outcome of acute coronary syndrome (ACS). Our prospective study aimed at analysing neutrophil phenotypes in ACS and their role in predicting 1-year major cardiovascular events. Methods: Blood neutrophil phenotypes were analysed by flow cytometry. Differential blood cell count and plasma levels of soluble markers were recorded at admission and at 6-month follow-up. Results: 108 patients categorized in chronic stable coronary artery disease (n=37), unstable angina (UA) (n=19), Non-ST-Elevation Myocardial Infarction (NSTEMI) (n=25), and ST-Elevation Myocardial Infarction (STEMI) (n=27) were included. STEMI and NSTEMI patients displayed higher neutrophil count and neutrophil-to-lymphocyte ratio (NLR) than stable and UA patients (P<0.0001), which normalized at 6-month after MI. STEMI patients were characterized by elevated percentages of band cells in low-density neutrophils (P=0.007) and in high-density neutrophils (P=0.019) compared to the other patients. Multivariable logistic regression analysis revealed that plasma levels of total MPO was associated with STEMI when compared to stable (OR: 1.434; 95% CI: 1.119-1.837; P<0.0001), UA (1.47; 1.146-1.886; P=0.002), and NSTEMI (1.213; 1.1-1.134; P=0.0001) patients, while increased neutrophil SSC signal intensity was associated with NSTEMI compared to stable patients (3.828; 1.033-14.184; P=0.045). Based on multivariable Cox regression analysis, elevated plasma levels of PCSK9 and low-density neutrophil percentage predicted 1-year outcome independently of cardiovascular risk factors (c-index: 0.915; IQR: 0.908-0.929). Conclusions: Changes in neutrophil phenotype are concomitant to ACS. These changes may differ between STEMI and NSTEMI. They may also contribute to ACS risk and patient outcome.

Background and Objectives: Acute Heart Failure (AHF) is a common disease and a cause of high morbidity and mortality, constituting a major health problem. The main purpose of this study was to determine the impact of multiorgan ultrasound in identifying the pulmonary hypertension (PH) in patients admitted due to AHF, predict the evolution of the disease during hospitalization and identify areas of improvement in the care of patients with AHF. Materials and Methods: Patients were evaluated with a standard exam of lung ultrasound, echocardiography, inferior vena cava (IVC) and femoral, renal, hepatic, portal venous Doppler flow patterns at admission and on the day of discharge. Results: Thirty patients were enrolled during November 2021. The mean age was seventy-nine years (Standard Deviation – SD 13,4). Seven patients (23.3%) had a renal function worsening. Regarding ultrasound findings, venous excess ultrasonography score (VExUS) score was calculated at admission and at discharge, surprisingly remaining unchanged or even worsened in most of them (21 patients, 70.0%). The area under the curve for the Lung Score was 83.9% (p = 0.008), obtaining a cutoff value of 10 that showed a sensitivity of 82.6% and a specificity of 71.4% in the identification of intermediate and high PH. It was possible to monitor significant changes between both exams on the lung score (p &lt;0.001), hepatic vein Doppler (p &lt;0.001), portal vein Doppler (p = 0.030), intra-renal vein Doppler (p = 0.025) and VExUS score (p = 0.023), remaining similar the femoral vein Doppler (p = 0.177) and IVC (p = 0.132). Conclusions: Our study results suggest that performing serial multiorgan Point-of-Care ultrasound can help us to better identify high and intermediate probability of PH patients with AHF. Currently proposed multi-organ, venous Doppler scanning protocols, such as the VExUS score, should be further studied in different populations before expanding its use in AHF patients.

Background: This study aimed to present the development process and characteristics of the Korean Registry of Acute Myocardial Infarction for Regional Cardiocerebrovascular Centers (KRAMI-RCC). Methods: We developed KRAMI-RCC, a web-based registry for patients with AMI. Patients from 14 RCCs were registered for more than 3 years from July 2016. It includes an automatic error-checking system, and user training and on-site monitoring are performed to manage data quality. Results: A total of 11,700 AMI patients were registered in KRAMI-RCC over 3 years (73.9% men). The proportions of patients with ST-elevation and non-ST-elevation myocardial infarction at discharge were 43.4% and 56.6%, respectively. Of the total 3-year patients, 5.6% died in the hospital and 4.4% died 12 months after discharge. The case fatality within 12 months was 9.7%. Prehospital care data showed delayed arrival time after onset of symptoms (median 153 min) and low transportation rate by public ambulance (25.2%). Post-hospital care data showed lower participation rate in the second rehabilitation program (16.8%). Conclusions: The recently developed KRAMI-RCC registry has been more focused on pre-hospital and post-hospital data, which will be helpful in understanding the current state of AMI disease management and in making policy decisions to reduce case fatality in Korea.

In recent years, many studies have highlighted the consistent finding of amoxicillin in waters destined for wastewater treatment plants, in addition to superficial waters of rivers and lakes in both Europe and North America. In this paper, the amoxicillin degradation pathway was investigated by simulating the chlorination process normally used in a wastewater treatment plant to reduce similar emerging pollutants at three different pH values. The structures of 16 isolated degradation byproducts (DPs), one of which was isolated for the first time, were separated on a C-18 column via a gradient HPLC method. Then, combining mass spectrometry (MALDI-MS/TOF) and nuclear magnetic resonance, we compared commercial standards and justified a proposed formation mechanism beginning from the parent drug. Microbial growth inhibition bioassays with Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus were performed to determine the potential loss of antibacterial activity in isolated degradation byproducts. An increase of antibacterial activity in the DPs was observed compared to the parent compound.

A Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown aetiology under growing interest now in view of the increasingly recognized post-COVID syndrome as a new entity with similar clinical presentation. We performed the first cross-sectional study of ME/CFS in community population in Russia and then described and compared some clinical and pathophysiological characteristics of ME/CFS and post-COVID syndrome as neuroimmune disorders. Of the cohort of 76 individuals who suggested themselves suffering from ME/CFS 56 subsequently were confirmed as having CFS/ME according to ≥1 of the 4 most commonly used case definition. Of the cohort of 14 individuals with post-COVID-19 syndrome 14 met diagnostic criteria for ME/CFS. The prevalence of clinically expressed and subclinical anxiety and depression in ME / CFS and post-COVID ME/CFS did not differ significantly from that in healthy individuals. Severity of anxiety / depressive symptoms did not correlate with the severity of fatigue neigther in ME / CFS nor in post-COVID ME/CFS, but the positive correlation was found between the severity of fatigue and 20 other symptoms of ME / CFS related to the domains of “post-exertional exhaustion”, “immune dysfunction”, “sleep disturbances”, "dysfunction of the autonomic nervous system", "neurological sensory / motor disorders" and "pain syndromes". Immunological abnormalities were identified in 12/12 patients with ME / CFS according to the results of laboratory testing. The prevalence of postural orthostatic tachycardia assessed by the active standing test was 37.5% in ME / CFS and 75.0% in post-COVID ME/CFS (the latter was higher than in healthy controls, p = 0.02) There was a more pronounced increase in heart rate starting from the 6th minute of the test in post-COVID ME/CFS compared with the control group. Assessment of the functional characteristics of microcirculation by laser doppler flowmetry revealed obvious and very similar changes in ME/CFS and post-COVID ME/CFS compared to the healthy controls. The identified pattern corresponded to the hyperemic form of microcirculation disorders, usually observed in acute inflammatory processes or in deficiency of systemic vasoconstriction influences.

Objective: The Acute Cystitis Symptom Score (ACSS) was developed and validated as a self-reporting questionnaire for diagnosing and monitoring acute, uncomplicated cystitis (AC) in female patients. The study aims at the translation of the ACSS into Greek from original Russian as a source and American English as a new master version and at its linguistic validation. Material and Methods: Three independent professional native Greek translators, two of them experts in Russian and one in English, translated the ACSS from Russian and American English into Greek. The second group of three translators translated each of the three versions back into the original language to detect or correct any important discrepancies. These three Greek versions were then used for linguistic validation. Results: The English to Greek translation reflected more the spoken language, the two Russian to Greek translations more the written, formal language. A total of 60 randomly selected females and 30 healthcare professionals was asked about their preferences and to comment on each of the three translations. Considering all comments the scientific committee (SC) developed the Greek consensus version. For cognitive assessment additional 30 healthcare professionals and 30 females were asked to comment on the intelligibility of all items. Considering their comments the linguistically validated Greek study version was established by the SC. Conclusion: The linguistically validated Greek version of the ACSS can now be used for the clinical validation study.

This conceptual article is aimed at evaluating the COVID19 impacts on the global economy and to postulating an ‘economic paradigm shift’. We argue that the existing economic, political, and trade principles have been challenged due to the global pandemic issue. We also compare the COVID19 impact on Western countries and Eastern countries with their control mechanisms. The emerging of new economies is due to the travel restrictions and disrupt of the global economies are discussed that pave a gateway to the economic paradigm shift. The article finally assesses the advent of 5G technology and its implications to face any future health threats that will lead to the next economic paradigm shift in the modern world.

Postpartum depression (PPD), a condition that affects up to the 15% of mothers in high-income countries, reduces attention toward the needs of the child and it is among the first causes of infanticide. PPD is usually identified using self-report measures and therefore the diagnosis may not always be valid. Previous studies highlighted the presence of significant differences in the acoustical properties of the vocalizations of children of depressed and healthy mothers. In this study, cry episodes of infants of depressed and non-depressed mothers are analyzed to investigate the possibility that a machine learning model can identify PPD in mothers from the acoustical properties of infants' vocalizations. Acoustic features (F0, F1-4, Intensity) are first extracted from recordings of crying infants, then novel cloud-based artificial intelligence models are employed to identify maternal depression versus non depression from estimated features. Trained model shows that commonly adopted acoustical features can be successfully used to individuate Post-Partum Depressed mothers with very high accuracy (89.5%).

Mild traumatic brain injury (mTBI) or concussion accounts for the bulk of all head injuries and represents a major health concern. Although an mTBI event may not manifest in neurobehavioral impairment, repeated injuries, known as repeated mTBI (rmTBI), can result in a cumulative effect that may progress to long-term cognitive and functional deficits. To date, there is no FDA-approved drug for TBI in general and rmTBI in particular. In previous studies, we have demonstrated the neuroprotective role of mitoquinone (MitoQ), a mitochondrial antioxidant, in an open head injury model and a model of repeated mild TBI (rmTBI) at a chronic time point (30 days). In this work, we set out to assess the neuroprotective potential of MitoQ at acute (3 days) and subacute time points (7 days) post-injury in a controlled cortical impact model of rmTBI. C57BL/6 male mice were injected intraperitoneally with MitoQ (5 mg/kg) one hour after the first mTBI, and three days after the first injury in both the 3-day and 7-day MitoQ + rmTBI subgroups, with an additional injection four days after the second injection in the 7-day group. Cognitive function was evaluated using the Morris water maze (MWM) while gross and fine motor functions were evaluated by the pole climbing, grip strength, and ladder rung tests. Dihydroethidium (DHE) staining was performed to evaluate oxidative stress while qRT-PCR was used to measure the gene expression of different antioxidant enzymes. Also, immunofluorescence staining was performed on brain tissue to assess the degree of microgliosis and astrocytosis. Our results showed that MitoQ conferred significant protection on days 3 and 7 post-injury against fine motor function impairment induced by rmTBI. Moreover, MitoQ enhanced cognitive function and reduced astrogliosis, microgliosis, and levels of oxidative stress on day 7 post-injury. However, antioxidant gene expression generally remained unaffected. In light of our results, MitoQ administration may be considered a preventive approach that helps to alleviate the neurological manifestations associated with rmTBI early before symptoms progress to long-term deficits.

Deep Learning is developing interesting tools which are of great interest for inverse imaging applications. In this work, we consider a medical imaging reconstruction task from subsampled measurements, which is an active research field where Convolutional Neural Networks have already revealed their great potential. However, the commonly used architectures are very deep and, hence, prone to overfitting and unfeasible for clinical usages. Inspired by the ideas of the green-AI literature, we here propose a shallow neural network to perform an efficient Learned Post-Processing on images roughly reconstructed by the filtered backprojection algorithm. The results obtained on images from the training set and on unseen images, using both the non-expensive network and the widely used very deep ResUNet show that the proposed network computes images of comparable or higher quality in about one fourth of time.

Acute myeloid leukemia (AML) is a hematological malignancy that is the culmination of genetic and epigenetic alterations in the hematopoietic progenitor cells, leading to uncontrolled proliferation at the expense of normal hematopoiesis and bone marrow exhaustion. Although the outcomes for pediatric AML have improved in recent decades, at least one third of children still have relapses. Recent studies have notably highlighted the important role of dysregulated epi-genetic mechanisms in myeloid leukemogenesis. Epigenetic modifications are frequently reversible compared to genetic alterations, thus providing opportunities for targeted epigenetic therapy. In this review, we summarize the landscape of epigenetic alterations and the progress to date in epigenetic targeted therapy, and focus on the future role of epigenetic abnormalities in predicting relapse and the precision therapy in pediatric AML.

This proposal was prepared in the very first weeks of 2020 because of the outbreak of COVID-19.There is good reason to suppose that rotavirus vaccine can be used as protection tool to effectively and safely fight and mitigate SARS-CoV-2 infection and the impact caused by COVID-19 in adult humans, due to the development of cross and trained immunity following rotavirus vaccination. Up-to-date, some rotavirus vaccines are available and approved, two of them have a large experience in results and safety. Little experience has been achieved in the use of rotavirus vaccine in adults. However, it can be expected that it would be safe and effective in adults and in the elderly as well. This proposal explains the background.

Abstract: Our goal is to create point-of-care (POC) strategies that accelerate decision making, increase efficiency, improve outcomes, and enhance standards of care in island communities faced with global warming, rising oceans, population migration, and intensifying weather disasters. We assessed needs in the Bantayan Archipelago and mainland Cebu Province, Visayas Islands, Philippines, to map POC diagnostics, rescue times, and spatial care paths. Significant deficiencies were lack of cardiac troponin testing for rapid diagnosis of acute myocardial infarction, absence of blood gas and pH testing for support of critically ill patients, and geographic gaps prolonging patient transfers and delaying treatment. Strengths comprised primary care that can be facilitated by POC testing, logical inter-island transfers for which decision making and triage could be accelerated with onboard diagnostic testing, and healthcare small-world networks amenable to POC advances, such as pre-hospital testing, that avoid overloading emergency rooms. Healthcare resources must be distributed to archipelago islands, not concentrated in large metropolitan areas inaccessible for emergency interventions. We conclude that a point-of-need focus will help improve public health, decrease disparities in mortality among rural islanders versus urban dwellers, and pave the way for heightened resilience in anticipation of the adverse impact of global warming on vulnerable coastal areas.

Chikungunya virus is an Alphavirus belonging to the family Togaviridae that is transmitted to humans by an infected Aedes mosquito. Patients develop fever, inflammatory arthritis, and rash during the acute stage of infection. Although the illness is self-limiting, atypical and severe cases are not uncommon, and 60% may develop chronic symptoms that persist for months or even for longer durations. Having a distinct periodical epidemiologic outbreak pattern, chikungunya virus reappeared in Thailand in December 2018. Here, we describe a cohort of acute chikungunya patients who had presented to the Bangkok Hospital for Tropical Diseases during October 2019. Infection was confirmed by real-time RT-PCR using serum collected at presentation to the Fever Clinic. Other possible acute febrile illnesses such as influenza, dengue, and malaria were excluded. We explored the sequence of clinical manifestations at presentation during the acute phase and associated the viral load with the clinical findings. Most of the patients were healthy individuals in their forties. Fever and arthralgia were the predominant clinical manifestations found in this patient cohort, with a small proportion of patients with systemic symptoms. Higher viral loads were associated with arthralgia, and arthralgia with the involvement of the large joints was more common in female patients

Background: Malnutrition is a frequent condition in the elderly and is associated with prolonged hospitalization and increased mortality. However, the impact of malnutrition among elderly patients with acute myocardial infarction has not been clarified yet. Methods and Results: We have enrolled 174 patients aged 65 years and over, admitted with the diagnosis of acute myocardial infarction (AMI) who underwent to the evaluation of nutritional status by Mini Nutritional Assessment (MNA) and of mortality risk by Grace score 2.0. All-cause mortality was the outcome considered for this study. Over a mean follow-up of 24.5 ± 18.2 months, 43 deaths have been registered (24.3%). Non-survivors were more likely to be older, with worse GFR, lower SBP, lower albumin and MNA score, higher prevalence of Killip classification III-IV grade, and higher Troponin I levels. Multivariate Cox proportional analysis revealed that Grace score and MNA showed a significant and independent impact on mortality, (HR = 1.76, 95% CI = 1.34–2.32 and HR = 0.56, 95% CI = 0.42–0.73, respectively). Moreover, the clinical decision curve revealed a higher clinical net benefit when the MNA was included compared to the partial models without MNA. Conclusions: Nutritional status is an independent predictor of long-term mortality among elderly patients with AMI. MNA score in elderly patients with AMI may help prognostic stratification and identification of patients with/at risk of malnutrition in order to apply interventions to improve nutritional status and maybe survival in this population.

Alcohol use disorder (AUD) is a chronically relapsing disease characterized by loss of control in seeking and consuming alcohol (ethanol) driven by recruitment of brain stress systems. However, AUD differs among the sexes: men are more likely to develop AUD, but women progress from casual to binge drinking and heavy alcohol use more quickly. The central amygdala (CeA) is a hub of stress and anxiety, with corticotropin releasing factor (CRF)-CRF1 receptor and GABAergic signaling dysregulation occurring in alcohol dependent male rodents. However, we recently showed that GABAergic synapses in female rats are less sensitive to the acute effects of ethanol. Here, we used patch clamp electrophysiology to examine the effects of alcohol dependence on the CRF-modulation of rat CeA GABAergic transmission of both sexes. We found that GABAergic synapses of naïve female rats were unresponsive to CRF application compared males, although alcohol dependence induced a similar CRF responsivity in both sexes. In situ hybridization revealed that females had less CeA neurons containing mRNA for the CRF1 receptor (Crhr1) than males, but in dependence, the percentage of Crhr1-expressing neurons in females increased, unlike males. Overall, our data provide evidence for sexually dimorphic CeA CRF system effects on GABAergic synapses in dependence.

Surfactants based on polyfluoroalky ethers are commonly used in fire-fighting foams on airport platforms, including for training sessions. Because of their persistence into the environment, their toxicity and their bioaccumulation, abnormal amounts can be found in ground and surface water following operations of airport platforms. As many other anthropogenic organic compounds, some concerns raised about their biodegradation. That is why the OECD 301 F protocol was implemented to appreciate the oxygen consumption during the biodegradation of a commercial fire-fighting foam. However, a Raman spectroscopic monitoring of the process was also attached to this experimental procedure to evaluate to what extent a polyfluoroalkyl ether disappeared from the environmental matrix. The relevance of our approach is to use chemometrics, including the Principal Component Analysis (PCA) and the Partial Least Square (PLS), in order to monitor the kinetics of the biodegradation reaction of one fire-fighting foam, Tridol S3B, containing a polyfluoroalkyl ether. This study provided a better appreciation of the partial biodegradation of some polyfluoroalkyl ethers by coupling Raman spectroscopy and chemometrics. This will ultimately facilitates the design of a future purification and remediation devices for the airport platforms.

B-cell acute lymphoblastic leukemia (B-ALL) is a hematologic disorder characterized by the abnormal proliferation and accumulation of immature B-lymphoblasts arrested at various stages of differentiation. Despite advances in treatment, a significant percentage of pediatric patients with precursor B-ALL still relapse. Therefore, alternative therapies are needed to improve the cure rates for pediatric patients. TPEN (N, N, N’, N’-tetrakis(2-pyridylmethyl)-ethylenediamine).is a pro-oxidant agent capable of selectively inducing apoptosis in leukemia cells. Consequently, it has been suggested that TPEN could be a potential agent for oxidative therapy. However, it is not yet known whether TPEN can selectively destroy leukemia cells in a more disease-like model, for example, the bloodstream and bone marrow (BM), in vitro. This investigation is an extension of a previous study that dealt with the effect of TPEN on ex vivo isolated/purified refractory B-ALL cells. Here, we evaluated the effect of TPEN on whole BM from nonleukemic patients (control) or pediatric patients diagnosed with de novo B-ALL or refractory B-ALL cells by analyzing the hematopoietic cell lineage marker CD34/CD19. Although TPEN was innocuous to nonleukemic BM (n=3), we found that TPEN significantly induced apoptosis in de novo (n = 5) and refractory B-ALL (n = 6) leukemic cell populations. Moreover, TPEN significantly increased the counts of cells positive for the oxidation of the stress sensor protein DJ-1, a sign of the formation of H2O2, and significantly increased the counts of cells positive for the pro-apoptotic proteins TP53, PUMA, and CASPASE-3 (CASP-3), indicative of apoptosis, in B-ALL cells. We demonstrate that TPEN selectively eliminates B-ALL cells independent of age, diagnosis status (de novo or refractory), sex, karyotype, or immunophenotype. Understanding TPEN-induced cell death in leukemia cells provides insight into more effective therapeutic oxidation-inducing anticancer agents.

Acute lymphoblastic leukemia is the most common malignancy in children and is characterized by numerous genetic and epigenetic abnormalities. Epigenetic mechanisms, which involve DNA methylations and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. Emerging studies are increasing our understanding of the epigenetic role of leukemogenesis and have demonstrated the potential of DNA methylations and histone modifications as a biomarker for lineage and subtypes classification, predicting relapse, and disease progression in ALL. Epigenetic abnormalities are relatively reversible when treated with some small molecule-based agents compared to genetic alterations. In this review, we conclude the genetic and epigenetic characteristics in ALL and discuss the future role of DNA methylation and histone modifications in predicting relapse, finally focus on the individual and precision therapy targeting epigenetic alterations.

Background To develop and validate the American-English version of the self-reporting Acute Cystitis Symptom Score (ACSS), a suitable tool for diagnosis and patient-reported outcome in female patients with acute uncomplicated cystitis (UC). Methods After certified translation into American-English and cognitive assessment, the clinical validation of the ACSS was performed as an embedded study in a US phase II trial (ClinicalTrials.gov Identifier: NCT03129295). Results A total of 167 female patients with typical symptoms of UC were included in the study following FDA guidance. At Day 1 (diagnosis) the mean(SD) sum score of the six ACSS typical symptoms reached 10.60(2.51). Of 100 patients followed-up last time on Day 5 or 6 (End-of-treatment, EoT), 91 patients showed clinical success according to the favoured ACSS criteria (sum score of typical symptoms 0.98(1.94)). There was no correlation between the severity of symptoms on Day 1 or between clinical success rate at EoT and level of bacteriuria on Day 1. Conclusion The American-English ACSS showed high predictive ability and responsiveness, and excellent levels of reliability and validity. It can now be recommended as the new master version in clinical and epidemiological studies, in clinical practice or for self-diagnosis of women with symptoms of UC.

This study delves into the dynamic intersection of artificial intelligence (AI) and English Language Teaching (ELT) within the post-pandemic educational landscape. Grounded in Constructivism, Connectivism, and Technological Pedagogical Content Knowledge (TPACK), this research explores how AI integration impacts language instruction efficiency, benefits and challenges perceived by St. Michael's College students, differences in learning outcomes, and its potential to address the digital divide. Employing a qualitative approach, the study employs a rigorous method that includes intensive in-depth reviews of literature, maximum purposeful sampling, informal interviews, observation, and thematic analysis. Through these methods, data was collected from 30 participants, leading to the identification of five key themes. Findings suggest that AI enhances instructional efficiency, offers personalized learning experiences, and bridges gaps in remote settings. However, challenges and the importance of pedagogical balance emerged. The study underscores the need for adaptive pedagogical strategies to fully harness AI's potential. Future directions and limitations are discussed, emphasizing the study's implications for shaping the future of ELT.

Current study was to estimation the post-harvest loss of avocado at the producer level using cross-sectional data obtained from 385 proportionately sampled respondents from Wolaita and Kembata Tembaro Zones, the SNNPR of Ethiopia. Descriptive and multiple regression analysis were used to the amount and determinant of post harvest loss of avocado fruits. Estimated total post harvest- loss of avocados was 24%; of which 5.7% unacceptable harvesting methods and 4.9% of improper storage practices. The respondent's sex, education, income, training, contact with extension agents, distance from the nearest road, and off-farm income were found to be negative determinants, whereas storage accessibility and avocado harvest techniques were found to be positive determinants of post-harvest loss of avocado fruits. Post-harvest management techniques for avocados need to be better understood and used by avocado growers if they are to minimize losses. Post-harvest losses contribute considerably to food insecurity and create a problem for the source of revenue for people and the economy of the country as well. Therefore, the use of a practical and effective post-harvest loss reduction technique could be a sustainable solution to increase food availability, eliminate hunger and improve farmers' livelihoods.

Biochirality is evident in the hierarchical relation of molecular and cellular physiology during organism development and aging. Chirality influences the higher levels of biological processes, such as perception, memory and cognition, through intermolecular interactions between DNA, proteins, and lipids. At the molecular level, an organism's aging is the accumulation of macro-molecules with the aberrant composition, chirality, and folding. Cellular aging is driven by the non-physiological phase transitions (PhTs) withing membrane-bound and membrane-less compartments. Genomic instability and protein aging, as the interconnected root-causes of cell and organism aging, share two essential feature – spontaneous nature and accumulation over a lifetime. Consequently, we will analyze the interaction between the enzymatic (Enz) and spontaneous (Sp) post-translational modifications (PTMs^Enz and PTMs ^Sp). Both forms of PTMs significantly contribute to the balance of L- and D-amino acids (L/D-AAs) in organisms, modulating the functions of nervous and immune systems. The most abundant form of PTM - enzymatic phosphorylation is bio-chemically associated with the spontaneous racemization (Rz^Sp). The crass talk of enzymatic phosphorylation and spontaneous racemization, as an essential determinant of protein aging and aggregation, associated with the aberrant autophagy, apoptosis, and cell signaling, is discussed in this review.

Rapid post-earthquake damage diagnosis of bridges can guide decision-making for emergency response management and recovery. This can be facilitated using digital technologies to remove the barriers of manual post-event inspections. Prior mechanics-based Finite Element (FE) models can be used for post-event response simulation using the measured ground motions at nearby stations; however, the damage assessment outcomes would suffer from uncertainties in structural and soil material properties, input excitations, etc. For instrumented bridges, these uncertainties can be reduced by integrating sensory data with prior models through a model updating approach. This study presents a sequential Bayesian model updating technique, through which a linear/nonlinear FE model, including soil-structure interaction effects, and the foundation input motions are jointly identified from measured acceleration responses. The efficacy of the presented model updating technique is first examined through a numerical verification study. Then, seismic data recorded from the San Rogue Canyon Bridge in California are used for a real-world case study. Comparison between the free-field and the foundation input motions reveals valuable information regarding the soil-structure interaction effects at the bridge site. Moreover, the reasonable agreement between the recorded and estimated bridge responses shows the potentials of the presented model updating technique for real-world applications. The updated FE model is considered as the digital twin of the bridge and can be used to analyze the bridge and monitor the structural response at element, section, and fiber levels to diagnose the location and severity of any potential damage mechanism.

The ongoing COVID-19 pandemic has profoundly affected millions of lives globally, with some individuals experiencing persistent symptoms even after recovering. Understanding and managing the long-term sequelae of COVID-19 is crucial for research, prevention, and control. As a result, to monitor the health of individuals affected by these conditions, they must maintain up-to-date health records using digital health informatics apps for surveillance. In this review, we provide an overview of the existing literature on identifying long COVID manifestations through hierarchical classification and the characterization of long COVID by different hierarchical groups based on the Human Phenotype Ontology (HPO). We outline the aspects of the National COVID Cohort Collaborative (N3C) and Researching COVID to Enhance Recovery (RECOVER) in artificial intelligence (AI) to identify long COVID. Knowledge exploration, using the concept map for the clinical pathways of long COVID presented in this paper, provides an overview of the data needed to explore tackling the long-term effect of COVID-19 by integrating innovative cohesive frameworks and designing health informatics-based applications. To the best of our knowledge, this is the first paper to explore the potential incorporation of long COVID as a variable risk factor within a digital health informatics application.

Background: Citicoline, a medical food, lacks proven efficacy for ischemic stroke and has uncertainties around its harms. The continued prescription should be reevaluated given the more robust, high-quality Evidence against that medical food. This essay is based on a recent Cochrane review and uses only one all-cause mortality as the primary outcome. Therefore, the essay should be considered as something other than an updated Cochrane review but like a reflection based on Evidence-based Medicine and Philosophy of Science analysis. Question Research: Why citicoline (a medical food) should not be prescribed to treat people with acute ischemic stroke: The certainty of the Evidence.? Objective: Demonstrate from evidence-based medicine and philosophy of science perspective that citicoline should not be prescribed for acute ischemic stroke due to lack of efficacy and harm uncertainties. Search publications: We searched in PubMed and Cochrane Library from 2020 until 30 October 2023. We, furthermore, used engineering machines Bing and Google Scholar to detect additional papers. Additionally, we also reviewed reference lists of the retrieved publications and review articles and searched the websites of the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA). Selection criteria: We included systematic reviews, meta-analyses, randomized clinical trials, clinical guidelines focused on acute ischemic stroke and comparing citicoline versus placebo or no intervention. We excluded narrative reviews, observational studies and ongoing trials. Data collection and analysis: We identified only new randomized clinical trials and assessed the risk of bias in seven domains. The other eight trials were already included in the mentioned Cochrane review. The systematic reviews with or without meta-analyses were assessed using McMaster University guidelines. We estimated risk ratios (RRs) for that outcome. We measured statistical heterogeneity using the I² statistic. We conducted our analyses using the fixed effect model. We did not use the GRADE approach due to what is shown in a Cochrane review published in 2020 by Martí-Carvajal et al. We used the RevMan 5.4 software from Cochrane Collaboration to conduct the forest plot. We used a Trial Sequential Analysis with Copenhagen Trial Unit Software. We estimated a Bayes factor from the relative risk and 95% confidence interval. Results: We identified only one new RCT (N = 99) reported mortality data and three clinical guidelines. We conducted a new meta-analysis with nine trials (N = 4461) having a high risk of bias and showing little to no difference in mortality between citicoline and placebo (17.1% vs 18.4%; RR 0.94, 95% CI 0.82 to 1.06; I2 = 0%). The Bayes factor was 0.7, indicating weak Evidence for the null over the alternative hypothesis. Trial sequential analysis suggested sufficiency of Evidence for mortality. No guidelines recommend citicoline. Conclusions: This essay reassessed citicoline for acute ischemic stroke after the 2020 Cochrane review. Adding a new RCT further supported the lack of mortality benefit with citicoline. The overall evidence quality could be better. Analyses using evidence-based medicine and philosophy of science approaches do not support prescribing citicoline due to a lack of efficacy substantiation and potential harms.

Public key encryption methods are often used to create a digital signature, and where Bob has a public key and a private key. In order to prove his identity, he will encrypt something related to the message with his private key, and which can then be checked with his public key. The main current methods of public-key encryption include RSA and ECC (Elliptic Curve Cryptography), and which involve computationally difficult operations. But these operations have not been proven to be hard in an era of quantum computers. One well-known hard problem is the solving of quadratic equations with $m$ equations with $n$ variables. This is a known NP-hard problem, even in a world of quantum computers. These can be used as post-quantum signature schemes and which involve multivariate equations. In order to understand these methods, this paper outlines a simple example of implementing the oil and vinegar method, and where we have a number of unknown oil variables and a number of known vinegar variables, and where the vinegar variables help convert the hard problem into an easy one.

The objective of the study was to report the health-related quality of life (HRQOL) following road traffic accidents (RTAs) among children. A community-based survey using EuroQol five-dimension questionnaire (EQ-5D-5L) in Hindi was used to collected data from community. The survey included 2620 households from urban and rural areas of Ujjain, India. From these households 229 children aged 5–18 years with a history of RTA in the last 1 year were identified, with 27%, 63%, and 10% children reporting mild, moderate, and severe injury based on length of hospitalization. Motorcycles, bicycles, and pedestrians constituted most RTAs. Helmet use was low (12%). EQ-5D-5L revealed that the most severe and extreme problem was pain and discomfort, whereas the least severe problem was usual activity and self-care. The most common (65%) injuries were either abrasion or fracture and dislocation. EQ-5D-5L severity index was maximum (mean 72) for lower extremity injuries. The results of the present study highlight the ability and requirement for quality of life measurement using EQ-5D-5L among children post-RTA.

We validated a new noninvasive tool (B4C) to assess intracranial pressure waveform (ICPW) morphology in a set of neurocritical patients, correlating the data with ICPW obtained from invasive catheter monitoring. Materials and Methods: Patients undergoing invasive intracranial pressure (ICP) monitoring were consecutively evaluated using the B4C sensor. Ultrasound-guided manual internal jugular vein (IJV) compression was performed to elevate ICP from the baseline. ICP values, amplitudes, and time intervals (P2/P1 ratio and time-to-peak [TTP]) between the ICP and B4C waveform peaks were analyzed. Results: Among 41 patients, the main causes for ICP monitoring included traumatic brain injury, subarachnoid hemorrhage, and stroke. Bland-Altman’s plot indicated agreement between the ICPW parameters obtained using both techniques. The strongest Pearson’s correlation for P2/P1 and TTP was observed among patients with no cranial damage (r = 0.72 and 0.85, respectively) in detriment of those who have undergone craniotomies or craniectomies. P2/P1 values of 1 were equivalent between the two techniques (area under the receiver operator curve [AUROC], 0.9) whereas B4C cut-off 1.2 was predictive of intracranial hypertension (AUROC 0.9, p < 000.1 for ICP > 20 mmHg). Conclusion: B4C provided biometric amplitude ratios correlated with ICPW variation morphology and is useful for noninvasive critical care monitoring.

Two ligands, 1, 3-bis(4-carboxyphenyl)imidazolium chloride and 4, 4՛-bipyridine, were employed to prepare nickel and zinc azolium based MOFs, 1 and 2 by the mixed ligand solvothermal approach. The positively charged azolium moieties in the imidazolium linker resulted in a charged environment in the as-synthesized frameworks. As a result, 1 and 2 demonstrated preferential adsorption of CO2 over methane molecules in the gas phase adsorption due to the higher quadruple moment of CO2, which interacts more with the positively charged frameworks. Besides, in aqueous media, 1 and 2 exhibited incredible adsorption efficiency for anionic dyes. In the following, MOF 1 was metallated at the carbene site of the azolium linker to generate the novel heterogeneous catalyst 1-Pd, which was successfully applied for Sonogashira and Suzuki-Miyaura coupling reactions without losing its activity after three cycles.

Post-translational modifications (PTMs) represent a cornerstone in the complexity of the proteome, significantly contributing to diversifying protein structure and function. PTMs can significantly influence protein function, stability, localization, and interactions with other molecules. Therefore, it is important when choosing a protein expression system to ensure the precise incorporation of PTMs during protein synthesis, which is paramount for producing biologically active proteins. Cell-free protein synthesis (CFPS) system has emerged as a powerful protein synthesis platform and research toolkit in synthetic biology. The open nature of the system allows the reaction environment to be tailored to any protein of interest to promote specific PTMs, thus allowing for the production of a protein with the desired modifications. This review presents various PTMs achieved in the CFPS systems, providing insights into the current challenges, successes, and future prospects.

In order to study the petrogenesis and tectonic setting of Permian A-type granites and their relationships with hydrothermal mineralization along the Hegenshan-Heihe suture zone (HHSZ) in northeastern China, we select the newly discovered Hongyan Cu-polymetallic deposit in the northeastern part of the HHSZ that develops three stages of mineralization associated with the Shanshenfu alkali-feldspar granite (SAFG). The zircon U-Pb dating and whole rock geochemistry suggest that the SAFG is a typical A-type granite formed in the Early Permian. The zircon Hf isotopes and trace elements suggest that the SAFG has high Ti-in-zircon temperature (721–990℃), high magmatic oxygen fugacity and largely positive εHf(t) (+6.0 to +9.9). Therefore, we propose that the SAFG was derived from the crustal assimilation and fractional crystallization of the charnockitized juvenile crust. The high oxygen fugacity favors the chalcophile elements (e.g., Cu, Au, Ag) of the source region enriched in the fluid phases after magmatic fractional crystallization, consequently facilitating subsequent hydrothermal mineralization, which is also consistent with the characteristics of ore-forming fluids that changed from the initial high temperature, high salinity, high fO2 and CO2-rich magmatic-hydrothermal fluids of stage I to CO2-poor, dilute, and cooling meteoric fluids of stage III. Combined with regional geological background, the Permian A2-type granites along the HHSZ can be formed in post-collisional slab break-off process. In subsequent exploration for hydrothermal deposits along the HHSZ, the Permian A-type granites with arc-related juvenile crustal source and high fO2 have great potential and need more attention.

Despite the relative scarcity of studies focusing on pharmacotherapy in aphasia, there is evidence in the literature indicating that remediation of language disorders via pharmaceutical agents could be a promising aphasia treatment option. Among the various agents used to treat chronic aphasic deficits, cholinergic drugs have provided interesting results. In the current review, we focused on published reports investigating the impact of acetylcholine on language and further cognitive disturbances. It has been suggested that acetylcholine plays an important role in neuroplasticity and is related to several aspects of cognition, such as memory and attention. Moreover, cholinergic input is diffused to a wide network of cortical areas, which have been associated with language sub-processes. This could be a possible explanation for the positive reported outcomes of cholinergic drugs in aphasia recovery, and specifically in distinct language processes, such as naming and comprehension, as well as overall communication competence. However, evidence with regard to functional alterations in specific brain areas after pharmacotherapy is rather limited. Finally, despite the positive results derived from the relevant studies, cholinergic pharmacotherapy treatment in post-stroke aphasia has not been widely implemented. The present review aims to provide an overview of the existing literature in cholinergic pharmacotherapy interventions in post-stroke aphasia, following an integrated approach by converging evidence from neuroanatomy, neurophysiology, and neuropsychology.

In humans, age-associated degrading changes are observed in molecular and cellular processes underly the time-dependent decline in spatial navigation, time perception, cognitive and psy-chological abilities, and memory. Cross talk of biological, cognitive, and psychological clocks provides an integrative contribution to healthy and advanced aging. At the molecular level, ge-nome, proteome, and lipidome instability are widely recognized as the primary causal factors in aging. We narrow attention to the roles of protein aging linked to prevalent amino acids chirali-ty, enzymatic and spontaneous (non-enzymatic) post-translational modifications (PTMs SP), and non-equilibrium phase transitions. The homochirality of protein synthesis, resulting in the steady-state non-equilibrium condition of protein structure, makes them prone to multiple types of enzymatic and spontaneous PTMs, including racemization and isomerization. Spontaneous racemization leads to the loss of the balanced prevalent chirality. Advanced biological aging re-lated to irreversible PTMs SP has been associated with the nontrivial interplay between poor so-matic and mental health conditions. Through stress response systems (SRS), the environmental and psychological stressors contribute to the age-associated “collapse” of protein homochirality. The role of prevalent protein chirality and entropy of protein folding in biological aging is mainly overlooked. In a more generalized context, the time-dependent shift from enzymatic to the non-enzymatic transformation of biochirality might represent an important and yet un-der-appreciated hallmark of aging.

The “tubulin code” combines different α/β-tubulin isotypes with several post-translational modifications (PTMs) to generate microtubule diversity in cells. During cell division, specific microtubule populations in the mitotic spindle are differentially modified, but only recently has the functional significance of these modifications started to be elucidated. In particular, α-tubulin detyrosination of stable microtubules in the spindle was shown to guide chromosomes during congression to the metaphase plate and allow the discrimination of mitotic errors, whose correction is required to prevent chromosomal instability (CIN), a hallmark of human cancers. Although alterations in certain tubulin PTMs have been reported in human cancers, it remains unclear whether and how tubulin PTMs have any functional implications for cancer cell properties. Here we review the role of the tubulin code in chromosome segregation during mitosis, together with the emerging cancer tubulin code and discuss possible links, as well as the respective diagnostic, prognostic and therapeutic implications for human cancers.

Extracorporeal membrane oxygenation (ECMO) is an established rescue therapy for patients with chronic respiratory failure waiting for lung transplantation (LTx). The therapy inherent immobilization may result in fatigue, consecutive deteriorated prognosis and even lost eligibility for transplantation. We conducted a feasibility study on a novel system designed for the deployment of a mobile ECMO device, enabling physical exercise of awake patients prior to LTx. The system comprises a novel mobile oxygenator with a directly connected blood pump, a double lumen cannula, gas blender and supply, as well as control, and energy management. In-vitro experiments included tests regarding performance, efficiency, and blood damage. A reduced system was tested in vivo for feasibility using a novel large animal model. Six anesthetized pigs were first positioned in supine position, followed by a 45° angle, simulating an upright position of the patients. We monitored performance and vital parameters. All in-vitro experiments showed good performance for the respective subsystems and the integrated system. The acute invivo trials of 8h duration confirmed the results. The novel mobile ECMO-system enables adequate oxygenation and decarboxylation sufficient for, e.g., physical exercise of designated LTx-recipients. These results are promising and suggest further preclinical studies on safety and efficacy to facilitate translation into clinical application.

Post-traumatic stress disorder (PTSD) is a debilitating mental health disorder that causes significant dysfunction in individuals. Currently, there are many approved Pharmacotherapy and Psychotherapy treatment options for PTSD, but unfortunately, half of the patients do not respond to traditional therapies. In this article, we reviewed clinical trials and research on 3,4-methylenedioxymethamphetamine (MDMA) assisted Psychotherapy in PTSD patients, its pharmacokinetics and current treatment guidelines for PTSD. Based on the results of the efficacy of MDMA assisted Psychotherapy from six phases II Randomized controlled trials. MDMA-assisted Psychotherapy for PTSD has received the “Breakthrough Therapy” designation from the FDA. MDMA can potentially reduce PTSD symptoms even in treatment-resistant cases by increasing certain neurohormones, i.e. dopamine, serotonin, norepinephrine and oxytocin. It also modulates activities in the brain regions involved in fear and anxiety. Future research is needed to show whether the advantages outweigh the disadvantages and whether its use can be integrated into available treatment options for PTSD.

Huntington’s Disease (HD) is a devastating neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene, for which no disease modifying therapies are currently available. Much of the recent research has focused on developing therapies to directly lower HTT expression, and while promising, these therapies have presented several challenges regarding administration and efficacy. Another promising therapeutic approach is the modulation of HTT post-translational modifications (PTMs) that are dysregulated in disease and have shown to play a key role in HTT toxicity. Among all PTMs, modulation of HTT phosphorylation has been proposed as an attractive therapeutic option due to the possibility of orally administering specific kinase effectors. One of the kinases described to participate in HTT phosphorylation is Protein Kinase CK2. CK2 has recently emerged as a target for the treatment of several neurological and psychiatric disorders, although its role in HD remains controversial. While pharmacological studies in vitro inhibiting CK2 resulted in reduced HTT phosphorylation and increased toxicity, genetic approaches in mouse models of HD have provided beneficial effects. In this review we discuss potential therapeutic approaches related to the manipulation of HTT-PTMs with special emphasis on the role of CK2 as a therapeutic target in HD.

Artificial intelligence methods may help in unveliling information hidden in high-dimensional oncological data. Flow cytometry studies of haematological malignancies provide quantitative data with the potential to be used for the construction of response biomarkers. Many computational methods from the bioinformatics toolbox can be applied to these data but have not been exploited in their full potential in leukaemias, specifically for the case of childhood B-cell acute lymphoblastic leukemia. In this paper we analysed flow cytometry data obtained on diagnosis from 54 paediatric B-cell acute lymphoblastic leukemia patients from two local institutions. We constructed classifiers based on the Fisher’s Ratio to quantify differences in expression levels of immunophenotypical markers between patients with relapsing and non-relapsing disease. The distribution of the marker CD38 was found and validated to have a strong discriminating power between both patient cohorts, thus providing a classifier.

Aim: Aim of our study to evaluate various factors responsible for surgical site infection after gastrointestinal and hepatobiliary surgeries. Material and Methods: Patient who underwent gastrointestinal and hepatobiliary surgery in our department were evaluated retrospectively. Various factors associated with surgical site infection were evaluated using univariate and multivariate analysis. Surgical site infection was defined as any culture positive discharge from the wound within 30 days of surgery.Statistical analysis was done using SPSS version 23. Results: We evaluated total 331 patients operated between April 2018 to March 2020. 14 patients were lost to follow up after discharge and before completing post operative day 30. 18 patients expired before 30 days without developing SSI and were excluded from the study as per exclusion criteria. 299 patient included in the study. Total 20 patients developed surgical site infection. It showed SSI rate in our study population was 6.68%. On univariate analysis prolonged hospital stay, more blood product used, higher cdc grade of surgery, higher ASA grade, more operative time, open surgeries,colorectal and HPB surgeries were associated with surgical site infections. On multivariate analysis only prolonged hospital stay independently predicted Surgical Site Infectins. (p=0.014,0dds ratio 1.223, 95% confidence interal 1.042-1.435). Conclusion: Prolonged hospital stay independently predicts surgical site infections after gastrointestinal and hepatobiliary surgery.

Hyperglycemia has been associated with increased inflammatory indexes and larger infarct sizes in patients with obstructive acute myocardial infarction (obs-AMI). In contrast, no studies have explored these correlations in non-obstructive acute myocardial infarction (MINOCA). We investigated the relationship between hyperglycemia, inflammation and infarct size in a cohort of AMI patients that included MINOCA. Patients with AMI undergoing coronary angiography between 2016 and 2020 were enrolled. The following inflammatory markers were evaluated: C-reactive protein, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and neutrophil-to-platelet ratio (NPR). Myocardial infarct size was measured by peak high sensitivity troponin I (Hs-TnI) levels, left-ventricular-end-diastolic-volume (LVEDV) and left ventricular ejection fraction (LVEF). The final study population consisted of 2450 patients with obs-AMI and 239 with MINOCA. Hyperglycemia was more prevalent among obs-AMI cases. In all hyperglycemic patients - obs-AMI and MINOCA - NLR, NPR, and LPR were markedly altered. Hyperglycemic obs-AMI subjects exhibited a higher Hs-TnI, a larger LVEDV and a lower LVEF compared to normoglycemic ones. Conversely, MINOCA patients showed similar myocardial damage, irrespective of glycemia. Our data confirm the association of hyperglycemic obs-AMI with elevated inflammatory markers and larger infarct sizes. MINOCA patients exhibited modest myocardial damage, regardless of admission glucose levels.

The hematopoietic transcription factor Ikaros (IKZF1) regulates normal B cell development and functions as a tumor suppressor in precursor B cell acute lymphoblastic leukemia (B-ALL). MicroRNAs (miRNAs) are small regulatory RNAs that through post-transcriptional gene regulation play critical roles in intracellular processes including cell growth in cancer. However, the role of Ikaros in the regulation of miRNA expression in developing B cells is unknown. In this study, we examined the Ikaros-regulated miRNA targets using patient-derived IKZF1-mutated B-ALL xenograft-derived cell lines. Inducible expression of wild-type Ikaros (the Ik1 isoform) caused B-ALL growth arrest and exit from the cell cycle. Global miRNA expression analysis revealed a total of 31 miRNAs regulated by IK1, and ChIP-seq analysis showed that Ikaros bound to several Ik1-responsive miRNA genes. Examination of the prognostic significance of miRNA expression in B-ALL indicate that the IK1-regulated miRNAs hsa-miR-26b, hsa-miR-130b and hsa-miR-4649 are significantly associated with outcome in B-ALL. Our findings establish a potential regulatory circuit between the tumor-suppressor Ikaros and the oncogenic miRNA networks in IKZF1-mutated B-ALL. These results indicate that Ikaros regulates the expression of a subset of miRNAs, of which several may contribute to B-ALL growth.

Numerous genes expression lead to inflammation in the individuals’ lungs that have chronic obstructive pulmonary disease (COPD) may be affected by epigenetic alteration. Important epigenetic processes include methylation of DNA and different histones post-translational changes, including ubiquitination, phosphorylation, methylation, SUMOylation and acetylation. Smoking can trigger the enzymes that control these epigenetic changes. According to the majority of publications, both environmental and genetic variables have a substantial role in the development of COPD. Although, the information about COPD epigenetic is not much but, a better perception of the disease pathophysiology and identifying new markers to create novel therapeutics for patients can be achieved via a better understanding of the epigenetic processes involved.

Prestress loss evaluation in prestressed strand is essential for prestressed structures. However, the sensors installed outside the duct can only measure the total prestress loss. The sensors attached on strand inside the duct also have several problems, such as inadequate durability in an aggressive environment, vulnerable damage at tensioning and so on. This paper proposes a new installation method for long-gauge fiber Bragg grating (LFBG) sensor to prevent accidental damage. Then the itemized prestress losses were determined in each stage of the pre-tensioning and post-tensioning according to the LFBG measurements. We verified the applicability of the LFBG sensors for prestress monitoring and the accuracy of the proposed prestress loss calculation method during pre-tensioning and post-tensioning. In the pre-tensioning case, the calculated prestress losses had less deviation from the true losses than those obtained from foil-strain gauges, and the durability of the LFBG sensors was better than foil-strain gauges, whereas in post-tensioning case, the calculated prestress losses were close to those derived from theoretical predictions. Finally, we monitored prestress variation in the strand for 90 days. The itemized prestress losses at each stages of post-tensioning were obtained by the proposed calculation method to show the prospect of the LFBG sensors in practical evaluation.

Leishmania infantum is causative of visceral leishmaniasis (kala-azar), the most severe form of leishmaniasis, lethal if untreated. Few years ago, re-sequencing and de novo assembling of the L. infantum (strain JPCM5) genome was accomplished, and now we aimed to describe and characterize the experimental proteome of this species. In this work, we have performed a proteomic analysis from axenic cultured promastigotes and carried out a detailed comparison with other Leishmania experimental proteomes published to date. We identified 2,352 proteins based on the search of mass spectrometry data against a database built from the six-frame translated genome sequence of L. infantum. We have detected many proteins belonging to organelles such as glycosomes, mitochondria or flagellum, as well as many metabolic enzymes, and a large number of putative RNA binding proteins and molecular chaperones. Moreover, we listed the proteins presenting post-translational modifications, such as phosphorylations, acetylations and methylations, among others. On the other hand, the identification of peptides mapping to genomic regions previously annotated as non-coding has allowed to correct annotations, leading to N-terminal extension of protein sequences, and the uncovering of eight novel protein-coding genes. The alliance of proteomics, genomics and transcriptomics has resulted in a powerful combination for improving the L. infantum reference genome annotation.

Anxiety disorders are among the most common mental disorders worldwide, and often respond incompletely to existing treatments. Selenium, a micronutrient that is a component of several biologically active selenoproteins, is also involved in several aspects of brain functioning, and may exert antidepressant and anxiolytic effects through multiple pathways. The current paper is a scoping review of translational, observational and interventional evidence on the potential role of selenium and its compounds in the management of anxiety and related disorders. Evidence from animal models suggests that this approach may be promising. Though evidence from observational studies in humans is inconsistent and affected by several confounding factors, the available evidence from randomized controlled trials suggests that selenium supplementation may be beneficial in the management of certain anxiety-related conditions, such as anxiety in medically ill patients, prevention of anxiety following exposure to traumatic stress, and obsessive-compulsive disorder. This paper provides a critical evaluation of the existing evidence base, including unanswered questions that could serve as the focus of further research, and outlines the potential benefits and risks associated with the use of selenium in anxiety disorders.

Despite exhaustive studies, researchers have made little progress in the field of adoptive cellular therapies for relapsed-refractory acute myeloid leukemia (AML), unlike the notable uptake for B cell malignancies. Various single antigen targeting chimeric antigen receptor (CAR) T cell Phase I trials have been established worldwide and have recruited approximately 100 patients. The high heterogeneity at the genetic and molecular levels within and between AML patients resembles a black hole: a great gravitational field that sucks in everything, considering only around 30% of patients show a response but with consequential off-tumor effects. It is obvious that a new point of view is needed to achieve more promising results. This review first introduces the unique therapeutic challenges of not only CAR T cells but also other adoptive cellular therapies in AML. Next, recent single cell sequencing data for AML to assess somatically acquired alterations at the DNA, epigenetic, RNA and protein levels are discussed to give a perspective on cellular heterogeneity, intercellular hierarchies, and the cellular ecosystem. Finally, promising novel strategies are summarized, including more sophisticated next-generation CAR T, TCR-T and CAR-NK therapies; approaches to tailor the microenvironment and target neoantigens; and allogeneic approaches.

Introduction: Decompensated heart failure (HF) is a complex and debilitating syndrome, which constitutes a severe emergency condition with high morbidity and mortality. The kidneys play fundamental roles in the pathophysiology of HF and, in the context of decompensations, acute kidney injury (AKI) has a bilateral cause-and-effect relationship, which can significantly worsen prognosis. However, the interaction between AKI and decompensated HF is poorly understood. Objective: This study aimed to assess the occurrence of AKI in patients hospitalized due to decompensated HF and to analyze its prognostic impact during hospitalization. Methods: Prospective single-center observational study that included patients hospitalized due to decompensated HF in a tertiary-level teaching hospital, conducted between July 2017 and January 2020. Patients who developed AKI during hospitalization were compared with those who did not develop it, until hospital discharge or death. AKI was defined as a serum creatinine increase greater than or equal to 0.3 mg/dl in 48 hours, a 1.5-fold increase in baseline creatinine in seven days or urinary volume <0.5 ml/kg/h during six hours, according to the Acute Kidney Injury Network (AKIN) criteria. The endpoints analyzed were death, need for invasive mechanical ventilation (IMV) and length of hospital stay. The Wilcoxon, Mann-Whitney and unpaired student t tests were used. Results: Ninety-nine patients were included, with a mean age of 65.4 ± 14 years, of which 47 (47.5%) were male and 52 (52.5%) were female. Reduced ejection fraction was observed in 77.8% of patients, whilst 22.2% had a diagnosis of HF with preserved EF. The decompensation clinical classifications were: dry and warm = 7 (7.1%), wet and warm = 72 (72.7%), wet and cold = 15 (15.1%) and dry and cold = 5 (5.1%). The average left ventricular ejection fraction was 38.3% ± 15. AKI ocurred in 22 patients (22.2%). Comparison between patients who evolved with and without AKI showed higher mortality (36.4% vs 10.4%, p = 0.004) and the need for IMV (54.5% vs 13%, p = 0.0001) in the first group. There was no significant difference regarding the length of in-hospital stay (22.9 ± 19 vs 18.8 ± 16 days, p = 0.26). Conclusions: The occurrence of AKI was frequent in patients with decompensated HF requiring hospitalization, affecting approximately one out of five patients. This complication was significantly associated with increased mortality and the need for IMV during hospitalization.

The global spread of COVID-19 led the World Health Organization to declare a pandemic on 11 March 2020. To decelerate this spread, countries have taken strict measures that affected the lifestyle and economy. Various studies have been focused on the identification of COVID-19 impact to mental health of children and adolescents via traditional statistical approaches. However, a machine learning methodology must be developed to explain the main factors that contribute to the change of mood state of children and adolescents during the first lockdown. Therefore, to this study an explainable machine learning pipeline is presented focusing on children and adolescents in Greece, where a strict lockdown was imposed. The target group consists of children and adolescents, recruited from children and adolescent mental health services, who present mental health problems diagnosed before the pandemic. The proposed methodology imposes: (i) data collection via questionnaires; (ii) a clustering process to identify the groups of subjects with amelioration, deterioration and stability to their mood state; (iii) a feature selection process to identify the most informative features that contribute to mood state prediction; (iv) a decision-making process based on an experimental evaluation among classifiers; (v) calibration of the best performing model and (v) a post-hoc interpretation of the features’ impact on the best performing model. The results showed that a blend of heterogeneous features from almost all feature categories is necessary to increase our understanding regarding the effect of COVID-19 pandemic on the mood state of children and adolescents.

Pulmonary thromboembolism is a very common cardiovascular disease, with a still high mortality rate. Despite the clear guidelines, this disease still represents a great challenge both in diagnosis and treatment. Heterogeneous clinical picture, often without pathognomonic signs and symptoms, represents a huge differential diagnostic problem even for experienced doctors. The decision on the therapeutic regimen also represents a major dilemma in the group of patients who are hemodynamically stable at initial presentation and have signs of right ventricular (RV) dysfunction proven by echocardiography and positive biomarker values (pulmonary embolism of intermediate-high risk). Studies have shown conflicting results about the benefit of using fibrinolytic therapy in this group of patients until hemodynamic decompensation, due to the risk of major bleeding. The latest recommendations give preference to new oral anticoagulants (NOACs) compared to vitamin K antagonists (VKA), except for certain categories of patients (patients with antiphospholipid syndrome, mechanical valves, pregnancy). When using oral anticoagulant therapy, special attention should be paid to drug-drug interactions, which can lead to many complications, even to the death of the patient. Special population groups such as pregnant women, obese patients, patients with antiphospholipid syndrome and cancer represent a great therapeutic challenge in the application of anticoagulant therapy. In these patients, not only the effectiveness of the drugs must be taken into account, but great attention must be paid to their safety and possible side effects, which is why a multidisciplinary approach is emphasized in order to provide the best therapeutic option.

The COVID-19 pandemic first observed in December 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has influenced every individual on the planet. The virus has influenced our lifestyle, education, economy and the environment. Though the vaccines against COVID-19 have provided protection against the disease; new strains of the virus have lowered the efficiency of the vaccines. There is still no effective therapy for the treatment of the disease. Understanding the protein structure of the virus may lead to the development of effective therapies for the disease. We recently mapped the structural proteins and non-structural proteins of SARS-CoV-2. The accessory proteins (Open reading frames, Orfs) of SARS-CoV-2 modulate the host environment to favor virus replication. This paper reports mapping the accessory proteins (Orfs) of SARS-CoV-2.

Post-mortem cardiac magnetic resonance (PMCMR) is an emerging tool supporting forensic medicine for the identification of the causes of cardiac death, as hypertrophic cardiomyopathy (HCM). We proposed a new method of PMCMR to diagnose HCM despite myocardial rigor mortis. Methods: we performed CMR in 49 HCM patients, 30 non-HCM hypertrophy and 32 healthy controls. In cine images, rigor mortis was simulated by the analysis of the cardiac phase corresponding to the 25% of diastole. Left ventricular mass, mean and standard deviation (SD) of WT, maximal WT, minimal WT and their difference, were compared for the identification of HCM. These parameters were validated at PMCMR, evaluating 8 hearts with HCM, 10 with coronary artery disease and 10 with non-cardiac death. Results: The SD of WT with a cut-off of > 2.4 had the highest accuracy to identify HCM (AUC 0.95, 95%CI 0.89-0.98). This was particularly evident in female population of HCM (AUC=0.998), with 100% specificity (95%CI 85-100%) and 96% sensitivity (95%CI 79-99%). Using this parameter, at PMCMR all the 8 patients with HCM were correctly identified with no false positive. Conclusions: PMCMR allows to identify HCM as cause of sudden death using the SD of WT >2.4 as diagnostic parameter.

In this work, we tried to emphasize whole transcriptome expression changes in the Wistar rats brainstem two hours after acute stress. Most of the genes were upregulated. We detected massive shift of neuropeptides Crh, Trh,Cga, Tshb, Uts2b, Tac4, Lep and neuropeptide receptors Hcrtr1, Sstr5, Bdkrb2, Crhr2 signaling, as well as Glutamate Grin3b, Grm2 and GABA Gpr156, Acetylcholine Chrm4,Chrne, Adreno- Adra2b receptors expression uprising. Intensive increase in expression of intermediate filaments Krt83/Krt86/Krt80/Krt84/Krt87/Krt4/Krt76 and motor proteins Myo7a, Klc3 was detected. Remarkably, at this time we also observed signs of microglia activation. Both expression of anti-inflammatory cytokines Il13, Ccl24 and proinflammatory cytokin’s receptors Il9r, Il12rb1, Tnfrsf14, Tnfrsf13c, Tnfrsf25, Tnfrsf1b were increased. In the Wnt signaling pathway, we have seen increased expression of ligands-receptors Wnt1, Wnt11, Ror2, and also negative regulators Notum, Sfrp5, Sost. Also we conducted cDNA libraries normalization with duplex specific nuclease and compared results. On the basis of our RNAseq data, we chose reference genes for RT-qPCR best suitable for experiments with acute stress.

Background: Disentangling adverse drug reactions from confounders remains a major challenge to assess causality and severity in neonates. Vancomycin and amikacin are perceived as nephrotoxic and often prescribed in neonates. We selected these compounds to assess their impact on creatinine dynamics as sensitive tool to detect a renal impairment signal. Methods: A recently developed dynamical model that characterized serum creatinine concentrations of 217 ELBW neonates (4036 serum creatinine observations) was enhanced with data on individual administration of vancomycin and/or amikacin to identify a potential effect of antibiotic exposure by nonlinear mixed-effects modelling analysis. Results: Of our ELBW patients, 77% were exposed to either vancomycin or amikacin. Antibiotic exposure resulted in transient lower overall creatinine clearance and a modest increase in serum creatinine. Dependency on gestational age was observed in the difference in serum creatinine when exposed to antibiotics during the third week after birth (difference in creatinine for a neonate at 24 weeks gestation decreased with 56% for a 32-week-old neonate). Conclusions: A previously described model on creatinine dynamics was used to explore and quantify the impact amikacin or vancomycin exposure on creatinine dynamics. Such tools can be used to explore minor changes, or compare minor differences between treatment modalities.

In celIs, microtubule location, length, and dynamics are regulated by a host of microtubule-associated proteins and enzymes that read where to bind and act based on the microtubule “tubulin code,” which is predominantly encoded in the tubulin carboxy-terminal tail (CTT). Katanin is a highly conserved AAA ATPase enzyme that binds to the tubulin CTTs to remove dimers and sever microtubules. We have previously demonstrated that short CTT peptides are able to inhibit katanin severing. Here, we examine effects of CTT sequences on this inhibition activity. Specifically, we examine CTT sequences found in nature, alpha1A (TUBA1A), detyrosinated alpha1A, Δ2 alpha1A, beta5 (TUBB/TUBB5), beta2a (TUBB2A), beta3 (TUBB3), and beta4b (TUBB4b). We find that these natural CTTs have distinct abilities to inhibit, most noticeably beta3 cannot inhibit katanin. Two non-native CTT tail constructs are also unable to inhibit – despite having 94% sequence identity with alpha1 or beta5 sequences. Surprisingly, we demonstrate that poly-E and poly-D peptides are capable of inhibiting katanin significantly. An analysis of the hydrophobicity of the CTT constructs indicates that more hydrophobic polypeptides are less inhibitory than more polar polypeptides. These experiments not only demonstrate inhibition, but also likely interaction and targeting of katanin to these various CTTs when they are part of a polymerized microtubule filament.

Background: Substance use continues to be on the rise in the United States and has been linked to new onset cardiovascular (CVDs) and cerebrovascular disorders (CeVDs) leading to hospitalizations. We aimed to study the association of different subtypes of substance use disorders (SUDs) among hospitalized patients, with the different subtypes of CVDs and CeVDs, using the National Inpatient Sample (NIS) Database. Additionally, we aimed to assess the odds of hospitalizations with new onset CVDs and CeVDs among patients with different types of SUDs. Methods: A retrospective study of the NIS database (2016-2017) using the ICD-10-CM codes was performed. The hospitalizations with a secondary diagnosis of SUDs were identified. Weighted univariate analysis using the chi-square test and multivariate survey logistic regression analysis was performed to evaluate for the incidence, prevalence, and odds of association between vascular events and SUDs. Results: There were a total of 58,259,589 hospitalizations, out of which 21.42% had SUDs. Out of all the hospitalized patients between the age 18-50, more patients had SUDs than not (31.83%, p< 0.0001). This difference existed for all the different subtypes of SUDs including alcohol related disorder (42.61%), amphetamine dependence (76.17% vs 31.83%), cannabis related disorder (75.17%), cocaine related disorders (57.87%), hallucinogen related disorder (82.91%), inhalant related disorders (67.25%), opioid related disorders (52.86%), and nicotine dependence (35.72%). We found a significant association of acute ischemic stroke with amphetamine dependence (OR 1.23, 95%CI 1.14-1.33), cocaine related disorders (1.17, 1.12-1.23) and nicotine dependence (1.42, 1.40-1.43). Similarly, the association of intracerebral hemorrhage was higher with amphetamine dependence (2.58, 2.26-2.93), and cocaine related disorders (1.62, 1.46-1.79). The association of subarachnoid hemorrhage was noted to be higher with amphetamine dependence (1.82, 1.48-2.24) and nicotine dependence (1.47, 1.39-1.55). In terms of association of cardiovascular disorders with SUDs,the patients with myocardial infarction had higher odds of nicotine dependence (1.85, 1.83-1.87) than not, Similarly, the patients with angina pectoris were noted to have a higher association with cocaine related disorders (2.21, 1.86-2.62), and those with atrial fibrillation had a higher association alcohol related disorders (1.14, 1.11-1.17). Conclusion: Our study demonstrates the variability of CVD and CeVD in patients hospitalized for SUD. Findings from our study may help promote increased awareness and early management of these events. Further studies are needed to evaluate specific effects of frequency and dose on the incidence and prevalence of CVD and CeVD in patients with SUD.

AIM: Aim of our study was to evaluate incidence and causative factors for acute kidney injury in gastrointestinal and hepatobiliary surgeries. Material and methods: All the gastrointestinal surgeries performed between April 2018 to March 2020, in our institution have been analysed for acute kidney injury. Acute kidney injury defined according to acute kidney injury network classification. Categorical variables were evaluated by chi square test and continuous variables by Mann Whitney U test. Statistical analysis was done using SPSS version 23. P< 0.05 was considered significant Results: We performed 331 gastrointestinal and hepatobiliary surgery from April 2018 to March 2020. After exclusion 317 patients were included in study population.14 patients (4.4%) were defined as having acute kidney injury according to acute kidney injury network classifications. On univariate analysis acute kidney injury was associated with open surgery (p= 0.002, Intra operative hypotension (p=0.006), CDC grade of surgery (p<0.001), increased used to blood products (p=0.004), higher ASA grade (p<0.0001), increased operative time(p<0.0001). On multivariate logistic regression analysis higher ASA grade (p=0.001) and increased operative time (0.015) independently predicted acute kidney injury. Acute kidney injury was also significantly associated with 90 days mortality. ( p= <0.0001) Conclusion:Post-operative acute kidney injury was associated with significant mortality in gastrointestinal and hepatobiliary surgery. Open surgery, higher CDC grade surgery, more blood products, higher ASA grades, increase operative time predicted acute kidney injury in post operative periods. Higher ASA grades and increased operative time predicted acute kidney injury.

Lung ultrasound (LUS) allows the detection of a series of manifestations of COVID-19 such as B lines and consolidations. The objective of this work was to study the inter-rater reliability (IRR) when detecting signs associated with COVID-19 in the LUS, as well as the impact of performing the test in the longitudinal or transverse orientation. 33 physicians with advanced experience in LUS, independently evaluated ultrasound videos previously acquired with the ULTRACOV system of 20 patients with confirmed COVID-19. In each patient, 24 videos of 3 seconds were acquired (using 12 positions with the probe in longitudinal and transverse orientations). Physicians had no information about the patients or other previous evaluations. The score assigned to each acquisition followed the convention applied in previous studies. A substantial IRR was found in the cases of normal LUS (κ = 0.74), only a fair IRR for the presence of individual B lines (κ = 0.36) and for confluent B lines occupying &lt;50% (κ = 0.26), and a moderate IRR in consolidations and B-lines &gt;50% (κ = 0.50). No statistically significant differences between the longitudinal and transverse scans were found. The IRR in LUS of COVID-19 patients may benefit from more standardization of the clinical protocols.

Our primary objectives were a) to determine the need for, and the availability of point-of-care testing (POCT) for infectious diseases and b) to recommend point-of-care testing strategies and spatial care paths (SCPs) that enhance public health preparedness in regional districts of Thua Thien Hue Province (TTHP), Central Vietnam, where we conducted field surveys. Medical professionals in 7 community health centers (CHCs), 7 district hospitals (DHs) and 1 provincial hospital (PH) participated. Survey questions (English and Vietnamese) determined the status of diagnostic testing capabilities for infectious diseases and other acute medical challenges in TTHP. Infectious disease testing was limited: 6 of 7 CHCs (86%) lacked infectious disease tests. One CHC (14%, 1/7) had two forms of diagnostic tests available for the detection of Malaria. All CHCs lacked adequate microbiology laboratories. District hospitals had few diagnostic tests for infectious diseases (Tuberculosis, Syphilis), blood culture (29%, 2/7), and pathogen culture (57%, 4/7) available. The PH had broader diagnostic testing capabilities but lacked preparedness for highly infectious disease threats (e.g., Ebola, MERS-CoV, SARS, Zika, and Monkeypox). All sites reported having COVID-19 rapid antigen tests; COVID-19 RT-PCR tests were limited to higher tier hospitals. We conclude that infectious disease diagnostic testing should be improved and POC tests must be supplied near patients’ homes and in primary care settings for the early detection of infected individuals and mitigation of the spread of new COVID-19 variants and other highly infectious diseases.

Here we will electrically-quantum model the neutron and proton as a three-phase alternating current electric generator, for this, we will use the theory of three-phase electric generators and vector or phasor diagrams. We will use this model to hypothesize how the quarks that form neutrons and protons with a combined mass of 10 MeV/c², can generate, through quarks-antiquarks-gluon interactions, a mass of 939.56 MeV/c² for the neutron and a mass of 938.27 MeV/c² for the proton. Using quantum mechanics and the theory of the generalization of the Boltzmann constant in curved space-time we will calculate the number of quarks-antiquarks-gluons and gravitons inside a neutron. We will also analyse βˉ decay using vector diagrams, we will calculate the tension of the string T₀ and the length of the string ℓs between quarks-antiquark and finally, we will model a black hole using a neutron equivalent model. In version 2 of this article, we will update the vector diagrams of the βˉ decay and theoretically calculate the energy of the W⁻ boson, the Z⁰ boson, and the Θ angle, Θ = arc cos (W⁻/Z⁰). We will demonstrate, through vector diagrams, that quarks-antiquarks-gluon interactions are the cause of the origin of the W⁻ boson and the Z⁰ boson. We will also demonstrate how the fine structure constant α originates. It is important to make clear, in future updates, we will describe the relationship that exists between the theory described in this paper and the Isospin theory, flavour and colour theory

Protein translational modifications (PTMs) generate an enormous, but as yet undetermined, expansion of the expressed proteoforms. In this Viewpoint, we firstly differentiate the concepts of proteoform and peptidoform by reviewing and discussing previous literature. We show that the current PTM biological investigation and annotation largely follow a PTM site-specific rather than proteoform-specific approach. We further illustrate a potentially useful matching strategy in which a particular “modified peptidoform” is matched to the corresponding “unmodified peptidoform” as a reference for the quantitative analysis between samples and conditions. We suggest this strategy could provide directly relevant information for learning the PTM site-specific biological functions. Accordingly, we advocate for the wider use of the nomenclature “peptidoform” in the future bottom-up proteomic studies.

Background. Gene rearrangements affecting KMT2A are frequent in acute myeloid leukemia (AML) and are often associated with a poor prognosis. KMT2A gene fusions are often detected by chromosome banding analysis and confirmed by fluorescence in-situ hybridization. However, small intragenic insertions, termed KMT2A partial tandem duplication (PTD), are particularly challenging to detect using standard molecular and cytogenetic approaches. Methods. We have validated the use of a custom hybrid capture based next-generation sequencing (NGS) panel for comprehensive profiling of AML patients seen at our institution. This NGS panel targets the entire consensus coding DNA sequence of KMT2A; to deduce the presence of a PTD we used the relative ratio of KMT2A exons coverage. We sought to corroborate the KMT2A-PTD NGS results using (1) multiplex-ligation probe amplification (MLPA) and (2) optical genome mapping (OGM). Results. We analyzed 932 AML cases and identified 41 individuals harboring a KMT2A-PTD. MLPA, NGS and OGM confirmed the presence of a KMT2A-PTD in 22 of the cases analyzed where orthogonal testing was possible. Two false positive PTD calls by NGS could be explained by the presence of cryptic structural variants impacting KMT2A and interfering with PTD analysis. OGM revealed the nature of these previously undetected gene rearrangements in KMT2A, while MLPA yielded in-conclusive results. MLPA analysis for KMT2A-PTD is limited to exon 4, whereas NGS and OGM resolved KMT2A-PTD sizes and copy number levels. Conclusion. KMT2A-PTDs are complex gene rearrangements that cannot be fully ascertained using a single genomic platform. MLPA, NGS panels and OGM are complementary technologies applied in standard of care testing for AML patients. MLPA and NGS panels are designed for targeted copy number analysis; however, our results show that integration of concurrent genomic alterations is needed for accurate KMT2A-PTD identification. Unbalanced chromosomal rearrangements overlapping with KMT2A can interfere with the diagnostic sensitivity and specificity of copy number based KMT2A-PTD detection methodologies.

Though there has been a decline in the number of new cases of viral hepatitis-induced acute liver failure in Europe and the United States of America, viral hepatitis still remains the leading cause of acute liver failure in Asia-Pacific and South America. However, the epidemiology of viral-hepatitis-induced acute liver failure in sub-Saharan Africa-the world epicenter of viral hepatitis-is unclear. The aim of this review was to collate data on the incidence, prevalence, specific etiologic agents, features/diagnosis, treatment and prognosis of viral-induced acute liver failure in sub-Saharan Africa. One hundred and forty-seven cases of viral-induced acute liver failure were recorded in 11 studies conducted in six countries between 1981-2020. Etiological agents were: Hepatitis viruses A, B, C, and E, as well as Adenovirus, Enterovirus, Parvovirus, Herpes Simplex Virus (HSV) and EBV. HAV was the most frequent in paediatric subjects: (11/16) 69% and (19/30) 63%. HBV was the only etiological agent in the study that only included adults. HEV (genotype 2 in one study) contracted amidst hepatitis E outbreaks was the most commonly reported cause of ALF in pregnant women. Treatment was mainly supportive, and liver transplantation reported only in South Africa. Where reported, case fatality rates were high. In conclusion, viral-hepatitis induced acute liver failure is largely understudied in sub-Saharan Africa. The few available data are consistent with literature from the other parts of the world regarding aetiologic agents. Liver transplantation is not available in most sub-Saharan African countries, and short-term case fatality rates of individuals with acute liver failure could outstrip current rates from the other world regions.