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Background: Stakeholder engagement plays a vital role in driving advancements in product development. This imperative now extends to the healthcare domain, driven by the scarcity of healthcare professionals and the pressing demand for effective solutions. Through the application of design thinking and co-design methodologies, this study endeavours to promote comprehensive stakeholder involvement, creating streamlined processes and adaptable templates geared towards fostering innovative solutions for tele-emergency medicine. Methods: In this study design thinking and co-design methods are developed, adapted, and tested, to create effective tools and demonstrate their application. This is part of a process involving stakeholders and lead users to develop a telemedicine solution for emergency medical services. This research is descriptive in kind, offering a transparent and holistic portrayal of the co-design process. The rural region of Burgenland in Austria was chosen for this study, with the challenges of its weak infrastructure offering valuable insights. The tools were tested in co-design workshops, with the participants continuously observed by the research team. Results: Seventeen healthcare professionals, emergency medical technicians and academics participated in a co-design process to develop a telemedicine solution for emergency medical services. The results section presents practical co-creative healthcare innovation tools and templates that have been shown to facilitate the co-design process. Conclusions: The study developed and applied co-design elements for the creation of a prototype concept for telemedicine in emergency medicine and offers valuable insights for similar projects involving diverse stakeholders. It shows that structured co-design activities help all stakeholders to jointly create solutions that meet the overall needs. [ABSTRACT FROM AUTHOR]

Background: In times of demographic change and an immense shortage of qualified personnel in emergency medical services, telemedicine could offer more efficient solutions for better care. Given the community-based nature of emergency services, local communities play an important role. This study explored the expectations of healthcare professionals and volunteers for telemedicine tools in prehospital emergency medicine. Methods: This mixed-methods study was conducted in the rural region of Burgenland in Austria with stakeholders of the local emergency medical service in two focus groups (13 participants) and 99 quantitative questionnaires. Results: Combining quantitative and qualitative data, we found that a majority of respondents (almost 80%) already experienced basic telemedicine and consider it valuable. In particular, there is a strong expectation for diagnostic support and inquiries related to potential hospitalization. Findings from two focus groups emphasized the importance of cultivating an improved learning culture, developing a specific mindset, and refining soft skills. The optimal telemedicine solution includes a knowledgeable and experienced tele-emergency physician coupled with user-friendly technology. Conclusion: To be clear about the expectations of stakeholders, it is essential to involve all stakeholders right from the beginning. The solution should prioritize the integration of existing structures and be seamlessly incorporated into an evolving learning culture, while also fostering the necessary mindsets alongside educational aspects. [ABSTRACT FROM AUTHOR]

Bone mass is maintained by osteoclasts that resorb bone and osteoblasts that promote matrix deposition and mineralization. Bone homeostasis is altered in chronic inflammation as well as in post-menopausal loss of estrogen, which favors osteoclast activity that leads to osteoporosis. The MAPK p38α is a key regulator of bone loss and p38 inhibitors preserve bone mass by inhibiting osteoclastogenesis. p38 function is regulated by two upstream MAPK kinases, namely MKK3 and MKK6. The goal of this study was to assess the effect of MKK3- or MKK6-deficiency on osteoclastogenesis in vitro and on bone loss in ovariectomy-induced osteoporosis in mice. We demonstrated that MKK3 but not MKK6, regulates osteoclast differentiation from bone marrow cells in vitro. Expression of NFATc1, a master transcription factor in osteoclastogenesis, is decreased in cells lacking MKK3 but not MKK6. Expression of osteoclast-specific genes Cathepsin K, osteoclast-associated receptor and MMP9, was inhibited in MKK3-/- cells. The effect of MKK-deficiency on ovariectomy-induced bone loss was then evaluated in female WT, MKK3-/- and MKK6-/- mice by micro-CT analysis. Bone loss was partially inhibited in MKK3-/- as well as MKK6-/- mice, despite normal osteoclastogenesis in MKK6-/- cells. This correlated with the lower osteoclast numbers in the MKK-deficient ovariectomized mice. These studies suggest that MKK3 and MKK6 differentially regulate bone loss due to estrogen withdrawal. MKK3 directly mediates osteoclastogenesis while MKK6 likely contributes to pro-inflammatory cytokine production that promotes osteoclast formation.

Childhood trauma is associated with an increased risk of psychosis, but the mechanisms that mediate this relationship are unknown. Exposure to trauma has been hypothesised to lead to cognitive biases that might have causal effects on psychotic symptoms. The literature on whether childhood trauma is associated with psychosis-related cognitive biases has not been comprehensively reviewed. A systematic review and meta-analysis or narrative synthesis of studies examining the association between childhood trauma and the following biases: external locus of control (LOC), external attribution, probabilistic reasoning, source monitoring, top-down processing, and bias against disconfirmatory evidence. Studies were assessed for quality, and sources of heterogeneity were explored. We included 25 studies from 3,465 studies identified. Individuals exposed to childhood trauma reported a more external LOC (14 studies: SMD Median = 0.40, Interquartile range 0.07 to 0.52), consistent with a narrative synthesis of 11 other studies of LOC. There was substantial heterogeneity in the meta-analysis (I2 = 93%) not explained by study characteristics examined. Narrative syntheses for other biases showed weaker, or no evidence of association with trauma. The quality of included studies was generally low. Our review provides some evidence of an association between childhood trauma and a more external LOC, but not with the other biases examined. The low quality and paucity of studies for most of the cognitive biases examined highlights the need for more rigorous studies to determine which biases occur after trauma, and whether they mediate an effect of childhood trauma on psychosis.

Inhibition of sodium/glucose cotransporter 2 (SGLT2), the key transport protein in renal glucose reabsorption, promotes glucose excretion and represents a new concept in the therapy of type-2 diabetes. In addition, SGLT2 inhibition elevates circulating glucagon concentrations and enhances hepatic glucose production. Since SGLT2 is expressed in human pancreatic α-cells and regulates glucagon release, we tested whether common variants of the SGLT2 gene SLC5A2 associate with altered plasma glucagon concentrations in the fasting state and upon glucose challenge.A study population of 375 healthy subjects at increased risk for type-2 diabetes, phenotyped by a 5-point oral glucose tolerance test (OGTT) and genotyped for recently described SLC5A2 tagging single nucleotide polymorphisms (SNPs), was selected for plasma glucagon measurements.After adjustment for gender, age, body mass index, and insulin sensitivity, the four tagging SNPs (rs9924771, rs3116150, rs3813008, rs9934336), tested separately or as genetic score, were neither significantly nor nominally associated with plasma glucagon concentrations at any time during the OGTT, with the inverse AUC of glucagon or the glucagon fold-change during the OGTT (p ≥ 0.2, all). Testing for genotype-related differences in the time course of the glucagon response using MANOVA did also not reveal any significant or nominal associations (p ≥ 0.5, all).We could not obtain statistically significant evidence for a role of common SLC5A2 variants in the regulation of glucagon release in the fasting state or upon glucose challenge. Moreover, the reported nominal effects of individual SLC5A2 variants on fasting and post-challenge glucose levels may probably not be mediated by altered glucagon release.

The aim of the study was to investigate whether obese children and adolescents have a disturbed body representation as compared to normal-weight participants matched for age and gender and whether their body representation changes in the course of an inpatient weight-reduction program.Sixty obese (OBE) and 27 normal-weight (NW) children and adolescents (age: 9-17) were assessed for body representation using a multi-method approach. Therefore, we assessed body size estimation, tactile size estimation, heartbeat detection accuracy, and attitudes towards one's own body. OBE were examined upon admission and before discharge of an inpatient weight-reduction program. NW served as cross-sectional control group.Body size estimation and heartbeat detection accuracy were similar in OBE and NW. OBE overestimated sizes in tactile size estimation and were more dissatisfied with their body as compared to NW. In OBE but not in NW, several measures of body size estimation correlated with negative body evaluation. After weight-loss treatment, OBE had improved in heartbeat detection accuracy and were less dissatisfied with their body. None of the assessed variables predicted weight-loss success.Although OBE children and adolescents generally perceived their body size and internal status of the body accurately, weight reduction improved their heartbeat detection accuracy and body dissatisfaction.

Pediatric liver transplantation is a highly specialized, challenging field. Selective reporting may introduce bias into evidence based clinical decision making, but the precise extent of unpublished data in pediatric liver transplantation is unknown today. We therefore assessed the public availability of completed clinical trials in pediatric liver transplantation.We determined the proportion of published and unpublished pre-registered, completed pediatric liver transplantation studies on ClinicalTrials.gov. The major trial and literature databases, i.e., clinicaltrials.gov, Pubmed, and Google Scholar were searched for publications. In addition, principal investigators or sponsors were contacted directly. STROBE criteria were applied for the descriptive analysis.Out of N = 33 studies focusing on pediatric liver transplantation registered as completed until March 2014 on clinicaltrials.gov, N = 19 (58%) studies were published until February 2015, whereas N = 14 (42%) studies remained unpublished. The unpublished trials contain data from N = 2105 (35%) patients out of a total population of N = 6044 study participants. Median time-to-publication, i.e., the period from completion of the trial until public availability of the data was 23 IQR 10 to 28 months. Most pertinent key questions in pediatric liver transplantation, i.e., surgical procedures, immunosuppression, concomitant infections, and graft rejection were addressed in 48% of studies (N = 16/33), half of which were published.Half of the clinical trials in pediatric liver transplantation focused on key questions such as surgical procedures, immunosuppression, concomitant infections, and graft rejection. There is still a considerable amount of unpublished studies results in pediatric liver transplantation. Time from study completion to publication was almost twice as long as the 12 months mandatory FDAAA-timeline with a trend towards acceleration over time. The data should serve as a baseline for future progress in the field. More stringent publication of completed trials and focused multicenter research should be encouraged.

The G1 cell cycle inhibitors tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) have been identified as promising biomarkers for the prediction of adverse outcomes including renal replacement therapy (RRT) and mortality in critically ill adult patients who develop acute kidney injury (AKI). However, the prognostic value of urinary TIMP-2 and IGFBP7 in neonatal and pediatric AKI for adverse outcome has not been investigated yet.The product of the urinary concentration of TIMP-2 and IGFBP7 ([TIMP-2]•[IGFBP7]) was assessed by a commercially available immunoassay (NephroCheck™) in a prospective cohort study in 133 subjects aged 0-18 years including 46 patients with established AKI according to pRIFLE criteria, 27 patients without AKI (non-AKI group I) and 60 apparently healthy neonates and children (non-AKI group II). AKI etiologies were: dehydration/hypovolemia (n = 7), hemodynamic instability (n = 7), perinatal asphyxia (n = 9), septic shock (n = 7), typical hemolytic-uremic syndrome (HUS; n = 5), interstitial nephritis (n = 5), vasculitis (n = 4), nephrotoxic injury (n = 1) and renal vein thrombosis (n = 1).When AKI patients were classified into pRIFLE criteria, 6/46 (13%) patients fulfilled the criteria for the category "Risk", 13/46 (28%) for "Injury", 26/46 (57%) for "Failure" and 1/46 (2%) for "Loss". Patients in the "Failure" stage had a median 3.7-fold higher urinary [TIMP-2]•[IGFBP7] compared to non-AKI subjects (P

To evaluate risk factors associated with alterations in venous structures adjacent to an ablation zone after percutaneous irreversible electroporation (IRE) of hepatic malignancies at subacute follow-up (1 to 3 days after IRE) and to describe evolution of these alterations at mid-term follow-up.43 patients (men/women, 32/11; mean age, 60.3 years) were identified in whom venous structures were located within a perimeter of 1.0 cm of the ablation zone at subacute follow-up after IRE of 84 hepatic lesions (primary/secondary hepatic tumors, 31/53). These vessels were retrospectively evaluated by means of pre-interventional and post-interventional contrast-enhanced magnetic resonance imaging or computed tomography or both. Any vascular changes in flow, patency, and diameter were documented. Correlations between vascular change (yes/no) and characteristics of patients, lesions, and ablation procedures were assessed by generalized linear models.191 venous structures were located within a perimeter of 1.0 cm of the ablation zone: 55 (29%) were encased by the ablation zone, 78 (41%) abutted the ablation zone, and 58 (30%) were located between 0.1 and 1.0 cm from the border of the ablation zone. At subacute follow-up, vascular changes were found in 19 of the 191 vessels (9.9%), with partial portal vein thrombosis in 2, complete portal vein thrombosis in 3, and lumen narrowing in 14 of 19. At follow-up of patients with subacute vessel alterations (mean, 5.7 months; range, 0 to 14 months) thrombosis had resolved in 2 of 5 cases; vessel narrowing had completely resolved in 8 of 14 cases, and partly resolved in 1 of 14 cases. The encasement of a vessel by ablation zone (OR = 6.36, p

Current guidelines recommend immunosuppressive treatment (IT) in patients with primary sclerosing cholangitis (PSC) and elevated aminotransferase levels more than five times the upper limit of normal and elevated serum IgG-levels above twice the upper limit of normal. Since there is no evidence to support this recommendation, we aimed to assess the criteria that guided clinicians in clinical practice to initiate IT in patients with previously diagnosed PSC.This is a retrospective analysis of 196 PSC patients from seven German hepatology centers, of whom 36 patients had received IT solely for their liver disease during the course of PSC. Analyses were carried out using methods for competing risks.A simplified autoimmune hepatitis (AIH) score >5 (HR of 36, p5 and a mHAI score >3, suggesting concomitant features of AIH, influenced the decision to introduce IT during the course of PSC. In German clinical practice, the cutoffs used to guide IT may be lower than recommended by current guidelines.

Bone mass is maintained by osteoclasts that resorb bone and osteoblasts that promote matrix deposition and mineralization. Bone homeostasis is altered in chronic inflammation as well as in post-menopausal loss of estrogen, which favors osteoclast activity that leads to osteoporosis. The MAPK p38α is a key regulator of bone loss and p38 inhibitors preserve bone mass by inhibiting osteoclastogenesis. p38 function is regulated by two upstream MAPK kinases, namely MKK3 and MKK6. The goal of this study was to assess the effect of MKK3- or MKK6-deficiency on osteoclastogenesis in vitro and on bone loss in ovariectomy-induced osteoporosis in mice. We demonstrated that MKK3 but not MKK6, regulates osteoclast differentiation from bone marrow cells in vitro. Expression of NFATc1, a master transcription factor in osteoclastogenesis, is decreased in cells lacking MKK3 but not MKK6. Expression of osteoclast-specific genes Cathepsin K, osteoclast-associated receptor and MMP9, was inhibited in MKK3-/- cells. The effect of MKK-deficiency on ovariectomy-induced bone loss was then evaluated in female WT, MKK3-/- and MKK6-/- mice by micro-CT analysis. Bone loss was partially inhibited in MKK3-/- as well as MKK6-/- mice, despite normal osteoclastogenesis in MKK6-/- cells. This correlated with the lower osteoclast numbers in the MKK-deficient ovariectomized mice. These studies suggest that MKK3 and MKK6 differentially regulate bone loss due to estrogen withdrawal. MKK3 directly mediates osteoclastogenesis while MKK6 likely contributes to pro-inflammatory cytokine production that promotes osteoclast formation.

BACKGROUND: Binge eating disorder (BED) represents a distinct eating disorder diagnosis. Current approaches assume increased impulsivity to be one factor leading to binge eating and weight gain. We used eye tracking to investigate both components of impulsivity, namely reward sensitivity and rash-spontaneous behaviour towards food in BED for the first time. METHODS: Overweight and obese people with BED (BED+; n = 25), without BED (BED-; n = 26) and healthy normal-weight controls (NWC; n = 25) performed a free exploration paradigm measuring reward sensitivity (experiment 1) and a modified antisaccade paradigm measuring disinhibited, rash-spontaneous behaviour (experiment 2) using food and nonfood stimuli. Additionally, trait impulsivity was assessed. RESULTS: In experiment 1, all participants located their initial fixations more often on food stimuli and BED+ participants gazed longer on food stimuli in comparison with BED- and NWC participants. In experiment 2, BED+ participants had more difficulties inhibiting saccades towards food and nonfood stimuli compared with both other groups in first saccades, and especially towards food stimuli in second saccades and concerning sequences of first and second saccades. BED- participants did not differ significantly from NWC participants in both experiments. Additionally, eye tracking performance was associated with self-reported reward responsiveness and self-control. CONCLUSIONS: According to these results, food-related reward sensitivity and rash-spontaneous behaviour, as the two components of impulsivity, are increased in BED in comparison with weight-matched and normal-weight controls. This indicates that BED represents a neurobehavioural phenotype of obesity that is characterised by increased impulsivity. Interventions for BED should target these special needs of affected patients.

The tumour suppressor p53 controls transcription of various genes involved in apoptosis, cell-cycle arrest, DNA repair and metabolism. However, its DNA-recognition specificity is not nearly sufficient to explain binding to specific locations in vivo. Here, we present evidence that KLF4 increases the DNA-binding affinity of p53 through the formation of a loosely arranged ternary complex on DNA. This effect depends on the distance between the response elements of KLF4 and p53. Using nuclear magnetic resonance and fluorescence techniques, we found that the amino-terminal domain of p53 interacts with the KLF4 zinc fingers and mapped the interaction site. The strength of this interaction was increased by phosphorylation of the p53 N-terminus, particularly on residues associated with regulation of cell-cycle arrest genes. Taken together, the cooperative binding of KLF4 and p53 to DNA exemplifies a regulatory mechanism that contributes to p53 target selectivity.

TGR5, the G protein-coupled bile acid receptor 1 (GPBAR1), has been linked to inflammatory pathways as well as bile homeostasis, and could therefore be involved in primary sclerosing cholangitis (PSC) a chronic inflammatory bile duct disease. We aimed to extensively investigate TGR5 sequence variation in PSC, as well as functionally characterize detected variants.Complete resequencing of TGR5 was performed in 267 PSC patients and 274 healthy controls. Six nonsynonymous mutations were identified in addition to 16 other novel single-nucleotide polymorphisms. To investigate the impact from the nonsynonymous variants on TGR5, we created a receptor model, and introduced mutated TGR5 constructs into human epithelial cell lines. By using confocal microscopy, flow cytometry and a cAMP-sensitive luciferase assay, five of the nonsynonymous mutations (W83R, V178M, A217P, S272G and Q296X) were found to reduce or abolish TGR5 function. Fine-mapping of the previously reported PSC and UC associated locus at chromosome 2q35 in large patient panels revealed an overall association between the TGR5 single-nucleotide polymorphism rs11554825 and PSC (odds ratio = 1.14, 95% confidence interval: 1.03-1.26, p = 0.010) and UC (odds ratio = 1.19, 95% confidence interval 1.11-1.27, p = 8.5 x 10(-7)), but strong linkage disequilibrium precluded demarcation of TGR5 from neighboring genes.Resequencing of TGR5 along with functional investigations of novel variants provided unique insight into an important candidate gene for several inflammatory and metabolic conditions. While significant TGR5 associations were detected in both UC and PSC, further studies are needed to conclusively define the role of TGR5 variation in these diseases.

Aim: Inhibition of sodium/glucose cotransporter 2 (SGLT2), the key transport protein in renal glucose reabsorption, promotes glucose excretion and represents a new concept in the therapy of type-2 diabetes. In addition, SGLT2 inhibition elevates circulating glucagon concentrations and enhances hepatic glucose production. Since SGLT2 is expressed in human pancreatic α-cells and regulates glucagon release, we tested whether common variants of the SGLT2 gene SLC5A2 associate with altered plasma glucagon concentrations in the fasting state and upon glucose challenge. Methods: A study population of 375 healthy subjects at increased risk for type-2 diabetes, phenotyped by a 5-point oral glucose tolerance test (OGTT) and genotyped for recently described SLC5A2 tagging single nucleotide polymorphisms (SNPs), was selected for plasma glucagon measurements. Results: After adjustment for gender, age, body mass index, and insulin sensitivity, the four tagging SNPs (rs9924771, rs3116150, rs3813008, rs9934336), tested separately or as genetic score, were neither significantly nor nominally associated with plasma glucagon concentrations at any time during the OGTT, with the inverse AUC of glucagon or the glucagon fold-change during the OGTT (p ≥ 0.2, all). Testing for genotype-related differences in the time course of the glucagon response using MANOVA did also not reveal any significant or nominal associations (p ≥ 0.5, all). Conclusion: We could not obtain statistically significant evidence for a role of common SLC5A2 variants in the regulation of glucagon release in the fasting state or upon glucose challenge. Moreover, the reported nominal effects of individual SLC5A2 variants on fasting and post-challenge glucose levels may probably not be mediated by altered glucagon release. [ABSTRACT FROM AUTHOR]

Background: Binge eating disorder (BED) represents a distinct eating disorder diagnosis. Current approaches assume increased impulsivity to be one factor leading to binge eating and weight gain. We used eye tracking to investigate both components of impulsivity, namely reward sensitivity and rash-spontaneous behaviour towards food in BED for the first time. Methods: Overweight and obese people with BED (BED+; n = 25), without BED (BED−; n = 26) and healthy normal-weight controls (NWC; n = 25) performed a free exploration paradigm measuring reward sensitivity (experiment 1) and a modified antisaccade paradigm measuring disinhibited, rash-spontaneous behaviour (experiment 2) using food and nonfood stimuli. Additionally, trait impulsivity was assessed. Results: In experiment 1, all participants located their initial fixations more often on food stimuli and BED+ participants gazed longer on food stimuli in comparison with BED− and NWC participants. In experiment 2, BED+ participants had more difficulties inhibiting saccades towards food and nonfood stimuli compared with both other groups in first saccades, and especially towards food stimuli in second saccades and concerning sequences of first and second saccades. BED− participants did not differ significantly from NWC participants in both experiments. Additionally, eye tracking performance was associated with self-reported reward responsiveness and self-control. Conclusions: According to these results, food-related reward sensitivity and rash-spontaneous behaviour, as the two components of impulsivity, are increased in BED in comparison with weight-matched and normal-weight controls. This indicates that BED represents a neurobehavioural phenotype of obesity that is characterised by increased impulsivity. Interventions for BED should target these special needs of affected patients. [ABSTRACT FROM AUTHOR]

Background: The G1 cell cycle inhibitors tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) have been identified as promising biomarkers for the prediction of adverse outcomes including renal replacement therapy (RRT) and mortality in critically ill adult patients who develop acute kidney injury (AKI). However, the prognostic value of urinary TIMP-2 and IGFBP7 in neonatal and pediatric AKI for adverse outcome has not been investigated yet. Methods: The product of the urinary concentration of TIMP-2 and IGFBP7 ([TIMP-2]•[IGFBP7]) was assessed by a commercially available immunoassay (NephroCheck™) in a prospective cohort study in 133 subjects aged 0–18 years including 46 patients with established AKI according to pRIFLE criteria, 27 patients without AKI (non-AKI group I) and 60 apparently healthy neonates and children (non-AKI group II). AKI etiologies were: dehydration/hypovolemia (n = 7), hemodynamic instability (n = 7), perinatal asphyxia (n = 9), septic shock (n = 7), typical hemolytic-uremic syndrome (HUS; n = 5), interstitial nephritis (n = 5), vasculitis (n = 4), nephrotoxic injury (n = 1) and renal vein thrombosis (n = 1). Results: When AKI patients were classified into pRIFLE criteria, 6/46 (13%) patients fulfilled the criteria for the category “Risk”, 13/46 (28%) for “Injury”, 26/46 (57%) for “Failure” and 1/46 (2%) for “Loss”. Patients in the “Failure” stage had a median 3.7-fold higher urinary [TIMP-2]•[IGFBP7] compared to non-AKI subjects (P<0.001). When analyzed for AKI etiology, highest [TIMP-2]•[IGFBP7] values were found in patients with septic shock (P<0.001 vs. non-AKI I+II). Receiver operating characteristic (ROC) curve analyses in the AKI group revealed good performance of [TIMP-2]•[IGFBP7] in predicting 30-day (area under the curve (AUC) 0.79; 95% CI, 0.61–0.97) and 3-month mortality (AUC 0.84; 95% CI, 0.67–0.99) and moderate performance in predicting RRT (AUC 0.67; 95% CI, 0.50–0.84). Conclusions: This study shows that urinary [TIMP-2]•[IGFBP7] has a good diagnostic performance in predicting adverse outcomes in neonatal and pediatric AKI of heterogeneous etiology. [ABSTRACT FROM AUTHOR]

The tumour suppressor p53 controls transcription of various genes involved in apoptosis, cell-cycle arrest, DNA repair and metabolism. However, its DNA-recognition specificity is not nearly sufficient to explain binding to specific locations in vivo. Here, we present evidence that KLF4 increases the DNA-binding affinity of p53 through the formation of a loosely arranged ternary complex on DNA. This effect depends on the distance between the response elements of KLF4 and p53. Using nuclear magnetic resonance and fluorescence techniques, we found that the amino-terminal domain of p53 interacts with the KLF4 zinc fingers and mapped the interaction site. The strength of this interaction was increased by phosphorylation of the p53 N-terminus, particularly on residues associated with regulation of cell-cycle arrest genes. Taken together, the cooperative binding of KLF4 and p53 to DNA exemplifies a regulatory mechanism that contributes to p53 target selectivity. [ABSTRACT FROM AUTHOR]

Background & Aims: Current guidelines recommend immunosuppressive treatment (IT) in patients with primary sclerosing cholangitis (PSC) and elevated aminotransferase levels more than five times the upper limit of normal and elevated serum IgG-levels above twice the upper limit of normal. Since there is no evidence to support this recommendation, we aimed to assess the criteria that guided clinicians in clinical practice to initiate IT in patients with previously diagnosed PSC. Methods: This is a retrospective analysis of 196 PSC patients from seven German hepatology centers, of whom 36 patients had received IT solely for their liver disease during the course of PSC. Analyses were carried out using methods for competing risks. Results: A simplified autoimmune hepatitis (AIH) score >5 (HR of 36, p<0.0001) and a modified histological activity index (mHAI) greater than 3/18 points (HR 3.6, p = 0.0274) were associated with the initiation of IT during the course of PSC. Of note, PSC patients who subsequently received IT differed already at the time of PSC diagnosis from those patients, who did not receive IT during follow-up: they presented with increased levels of IgG (p = 0.004) and more frequently had clinical signs of cirrhosis (p = 0.0002). Conclusions: This is the first study which investigates the parameters associated with IT in patients with PSC in clinical practice. A simplified AIH score >5 and a mHAI score >3, suggesting concomitant features of AIH, influenced the decision to introduce IT during the course of PSC. In German clinical practice, the cutoffs used to guide IT may be lower than recommended by current guidelines. [ABSTRACT FROM AUTHOR]

Background: TGR5, the G protein-coupled bile acid receptor 1 (GPBAR1), has been linked to inflammatory pathways as well as bile homeostasis, and could therefore be involved in primary sclerosing cholangitis (PSC) a chronic inflammatory bile duct disease. We aimed to extensively investigate TGR5 sequence variation in PSC, as well as functionally characterize detected variants. Methodology/Principal Findings: Complete resequencing of TGR5 was performed in 267 PSC patients and 274 healthy controls. Six nonsynonymous mutations were identified in addition to 16 other novel single-nucleotide polymorphisms. To investigate the impact from the nonsynonymous variants on TGR5, we created a receptor model, and introduced mutated TGR5 constructs into human epithelial cell lines. By using confocal microscopy, flow cytometry and a cAMP-sensitive luciferase assay, five of the nonsynonymous mutations (W83R, V178M, A217P, S272G and Q296X) were found to reduce or abolish TGR5 function. Fine-mapping of the previously reported PSC and UC associated locus at chromosome 2q35 in large patient panels revealed an overall association between the TGR5 single-nucleotide polymorphism rs11554825 and PSC (odds ratio = 1.14, 95% confidence interval: 1.03-1.26, p = 0.010) and UC (odds ratio = 1.19, 95% confidence interval 1.11- 1.27, p = 8.5×10-7), but strong linkage disequilibrium precluded demarcation of TGR5 from neighboring genes. Conclusions/Significance: Resequencing of TGR5 along with functional investigations of novel variants provided unique insight into an important candidate gene for several inflammatory and metabolic conditions. While significant TGR5 associations were detected in both UC and PSC, further studies are needed to conclusively define the role of TGR5 variation in these diseases [ABSTRACT FROM AUTHOR]

Brucellosis and Tuberculosis, both of which are contagious diseases, have presented significant challenges to global public health security in recent years. Delayed treatment can exacerbate the conditions, jeopardizing patient lives. Currently, no vaccine has been approved to prevent these two diseases simultaneously. In contrast to traditional vaccines, mRNA vaccines offer advantages such as high efficacy, rapid development, and low cost, and their applications are gradually expanding. This study aims to develop multi-epitope mRNA vaccines argeting Brucella melitensis and Mycobacterium tuberculosis H37Rv (L4 strain) utilizing immunoinformatics approaches. The proteins Omp25, Omp31, MPT70, and MPT83 from the specified bacteria were selected to identify the predominant T- and B-cell epitopes for immunological analysis. Following a comprehensive evaluation, a vaccine was developed using helper T lymphocyte epitopes, cytotoxic T lymphocyte epitopes, linear B-cell epitopes, and conformational B-cell epitopes. It has been demonstrated that multi-epitope mRNA vaccines exhibit increased antigenicity, non-allergenicity, solubility, and high stability. The findings from molecular docking and molecular dynamics simulation revealed a robust and enduring binding affinity between multi-epitope peptides mRNA vaccines and TLR4. Ultimately, Subsequently, following the optimization of the nucleotide sequence, the codon adaptation index was calculated to be 1.0, along with an average GC content of 54.01%. This indicates that the multi-epitope mRNA vaccines exhibit potential for efficient expression within the Escherichia coli(E. coli) host. Analysis through immune modeling indicates that following administration of the vaccine, there may be variation in immunecell populations associated with both innate and adaptive immune reactions. These types encompass helper T lymphocytes (HTL), cytotoxic T lymphocytes (CTL), regulatory T lymphocytes, natural killer cells, dendritic cells and various immune cell subsets. In summary, the results suggest that the newly created multi-epitope mRNA vaccine exhibits favorable attributes, offering novel insights and a conceptual foundation for potential progress in vaccine development. [ABSTRACT FROM AUTHOR]

Purpose: To identify characteristics of SARS-CoV-2 infection that are associated with hospitalization in children initially evaluated in a Pediatric Emergency Department (ED). Methods: We identified cases of SARS-CoV-2 positive patients seen in the Arkansas Children's Hospital (ACH) ED or hospitalized between May 27, 2020, and April 28, 2022, using ICD-10 codes within the Pediatric Hospital Information System (PHIS) Database. We compared infection waves for differences in patient characteristics and used logistic regressions to examine which features led to a higher chance of hospitalization. Findings: We included 681 pre-Delta cases, 673 Delta cases, and 970 Omicron cases. Almost 17% of patients were admitted to the hospital. Compared to Omicron-infected children, pre-Delta and Delta-infected children were twice as likely hospitalized (OR = 2.2 and 2.0, respectively; p<0.0001). Infants under one year were >3 times as likely to be hospitalized than children ages 5–14 years regardless of wave (OR = 3.42; 95%CI = 2.36–4.94). Rural children were almost three times as likely than urban children to be hospitalized across all waves (OR = 2.73; 95%CI = 1.97–3.78). Finally, those with a complex condition had nearly a 15-fold increase in odds of admission (OR = 14.6; 95%CI = 10.6–20.0). Conclusions: Children diagnosed during the pre-Delta or Delta waves were more likely to be hospitalized than those diagnosed during the Omicron wave. Younger and rural patients were more likely to be hospitalized regardless of the wave. We suspect lower vaccination rates and larger distances from medical care influenced higher hospitalization rates. [ABSTRACT FROM AUTHOR]

Tuberculosis(TB) of the Central nervous system (CNS) is a rare and highly destructive disease. The emergence of drug resistance has increased treatment difficulty, leaving the Bacillus Calmette-Guérin (BCG) vaccine as the only licensed preventative immunization available. This study focused on identifying the epitopes of PknD (Rv0931c) and Rv0986 from Mycobacterium tuberculosis(Mtb) strain H37Rv using an in silico method. The goal was to develop a therapeutic mRNA vaccine for preventing CNS TB. The vaccine was designed to be non-allergenic, non-toxic, and highly antigenic. Codon optimization was performed to ensure effective translation in the human host. Additionally, the secondary and tertiary structures of the vaccine were predicted, and molecular docking with TLR-4 was carried out. A molecular dynamics simulation confirmed the stability of the complex. The results indicate that the vaccine structure shows effectiveness. Overall, the constructed vaccine exhibits ideal physicochemical properties, immune response, and stability, laying a theoretical foundation for future laboratory experiments. [ABSTRACT FROM AUTHOR]

The possible impact of gender-sensitive language on readers is among the most controversially debated issues in linguistics and beyond. Previous studies have suggested that there is an effect of gender-sensitive language on mental representations, based on data gathered in laboratory settings with small groups of participants. We add a new perspective by examining correlations of authentic language use with authentic user interaction on a recruitment website. Drawing upon a large dataset provided by the recruitment platform StepStone, we evaluate whether job advertisements using certain kinds of gender-sensitive language in their titles correlate with higher proportions of views by female users. Our results indicate that there are differing effects depending on the type of gender-sensitive language that is used. Overall, the strongest correlation can be found with terms that include the feminine suffix -in. [ABSTRACT FROM AUTHOR]

Women's empowerment has been promoted by researchers and development practitioners as one of the most promising strategies to address widespread hunger and malnutrition. However, the relationship between women's empowerment and dietary diversity and child nutrition has rarely been studied among vulnerable populations or individuals at greater risk of poor physical and social health status. Moreover, the effects of different domains of women's empowerment on nutritional outcomes, including dietary diversity and child anthropometry, have rarely been examined, especially with panel data. Using two rounds of panel data from 1900 households and fixed effects regression models, we analyze the effect of women's empowerment on household dietary diversity score (HDDS) and child anthropometry among the particularly vulnerable tribal groups in Odisha, India. We also estimate the effects of various decision-making domains of women's empowerment on HDDS and child anthropometry to understand which empowerment domains matter for nutrition. Results show that women's empowerment is positively associated with HDDS (coef. 0.41 food groups; p < 0.1) and reduces the prevalence of underweight (coef. 39%; p < 0.05) and wasting (coef. 56%; p < 0.1) in children but has no effect on the prevalence of child stunting. Women's empowerment in agricultural input use; output sales; income; food purchases; and credit, group membership, and employment contribute to improved dietary diversity and child nutrition. We conclude that women's empowerment contributes to improved dietary diversity and child nutrition and is a promising strategy to improve farm household diets and child nutrition among vulnerable populations. Strengthening women's empowerment through the promotion of women's access to land and other agricultural inputs, market participation, access to information, capital, and credit is important. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the impact of diaper change frequency, clinical characteristics, and skin health metrics on development of the skin microbiota in preterm infants. Design: A randomized controlled parallel design was used. Methods: Medically stable preterm infants born <33 weeks' gestation were randomized to receive diaper changes at a frequency of every 3-hours or every 6-hours. Skin swabs were collected longitudinally from the diapered skin (buttocks) and chest. Skin pH and transepidermal water loss were measured with each sample collection. Stool samples were collected from the diaper. The microbiome at each site was characterized by 16S rRNA gene sequencing. Associations between microbiome features, diaper change frequency, and other covariates were examined using mixed effect models and redundancy analysis. Results: A total of 1179 samples were collected from 46 preterm infants, beginning at a median postnatal age of 44 days and continuing through hospital discharge. Alpha-diversity of the skin microbiota increased over time, but did not differ significantly between 3-hour (n = 20) and 6-hour (n = 26) diaper change groups. Alpha-diversity of the skin microbiota was inversely correlated with skin pH, but not transepidermal water loss. Microbiota community structure differed significantly between body sites (buttocks, chest, and stool) and between individuals. Among samples collected from the diapered skin, diaper change frequency, infant diet, antibiotic exposure, and delivery mode accounted for minor proportions of the variation in microbiota community structure between samples. Relative abundances of multiple genera differed between 3- and 6-hour diaper change groups over time. Discussion/Conclusion: The diversity and composition of the diapered skin microbiota is dynamic over time and differs from other body sites. Multiple factors including interindividual effects, diaper change frequency, diet, and antibiotics contribute to variation in the diapered skin microbiota. [ABSTRACT FROM AUTHOR]

This study examines the impact of the COVID-19 pandemic on individuals' mental health and their online interactions, particularly within Reddit's mental health communities. By analyzing data from 15 subreddits categorized into mental health and control groups from 2018 to 2022, we observed that forums dedicated to mental health exhibited higher levels of user engagement and received more supportive responses than those in other categories. However, as the pandemic evolved, a significant decrease in online support was noted, especially within these mental health groups. This decline hints at a risk of emotional burnout among users, which poses a particularly acute challenge for individuals grappling with mental health issues. Intimate relationships have also an impact on online expression of mental health. The research underscores the pandemic's effect on online support and interaction dynamics, signaling the necessity for a deeper understanding and the development of strategies to maintain support within online communities during times of crisis. [ABSTRACT FROM AUTHOR]

Advancing public health through prevention necessitates collaboration among public, private, and community actors. Only together can these different actors amass the resources, knowledge, and community outreach required to promote health. Recent studies have suggested that university medical centres (UMCs) can play a key role in regional prevention networks, given their capacity to initiate, coordinate, drive, and monitor large partnerships. Yet, the literature often refers to prevention activities in general, leaving underexplored what UMCs can add to primary, universal prevention networks specifically. Moreover, UMCs operate in a crowded field of other organizations with extensive experience in primary prevention, who will already have an idea about what role UMCs should play in the network. This article presents a case study examining the potential role of a UMC within a densely interconnected stakeholder environment in the surroundings of a large city in the Netherlands. Combining insights from public health studies and network governance research, and integrating data from various methods, this study concludes that UMCs can enhance their contributions to prevention by assuming the role of network servants rather than network leaders. Stakeholders consider public health authorities or municipal governments as more logical candidates for coordinating the network. Moreover, partners often perceive–deservedly or not–UMCs as overly focused on the medical aspects of prevention, potentially neglecting social interventions, and as favouring universal treatments over tailor-made community interventions. At the same time, partner organizations hope that the UMCs join collaborations within the community, using their expertise to measure the impact of interventions and leveraging their prestige to generate attention for primary prevention. By synthesizing theoretical insights from multiple disciplines and analysing the empirics of network leaderships through multiple methods, this study offers UMCs a contextually-informed perspective on how to position themselves effectively within primary prevention networks. [ABSTRACT FROM AUTHOR]

The bovine rumen contains a large consortium of residential microbes that release a variety of digestive enzymes for feed degradation. However, the utilization of these microbial enzymes is still limited because these rumen microorganisms are mostly anaerobes and are thus unculturable. Therefore, we applied a sequence-based metagenomic approach to identify a novel 2,445-bp glycoside hydrolase family 3 β-glucosidase gene known as BrGH3A from the metagenome of bovine ruminal fluid. BrGH3A β-glucosidase is a 92-kDa polypeptide composed of 814 amino acid residues. Unlike most glycoside hydrolases in the same family, BrGH3A exhibited a permuted domain arrangement consisting of an (α/β)6 sandwich domain, a fibronectin type III domain and a (β/α)8 barrel domain. BrGH3A exhibited greater catalytic efficiency toward laminaribiose than cellobiose. We proposed that BrGH3A is an exo-acting β-glucosidase from Spirochaetales bacteria that is possibly involved in the intracellular degradation of β-1,3-/1,4-mixed linkage glucans that are present in grass cell walls. BrGH3A exhibits rich diversity in rumen hydrolytic enzymes and may represent a member of a new clan with a permuted domain topology within the large family. [ABSTRACT FROM AUTHOR]

This body image study tests the viability of transferring a complex psychophysical paradigm from a controlled in-person laboratory task to an online environment. 172 female participants made online judgements about their own body size when viewing images of computer-generated female bodies presented in either in front-view or at 45-degrees in a method of adjustment (MOA) paradigm. The results of these judgements were then compared to the results of two laboratory-based studies (with 96 and 40 female participants respectively) to establish three key findings. Firstly, the results show that the accuracy of online and in-lab estimates of body size are comparable, secondly that the same patterns of visual biases in judgements are shown both in-lab and online, and thirdly online data shows the same view-orientation advantage in accuracy in body size judgements as the laboratory studies. Thus, this study suggests that that online sampling potentially represents a rapid and accurate way of collecting reliable complex behavioural and perceptual data from a more diverse range of participants than is normally sampled in laboratory-based studies. It also offers the potential for designing stratified sampling strategies to construct a truly representative sample of a target population. [ABSTRACT FROM AUTHOR]

Citation illustrates the link between citing and cited documents. Different aspects of achievements like the journal's impact factor, author's ranking, and peers' judgment are analyzed using citations. However, citations are given the same weight for determining these important metrics. However academics contend that not all citations can ever have equal weight. Predominantly, such rankings are based on quantitative measures and the qualitative aspect is completely ignored. For a fair evaluation, qualitative evaluation of citations is needed in addition to quantitative ones. Many existing works that use qualitative evaluation consider binary class and categorize citations as important or unimportant. This study considers multi-class tasks for citation sentiments on imbalanced data and presents a novel framework for sentiment analysis in in-text citations of research articles. In the proposed technique, features are retrieved using a convolutional neural network (CNN), and classification is performed using a voting classifier that combines Logistic Regression (LR) and Stochastic Gradient Descent (SGD). The class imbalance problem is handled by the synthetic minority oversampling technique (SMOTE). Extensive experiments are performed in comparison with the proposed approach using SMOTE-generated data and machine learning models by term frequency (TF), and term frequency-inverse document frequency (TF-IDF) to evaluate the efficacy of the proposed approach for citation analysis. It is found that the proposed voting classifier using CNN features achieves an accuracy, precision, recall, and F1 score of 0.99 for all. This work not only advances the field of sentiment analysis in academic citations but also underscores the importance of incorporating qualitative aspects in evaluating the impact and sentiments conveyed through citations. [ABSTRACT FROM AUTHOR]

Importance: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults. Observations: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science. Conclusions and relevance: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. Clinical trials.gov identifier: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011. [ABSTRACT FROM AUTHOR]

Background: Patients with Anorexia Nervosa (AN) exhibit significant cognitive and neural disturbances compared to healthy individuals when processing food and body-related stimuli. These disturbances not only contribute to the manifestation and chronification of their pathological eating behaviour but also underscore the complex interplay of cognitive, emotional, and neurobiological factors in AN. However, the precise underlying cognitive and neural mechanisms of these disturbances remain a compelling area of investigation. Methods: This study presents a protocol developed for conducting a cross-sectional quasi-experimental study using a mixed model ANOVA approach with a crossover design. Our participants will consist of 20 patients with an active diagnosis of AN, 20 Overweight/obese individuals, and 20 Healthy Controls (HCs) with a normal BMI. An integrated eye-tracking and EEG methodology will be used in conjunction, with the primary aim of assessing participants' cognitive and neural processing towards high and low-calorie food stimuli. On an exploratory level, by utilizing the same methods, the present study will also investigate AN patients' responses towards high weight, normal weight, low weight, and self-body pictures, as well as towards images from the International Affective Picture System (IAPS) characterized by elevated valence and arousal levels. Additionally, behavioural methods such as yes or no questions, and self-reported questionnaires will be administered. The EEG and eye-tracking data will be analysed at early (50–300 ms) and late (350–500 ms) time intervals. Discussion: The investigation of the underlying cognitive and neural processes employed by patients with AN during the processing of food and body-related stimuli can help us develop a better understanding of the cognitive and neural mechanisms that contribute to the manifestation and maintenance of the disorder and assist in the development of more effective screening methods. Ethical approval and consent to participate: Ethical approval for the study has been obtained by the Cyprus National Bioethics Committee on 27.04.2023 (ΕΕΒΚ/ΕΠ/2023/19), and by the University of Cyprus (20.02.2023). Written informed consent will be obtained from all participants. [ABSTRACT FROM AUTHOR]

Freshwater salinization poses global challenges for aquatic organisms inhabiting urban streams, impacting their physiology and ecology. However, current salinization research predominantly focuses on mortality endpoints in limited model species, overlooking the sublethal effects on a broader spectrum of organisms and the exploration of adaptive mechanisms and pathways under natural field conditions. To address these gaps, we conducted high-throughput sequencing transcriptomic analysis on the gill tissue of the euryhaline fish Gasterosteus aculeatus, investigating its molecular response to salinity stress in the highly urbanized river Boye, Germany. We found that in stream sections with sublethal concentrations of chloride costly osmoregulatory systems were activated, evidenced by the differential expression of genes related to osmoregulation. Our enrichment analysis revealed differentially expressed genes (DEGs) related to transmembrane transport and regulation of transport and other osmoregulation pathways, which aligns with the crucial role of these pathways in maintaining biological homeostasis. Notably, we identified candidate genes involved in increased osmoregulatory activity under salinity stress, including those responsible for moving ions across membranes: ion channels, ion pumps, and ion transporters. Particularly, genes from the solute carrier family SLC, aquaporin AQP1, chloride channel CLC7, ATP-binding cassette transporter ABCE1, and ATPases member ATAD2 exhibited prominent differential expression. These findings provide insights into the potential molecular mechanisms underlying the adaptive response of euryhaline fish to salinity stress and have implications for their conservation and management in the face of freshwater salinization. [ABSTRACT FROM AUTHOR]

In Industry 4.0, the adoption of new technology has played a major role in the transportation sector, especially in the electric vehicles (EVs) domain. Nevertheless, consumer attitudes towards EVs have been difficult to gauge but researchers have tried to solve this puzzle. The prior literature indicates that individual attitudes and technology factors are vital to understanding users' adoption of EVs. Thus, the main aim is to meticulously investigate the unexplored realm of EV adoption within nations traditionally reliant on oil, exemplified by Saudia Arabia. By integrating the "task technology fit" (TTF) model and the "unified theory of acceptance and usage of technology" (UTAUT), this research develops and empirically validates the framework. A cross-section survey approach is adopted to collect 273 valid questionnaires from customers through convincing sampling. The empirical findings confirm that the integration of TTF and UTAUT positively promotes users' adoption of EVs. Surprisingly, the direct effect of TTF on behavioral intentions is insignificant, but UTAUT constructs play a significant role in establishing a significant relationship. Moreover, the UTAUT social influence factor has no impact on the EVs adoption. This groundbreaking research offers a comprehensive and holistic methodology for unravelling the complexities of EV adoption, achieved through the harmonious integration of two well-regarded theoretical frameworks. The nascent of this research lies in the skilful blending of technological and behavioral factors in the transportation sector. [ABSTRACT FROM AUTHOR]

Deficits in social cognition in attention deficit hyperactivity disorder (ADHD) have been associated with difficulties in functioning. Since recognizing emotional facial expressions is essential for developing the perceptual components of the theory of mind (ToM), it is important to assess this relationship in children with ADHD. This study therefore compared the recognition of emotional stimuli and gaze patterns between children with ADHD and healthy children using eye-tracking with dynamic facial images. It also examined the relationship between facial emotion recognition accuracy, gaze patterns, ToM scores, and ADHD symptoms. Children with ADHD aged 8–13 (n = 47) and a control group (n = 38) completed a facial emotion recognition test, ToM tests, and the Conners' Parent Rating Scale. Participants' gaze patterns in response to dynamic facial emotion expressions were recorded using eye-tracking technology. Children with ADHD exhibited significantly lower accuracy in the recognition of the facial expressions of disgust and anger. The percentage fixation in the eye region was also significantly lower for happy, angry, sad, disgusted, and neutral emotions in the children with ADHD compared to the control group. No relationship was determined between the percentage of fixations on facial areas of interests and ADHD symptoms or ToM tests. This study provides evidence that children with ADHD experience deficits in visual attention to emotional cues. In addition, it suggests that facial emotion recognition deficits in children with ADHD represent a separate domain of social cognition that develops independently of ToM skills and core symptoms. Understanding and treating the social difficulties of individuals with ADHD may help improve their social functioning. [ABSTRACT FROM AUTHOR]

The molecular pathogenesis of Hepatocellular Carcinoma (HCC) is a complex process progressing from premalignant stages to cancer in a stepwise manner. Mostly, HCC is detected at advanced stages, leading to high mortality rates. Hence, characterising the molecular underpinnings of HCC from normal to cancer state through precancerous state may help in early detection and improve its prognosis and treatment. In this work, we analysed the transcriptomic profile of tumour and premalignant samples from HCC or chronic liver disease patients, who had undergone either total or partial hepatectomy. The normal samples from patients with metastatic cancer/polycystic liver disease/ cholangiocarcinoma were also included. A gene co-expression network approach was applied to identify hierarchical changes: modules, pathways, and genes related to different trajectories of HCC and patient survival. Our analysis shows that the progression from premalignant conditions to tumour is accompanied by differences in the downregulation of genes associated with HNF4A activity and the immune system and upregulation of cell cycle genes, bringing about variability in patient outcomes. However, an increase in immune and cell cycle activity is observed in premalignant samples. Interestingly, co-expression modules and genes from premalignant stages are associated with survival. THBD, a classical marker for dendritic cells, is a predictor of survival at the premalignant stage. Further, genes linked to microtubules, kinetochores, and centromere are altered in both premalignant and tumour conditions and are associated with survival. Our analysis revealed a three-way molecular axis of liver function, immune pathways, and cell cycle driving HCC pathogenesis. [ABSTRACT FROM AUTHOR]