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Background: Shock index is the ratio of heart rate to the systolic blood pressure. The use of shock index for risk stratification or as an indicator of clinical improvement is helpful in early recognition of shock and optimizing treatment in sepsis and septic shock. Aims and Objectives: The objective of the study was to assess the shock index and associated outcome in children with sepsis/septic shock at the tertiary care hospital. Materials and Methods: A cross-sectional study was conducted among 95 patients admitted with sepsis or septic shock to the pediatric intensive care unit and pediatric wards of a tertiary center in Surat. The study was done over a period of 2 years from January 2020 to December 2021. The study was carried out after obtaining ethical approval from the Human Research Ethics Committee, GMC Surat. Through-out the study privacy and confidentiality was maintained at all cost for each participant by coding of patients data. Results: The mean age of the study population was 3.12±2.40 years, with age range from 1 month to 12 years. The gender distribution of the study population had 51.6% male and 48.4% female. On analysis of the shock index to the mortality of the patients at 0, 1, 2, 4, and 6 h after admission, the cutoff value of shock index at 1.6, 1.7, 1.7, 1.4, and 1.3 had a sensitivity of 89.4%, 84.8%, 78.8%, 82.3%, and 86.4%, with a specificity of 62.4%, 69%, 75.9%, 72.4%, and 75.9%, respectively. The cutoff values of the various age groups decrease as the ages of the patients increase. The overall survival rate in the study was 30.5% and mortality rate at 69.5%. Conclusion: The study concluded that shock index can be used in emergency for triage of critically ill patients. Shock index and mortality were higher compared to other studies as majority of the study participants were referred cases and were in critical stages of shock on admission to the tertiary care center.

Background: Cardiovascular diseases are the leading cause of mortality in India. Ischemic heart disease is a result of an inadequate supply of blood to a portion of the myocardium caused by atherosclerotic disease of an epicardial coronary artery. The increasing incidence of myocardial infarction (MI) and associated mortality is a concern. Aims and Objectives: The aims and objectives of the study were to evaluate the clinical profile and determine the association of risk factors in patients presenting with acute MI. The study highlights the trend of occurrence of acute MI so as appropriate measures can be taken to mitigate the incidence of coronary artery disease (CAD). Materials and Methods: A cross-sectional study was conducted among 100 patients with acute MI admitted to the intensive coronary care unit and medicine wards of a tertiary center in North-East India. The study was carried out for a period of 2 years from September 2019 to August 2021. Results: The mean age of the study population was 63.13±10.47 years, with an age range from 41 to 90 years. The study population had 75% males and 25% females. The most common presenting symptom was chest pain in 96% of patients. Hypertension in 75% of patients was the most common risk factor studied. About 97% of patients had at least one cardinal risk factor for MI. Inferior wall MI in 47% of patients was the most common site of MI. The highest mortality was seen in those who presented with Killip Class IV. Conclusions: Increasing age and male gender predisposed to MI. The association of risk factors such as hypertension, diabetes, obesity, and family history was higher in females. To bring about a reduction in the risk of CAD, emphasis should be laid on the adoption of a healthy lifestyle particularly for those at risk of CAD.

Background: Shock index is the ratio of heart rate to the systolic blood pressure. The use of shock index for risk stratification or as an indicator of clinical improvement is helpful in early recognition of shock and optimizing treatment in sepsis and septic shock. Aims and Objectives: The objective of the study was to assess the shock index and associated outcome in children with sepsis/septic shock at the tertiary care hospital. Materials and Methods: A cross-sectional study was conducted among 95 patients admitted with sepsis or septic shock to the pediatric intensive care unit and pediatric wards of a tertiary center in Surat. The study was done over a period of 2 years from January 2020 to December 2021. The study was carried out after obtaining ethical approval from the Human Research Ethics Committee, GMC Surat. Through-out the study privacy and confidentiality was maintained at all cost for each participant by coding of patients data. Results: The mean age of the study population was 3.12±2.40 years, with age range from 1 month to 12 years. The gender distribution of the study population had 51.6% male and 48.4% female. On analysis of the shock index to the mortality of the patients at 0, 1, 2, 4, and 6 h after admission, the cutoff value of shock index at 1.6, 1.7, 1.7, 1.4, and 1.3 had a sensitivity of 89.4%, 84.8%, 78.8%, 82.3%, and 86.4%, with a specificity of 62.4%, 69%, 75.9%, 72.4%, and 75.9%, respectively. The cutoff values of the various age groups decrease as the ages of the patients increase. The overall survival rate in the study was 30.5% and mortality rate at 69.5%. Conclusion: The study concluded that shock index can be used in emergency for triage of critically ill patients. Shock index and mortality were higher compared to other studies as majority of the study participants were referred cases and were in critical stages of shock on admission to the tertiary care center. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular diseases are the leading cause of mortality in India. Ischemic heart disease is a result of an inadequate supply of blood to a portion of the myocardium caused by atherosclerotic disease of an epicardial coronary artery. The increasing incidence of myocardial infarction (MI) and associated mortality is a concern. Aims and Objectives: The aims and objectives of the study were to evaluate the clinical profile and determine the association of risk factors in patients presenting with acute MI. The study highlights the trend of occurrence of acute MI so as appropriate measures can be taken to mitigate the incidence of coronary artery disease (CAD). Materials and Methods: A cross-sectional study was conducted among 100 patients with acute MI admitted to the intensive coronary care unit and medicine wards of a tertiary center in North-East India. The study was carried out for a period of 2 years from September 2019 to August 2021. Results: The mean age of the study population was 63.13±10.47 years, with an age range from 41 to 90 years. The study population had 75% males and 25% females. The most common presenting symptom was chest pain in 96% of patients. Hypertension in 75% of patients was the most common risk factor studied. About 97% of patients had at least one cardinal risk factor for MI. Inferior wall MI in 47% of patients was the most common site of MI. The highest mortality was seen in those who presented with Killip Class IV. Conclusions: Increasing age and male gender predisposed to MI. The association of risk factors such as hypertension, diabetes, obesity, and family history was higher in females. To bring about a reduction in the risk of CAD, emphasis should be laid on the adoption of a healthy lifestyle particularly for those at risk of CAD. [ABSTRACT FROM AUTHOR]

In the last decade, gender diversity on boards or women in the boardroom has gained the attention of academics and practitioners. This paper aims to explore how women directors affect corporate cash holdings in Indonesia. This study utilizes data on Kompas 100 index firms for 2014–2021. A fixed-effect estimator is used to analyze data. The study reveals that female directors positively influence cash holdings. This finding remains robust when employing an alternative proxy for female directors and excluding observations during the COVID-19 period. Additionally, the findings indicate notable variations in cash holdings between companies with and without female directors. Regarding control variables, a firm’s cash holdings are negatively influenced by board size, leverage, company size, and net working capital. Firm profitability and growth opportunities positively influence cash holdings. This paper also documents that institutional ownership weakens the nexus between female directors and cash holding. The findings highlight that female directors hold higher amounts of cash because of their increased risk aversion. This study enriches the discussion on female directors and cash-holding levels in a developing country with a two-tiered board system. AcknowledgmentsThis study is not funded by any funding agency.

This study describes the identification of anti-bullying message and the construction of social reality in Burger King ad version “Bullying Jr.” through semiotics analysis on signs. Semiotics theory used in this study is focusing on Roland Barthes perspective. The analysis shows that majority of society tends to be antipathy towards bullying that happens around them. The message included in this advertisement is for the society to be braver to fight bullying around them.

Major risk factors of head and neck squamous cell carcinoma (HNSCC) are tobacco use and human papillomavirus (HPV). HPV E6 oncoprotein leads to p53 degradation, whereas HPV-negative cancers are frequently associated with TP53 mutations. Peposertib is a potent and selective, orally administered small-molecule inhibitor of the catalytic subunit of the DNA-dependent kinase (DNA-PKcs), a key regulator of non-homologous end joining (NHEJ). NHEJ inhibition along with irradiation (IR)-induced DNA double-strand breaks has the potential to increase antitumor treatment efficacy. Here, we investigated the responses of a panel of HNSCC models with distinct HPV and p53 status to treatments with IR, DNA-PKcs inhibition, and their combination in-vitro and in-vivo. IR-induced DNA damage combined with peposertib administration shortly before IR results in decreased cell viability and proliferation and causes DNA repair delay in all studied HNSCC cell lines. However, our data confirm that the actual cell fate upon this treatment is determined by cellular p53 and/or HPV status. Cells lacking functional p53 due to its degradation by HPV or due to a loss-of-function mutation are arrested in the G2/M phase of the cell cycle and eliminated by apoptosis whereas p53-proficient HNSCC cell lines preferentially undergo senescence. This is also recapitulated in-vivo, where HPV+ UD-SCC-2 xenografts display stronger and more durable responses to the combined treatment as compared to p53 wild-type UM-SCC-74A tumors. In conclusion, DNA-PKcs inhibitor peposertib should be further studied as a potential radiosensitizer for HNSCCs, taking into consideration the genetic background and the HPV status of a particular tumor.

Mutational signatures connect characteristic mutational patterns in the genome with biological or chemical processes that take place in cancers. Analysis of mutational signatures can help elucidate tumor evolution, prognosis, and therapeutic strategies. Although tools for extracting mutational signatures de novo have been extensively benchmarked, a similar effort is lacking for tools that fit known mutational signatures to a given catalog of mutations. We fill this gap by comprehensively evaluating twelve signature fitting tools on synthetic mutational catalogs with empirically driven signature weights corresponding to eight cancer types. On average, SigProfilerSingleSample and SigProfilerAssignment/MuSiCal perform best for small and large numbers of mutations per sample, respectively. We further show that ad hoc constraining the list of reference signatures is likely to produce inferior results. Evaluation of real mutational catalogs suggests that the activity of signatures that are absent in the reference catalog poses considerable problems to all evaluated tools., (© 2024. The Author(s).)

Competing Interests: Competing interests statement:The authors declare no competing interest.

Various lines of investigation support a signaling interphase shared by receptor tyrosine kinases and the DNA damage response. However, the underlying network nodes and their contribution to the maintenance of DNA integrity remain unknown. We explored MET-related metabolic pathways in which interruption compromises proper resolution of DNA damage. Discovery metabolomics combined with transcriptomics identified changes in pathways relevant to DNA repair following MET inhibition (METi). METi by tepotinib was associated with the formation of γH2AX foci and with significant alterations in major metabolic circuits such as glycolysis, gluconeogenesis, and purine, pyrimidine, amino acid, and lipid metabolism. 5'-Phosphoribosyl-N-formylglycinamide, a de novo purine synthesis pathway metabolite, was consistently decreased in in vitro and in vivo MET-dependent models, and METi-related depletion of dNTPs was observed. METi instigated the downregulation of critical purine synthesis enzymes including phosphoribosylglycinamide formyltransferase, which catalyzes 5'-phosphoribosyl-N-formylglycinamide synthesis. Genes encoding these enzymes are regulated through E2F1, whose levels decrease upon METi in MET-driven cells and xenografts. Transient E2F1 overexpression prevented dNTP depletion and the concomitant METi-associated DNA damage in MET-driven cells. We conclude that DNA damage following METi results from dNTP reduction via downregulation of E2F1 and a consequent decline of de novo purine synthesis., Significance: Maintenance of genome stability prevents disease and affiliates with growth factor receptor tyrosine kinases. We identified de novo purine synthesis as a pathway in which key enzymatic players are regulated through MET receptor and whose depletion via MET targeting explains MET inhibition-associated formation of DNA double-strand breaks. The mechanistic importance of MET inhibition-dependent E2F1 downregulation for interference with DNA integrity has translational implications for MET-targeting-based treatment of malignancies., (©2024 The Authors; Published by the American Association for Cancer Research.)

Objective: Our aim was to compare the costs and efficacy of ambroxol in combination with imiglucerase with the costs and efficacy of imiglucerase only in the treatment of Gaucher disease type 2 (GD2) in the socio-economic settings of the Republic of Serbia, an upper-middle-income European economy., Methods: The perspective of the Serbian Republic Health Insurance Fund was chosen for this study, and the time horizon was 6 years. The main outcomes of the study were quality-adjusted life years gained with ambroxol + imiglucerase and comparator, and direct costs of treatment. The study was conducted through the generation and simulation of the Markov chain model. The model results were obtained after Monte Carlo microsimulation of a sample with 1,000 virtual patients., Results: Treatment with ambroxol in combination with imiglucerase was cost-effective when compared with imiglucerase only and was associated with positive values of net monetary benefit regardless of the onset of the disease. Such beneficial result for ambroxol and imiglucerase combination is primarily driven by the low cost of ambroxol and its considerable clinical effectiveness in slowing the progression of neural complications of GD2., Conclusion: If ambroxol and imiglucerase are used in combination for the treatment of GD2, it is more cost-effective than using imiglucerase alone., Competing Interests: Conflict of interest: MNM serves as Editor for Open Medicine, but it did not affected peer-review process. There is no other conflict of interest., (© 2024 the author(s), published by De Gruyter.)

Background: We aimed to identify the quality of life (QoL) of patients with psoriasis, to determine the possible differences depending on the therapeutic modalities (biologic, conventional treatment and phototherapy), and to examine other variables that could affect the success of the treatment., Methods: This research was a non-experimental, quantitative, observational study that included 183 psoriasis patients. The study was conducted from November 2021 to December 2022 at the University Clinical Center Kragujevac, Serbia. The following instruments were used: Dermatology Life Quality Index (DLQI), Psoriasis Area and Severity Index (PASI), as well as a general questionnaire that contained a set of questions which referred to sociodemographic data., Results: There was a statistically significant difference in the average values of the DLQI score concerning the application of different therapeutic modalities ( P <0.001). Biologic treatment was the modality with the lowest impairments in the QoL domain (average value of DLQI score 10.6±7.3), followed by patients on conventional treatment (average value of DLQI score 12.9±7.9), and the highest levels of impaired QoL were in patients who received phototherapy (average value of the DLQI score 13.7±9.3)., Conclusion: Patients on biological therapy at all four time points individually (baseline, 4, 12 and 16 weeks) had the lowest average values of the DLQI score, i.e. the best QoL compared to subjects who received other therapy., (Copyright© 2023 Milidrag et al. Published by Tehran University of Medical Sciences.)

Long noncoding RNAs (lncRNAs) are linked to cancer via pathogenic changes in their expression levels. Yet, it remains unclear whether lncRNAs can also impact tumour cell fitness via function-altering somatic "driver" mutations. To search for such driver-lncRNAs, we here perform a genome-wide analysis of fitness-altering single nucleotide variants (SNVs) across a cohort of 2583 primary and 3527 metastatic tumours. The resulting 54 mutated and positively-selected lncRNAs are significantly enriched for previously-reported cancer genes and a range of clinical and genomic features. A number of these lncRNAs promote tumour cell proliferation when overexpressed in in vitro models. Our results also highlight a dense SNV hotspot in the widely-studied NEAT1 oncogene. To directly evaluate the functional significance of NEAT1 SNVs, we use in cellulo mutagenesis to introduce tumour-like mutations in the gene and observe a significant and reproducible increase in cell fitness, both in vitro and in a mouse model. Mechanistic studies reveal that SNVs remodel the NEAT1 ribonucleoprotein and boost subnuclear paraspeckles. In summary, this work demonstrates the utility of driver analysis for mapping cancer-promoting lncRNAs, and provides experimental evidence that somatic mutations can act through lncRNAs to enhance pathological cancer cell fitness., (© 2023. The Author(s).)

The DNA damage response (DDR) is intertwined with signaling pathways downstream of oncogenic receptor tyrosine kinases (RTKs). To drive research into the application of targeted therapies as radiosensitizers, a better understanding of this molecular crosstalk is necessary. We present here the characterization of a previously unreported MET RTK phosphosite, Serine 1016 (S1016) that represents a potential DDR-MET interface. MET S1016 phosphorylation increases in response to irradiation and is mainly targeted by DNA-dependent protein kinase (DNA-PK). Phosphoproteomics unveils an impact of the S1016A substitution on the overall long-term cell cycle regulation following DNA damage. Accordingly, the abrogation of this phosphosite strongly perturbs the phosphorylation of proteins involved in the cell cycle and formation of the mitotic spindle, enabling cells to bypass a G2 arrest upon irradiation and leading to the entry into mitosis despite compromised genome integrity. This results in the formation of abnormal mitotic spindles and a lower proliferation rate. Altogether, the current data uncover a novel signaling mechanism through which the DDR uses a growth factor receptor system for regulating and maintaining genome stability., (© 2023. The Author(s).)

Background: Cerliponase alfa is an orphan drug approved for the treatment of late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2)., Aim: Our goal was to assess the cost-effectiveness of cerliponase alfa in patients with CLN2 in the socioeconomic context of the Republic of Serbia in contrast to symptomatic therapy., Method: For this study, a forty-year horizon and the perspective of the Serbian Republic Health Insurance Fund were used. Quality-adjusted life years gained with cerliponase alfa and comparator, as well as direct treatment costs, were the study's key outcomes. The creation and simulation of a discrete-event simulation model served as the basis for the investigation. Monte Carlo microsimulation was performed on a sample of 1000 virtual patients., Results: When compared to symptomatic therapy, cerliponase alfa treatment was not cost-effective and was linked to negative net monetary benefit regardless of when the illness signs started. , Conclusion: Cerliponase alfa is not more economical than symptomatic therapy for the treatment of CLN2 when using typical pharmacoeconomic analysis. Cerliponase alfa has been shown to be effective but more has to be done to make it accessible to all CLN2 patients.

The COVID-19 pandemic has caused unprecedented stress on healthcare professionals worldwide. Since resilience and mentalizing capacity play very important preventive roles when it comes to mental health, the main goal of this study was to determine whether the capacity for mentalizing and resilience could explain the levels of depression, anxiety, and stress among healthcare workers during the COVID-19 pandemic. The study was conducted in Serbia on a sample of 406 healthcare workers (141 doctors and 265 nurses) aged 19 to 65 (M = 40.11, SD = 9.41). The participants' mental health status was evaluated using the Depression, Anxiety, and Stress Scale-DASS-42. The Reflective Functioning Questionnaire was used to evaluate the capacity for mentalizing. Resilience was assessed using the Brief Resilience Scale. The results of the correlation analysis showed that there were negative correlations between resilience and all three dimensions of mental health status: depression, anxiety, and stress. Hypermentalizing was negatively correlated with depression, anxiety, and stress, while hypomentalizing was positively correlated. Hierarchical linear regression analysis showed that both resilience and hypermentalizing were significant negative predictors of depression, anxiety, and stress, and that hypomentalizing was a significant positive predictor of depression, anxiety, and stress. Furthermore, socioeconomic status was a significant negative predictor of depression, anxiety, and stress. Marital status, number of children, and work environment were not statistically significant predictors of any of the three dimensions of mental health status among the healthcare workers in this study. There is an urgent need to establish and implement strategies to foster resilience and enhance the capacity for mentalizing among healthcare workers in order to minimize the devastating effects of the COVID-19 pandemic on mental health.

Background: Teaching is considered a high-risk profession due to the high impact of occupational risk factors which can endanger educators' mental health and lead to burnout syndrome. This study aimed to examine whether the capacity for mentalizing in teachers explains the degree of their burnout syndrome. The expectation was that a low capacity for mentalizing increases the degree of burnout., Methods: A cross-sectional study was conducted on a sample of 823 teachers. The Maslach Burnout Inventory-Educators Survey was used to examine the burnout syndrome. The capacity for mentalizing was examined using hypomentalizing and hypermentalizing scales from the Reflective Functioning Questionnaire., Results: The expectation that a low capacity for mentalizing increases teachers' burnout confirms the finding that hypomentalizing is a positive predictor of their emotional exhaustion as a dimension of burnout (ß = 0.09; p < 0.01). Unexpectedly, hypomentalizing proved to be a positive predictor of personal accomplishment (ß = 0.09; p < 0.05), which indicates that with a lower capacity for mentalizing, teachers experience greater personal accomplishment. Also, hypermantalizing was a negative predictor of emotional exhaustion (ß = -0.17; p < 0.01) and depersonalization (ß = -0.31; p < 0.01), and a positive predictor of personal accomplishment (ß = 0.30; p < 0.01). The findings showed that with higher socioeconomic status, with marriage and having children, the burnout of teachers is lower, as expected., Conclusions: Capacity for mentalizing and burnout syndrome in teachers are interrelated phenomena. With a good capacity for mentalizing, emotional exhaustion and burnout in teachers are reduced. Knowledge and skills that enable a good capacity for mentalizing should be included in educational and teacher training programs., Competing Interests: Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Safiye et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Oncogene addiction provides important therapeutic opportunities for precision oncology treatment strategies. To date the cellular circuitries associated with driving oncoproteins, which eventually establish the phenotypic manifestation of oncogene addiction, remain largely unexplored. Data suggest the DNA damage response (DDR) as a central signaling network that intersects with pathways associated with deregulated addicting oncoproteins with kinase activity in cancer cells., Experimental: DESIGN: We employed a targeted mass spectrometry approach to systematically explore alterations in 116 phosphosites related to oncogene signaling and its intersection with the DDR following inhibition of the addicting oncogene alone or in combination with irradiation in MET-, EGFR-, ALK- or BRAF (V600)-positive cancer models. An NSCLC tissue pipeline combining patient-derived xenografts (PDXs) and ex vivo patient organotypic cultures has been established for treatment responsiveness assessment., Results: We identified an 'oncogene addiction phosphorylation signature' (OAPS) consisting of 8 protein phosphorylations (ACLY S455, IF4B S422, IF4G1 S1231, LIMA1 S490, MYCN S62, NCBP1 S22, P3C2A S259 and TERF2 S365) that are significantly suppressed upon targeted oncogene inhibition solely in addicted cell line models and patient tissues. We show that the OAPS is present in patient tissues and the OAPS-derived score strongly correlates with the ex vivo responses to targeted treatments., Conclusions: We propose a score derived from OAPS as a quantitative measure to evaluate oncogene addiction of cancer cell samples. This work underlines the importance of protein phosphorylation assessment for patient stratification in precision oncology and corresponding identification of tumor subtypes sensitive to inhibition of a particular oncogene., (© 2022. The Author(s).)