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The Hira complex regulates Gli3R-dependent transcription in Hedgehog signaling and medulloblastoma cell growth and migration
TILTomorrow today: dynamic factors predicting changes in intracranial pressure treatment intensity after traumatic brain injury
AbstractPractices for controlling intracranial pressure (ICP) in traumatic brain injury (TBI) patients admitted to the intensive care unit (ICU) vary considerably between centres. To help understand the rational basis for such variance in care, this study aims to identify the patient-level predictors of changes in ICP management. We extracted all heterogeneous data (2008 pre-ICU and ICU variables) collected from a prospective cohort (n = 844, 51 ICUs) of ICP-monitored TBI patients in the Collaborative European NeuroTrauma Effectiveness Research in TBI study. We developed the TILTomorrow modelling strategy, which leverages recurrent neural networks to map a token-embedded time series representation of all variables (including missing values) to an ordinal, dynamic prediction of the following day’s five-category therapy intensity level (TIL(Basic)) score. With 20 repeats of fivefold cross-validation, we trained TILTomorrow on different variable sets and applied the TimeSHAP (temporal extension of SHapley Additive exPlanations) algorithm to estimate variable contributions towards predictions of next-day changes in TIL(Basic). Based on Somers’ Dxy, the full range of variables explained 68% (95% CI 65–72%) of the ordinal variation in next-day changes in TIL(Basic) on day one and up to 51% (95% CI 45–56%) thereafter, when changes in TIL(Basic) became less frequent. Up to 81% (95% CI 78–85%) of this explanation could be derived from non-treatment variables (i.e., markers of pathophysiology and injury severity), but the prior trajectory of ICU management significantly improved prediction of future de-escalations in ICP-targeted treatment. Whilst there was no significant difference in the predictive discriminability (i.e., area under receiver operating characteristic curve) between next-day escalations (0.80 [95% CI 0.77–0.84]) and de-escalations (0.79 [95% CI 0.76–0.82]) in TIL(Basic) after day two, we found specific predictor effects to be more robust with de-escalations. The most important predictors of day-to-day changes in ICP management included preceding treatments, age, space-occupying lesions, ICP, metabolic derangements, and neurological function. Serial protein biomarkers were also important and may serve a useful role in the clinical armamentarium for assessing therapeutic needs. Approximately half of the ordinal variation in day-to-day changes in TIL(Basic) after day two remained unexplained, underscoring the significant contribution of unmeasured factors or clinicians’ personal preferences in ICP treatment. At the same time, specific dynamic markers of pathophysiology associated strongly with changes in treatment intensity and, upon mechanistic investigation, may improve the timing and personalised targeting of future care.
Hypoxia-tolerant polymeric photosensitizer prodrug for cancer photo-immunotherapy
Intratumor heterogeneity of EGFR expression mediates targeted therapy resistance and formation of drug tolerant microenvironment
AbstractEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are commonly used to treat non-small cell lung cancers with EGFR mutations, but drug resistance often emerges. Intratumor heterogeneity is a known cause of targeted therapy resistance and is considered a major factor in treatment failure. This study identifies clones of EGFR-mutant non-small cell lung tumors expressing low levels of both wild-type and mutant EGFR protein. These EGFR-low cells are intrinsically more tolerant to EGFR inhibitors, more invasive, and exhibit an epithelial-to-mesenchymal-like phenotype compared to their EGFR-high counterparts. The EGFR-low cells secrete Transforming growth factor beta (TGFβ) family cytokines, leading to increased recruitment of cancer-associated fibroblasts and immune suppression, thus contributing to the drug-tolerant tumor microenvironment. Notably, pharmacological induction of EGFR using epigenetic inhibitors sensitizes the resistant cells to EGFR inhibition. These findings suggest that intrinsic drug resistance can be prevented or reversed using combination therapies.
Self /other recognition and distinction in adolescents with anorexia nervosa: A pilot study using a double mirror paradigm
Background Abnormalities in body perception in patients affected by anorexia nervosa have been widely studied, but without explicit reference to their relationship to others and the social processes involved. Yet, there are a several arguments supporting impairments in interpersonal relationships in these patients. Notably, some evidence suggests that self/other distinction (SOD), the ability to distinguish one’s own body, actions and mental representations from those of others could be impaired. But research remains scarce in this area. Material and methods A single-centre, prospective pilot study was conducted to investigate, for the first time, self-recognition and SOD in seven adolescents with anorexia nervosa compared with matched healthy controls (HCs) using the "Alter Ego"TM double mirror paradigm. This innovative device allows the progressive morphing of one’s own face to that of another and vice versa between two subjects that interact on opposite sides of the device. Two judgement criteria were used: 1) M1: the threshold at which subjects start to recognize their own face during other-to-self morphing, and 2) M2: the threshold at which subjects start to recognize the other’s face during self-to-other morphing. In a second part, SOD was reassessed during five different sensorimotor tasks aimed at increasing body self-consciousness in participants with anorexia nervosa. Results The results showed that the participants with anorexia nervosa exhibited earlier self-recognition in the other-to-self sequence and delayed other-recognition in the self-to-other sequence. Furthermore, in contrast with that of HCs, the critical threshold for switching between self and other varied with the direction of morphing in anorexia nervosa participants. Finally, when participants with anorexia were seated in a chair with a backrest and footrest strengthening the median axis of their body, the self-recognition threshold (M1) increased significantly, approaching that of controls. Conclusions Although additional research is needed to replicate the results of this pilot study, it revealed the first behavioural evidence of altered SOD in individuals affected by anorexia nervosa through an embodied, semiecological face-recognition paradigm. The relationships between anomalies in body perception and alterations in interpersonal relationships are discussed within an integrative framework from phenomenology to neuroscience, and new research and therapeutic perspectives are presented.
In vitro assays identified thiohydantoins with anti-trypanosomatid activity and molecular modelling studies indicated possible selective CYP51 inhibition
Assessment of the efficacy of on-demand tegoprazan therapy in gastroesophageal reflux disease through a randomized controlled trial
Deciphering the effect of UM171 on human hematopoietic progenitor cell fate through clonal analysis
Dynamics of specialization in neural modules under resource constraints
AbstractThe brain is structurally and functionally modular, although recent evidence has raised questions about the extent of both types of modularity. Using a simple, toy artificial neural network setup that allows for precise control, we find that structural modularity does not in general guarantee functional specialization (across multiple measures of specialization). Further, in this setup (1) specialization only emerges when features of the environment are meaningfully separable, (2) specialization preferentially emerges when the network is strongly resource-constrained, and (3) these findings are qualitatively similar across several different variations of network architectures. Finally, we show that functional specialization varies dynamically across time, and these dynamics depend on both the timing and bandwidth of information flow in the network. We conclude that a static notion of specialization is likely too simple a framework for understanding intelligence in situations of real-world complexity, from biology to brain-inspired neuromorphic systems.
Comparison of core temperature using tracheal thermometer and pulmonary artery catheter in adult patients undergoing coronary artery bypass graft surgery
Background Monitoring core temperature is important for patients under anesthesia. Esophageal and pulmonary artery blood temperatures can be used for measuring core temperature during general anesthesia. However, these methods pose challenges, especially when the placement of an esophageal thermometer and pulmonary artery catheter (PAC) is either impractical or not the preferred approach. An endotracheal tube (ETT) with a thermometer on the cuff allows for the measurement of tracheal temperature, providing a suitable alternative to core temperature measurement. This study aimed to assess the clinical reliability and accuracy of the thermometer in the ETT in comparison to the core temperature measured using a PAC. Methods Eleven patients who underwent coronary artery bypass graft (CABG) surgery were enrolled in this study. The patients were intubated using an ETT equipped with a thermometer on the cuff, and a PAC was inserted. Temperature measurements of both the trachea and pulmonary artery blood were recorded at 5-minute intervals for 1 hour before starting cardiopulmonary bypass. The agreement between the two temperature measurement methods was investigated using the Bland-Altman plot with multiple measurements per subject, and the correlation was evaluated using the concordance correlation coefficient (CCC). Results Eleven patients with a total of 143 pairs of data were included for analysis. The mean difference between the tracheal and pulmonary artery temperatures was −0.10°C. The 95% limit of agreement (LoA), calculated as ± 1.96 standard deviation, ranged from −0.35°C to 0.15°C. The 95% confidence interval for the lower and upper LoA was −0.51°C to −0.27°C and 0.07°C to 0.31°C, respectively. The maximum allowed difference (Δ) was set at 0.5°C. The majority of temperature differences fell within the LoA and were well below the maximum allowed difference. The CCC was 0.95, which indicates a substantial strength of agreement. Conclusions The agreement between the tracheal and pulmonary artery temperature measurements using the ETT thermometer and pulmonary artery catheter, respectively, was found to be clinically reliable and accurate. Therefore, the tracheal temperature measurement can effectively represent the core temperature of the patients. Employing an ETT equipped with a thermometer on the cuff can serve as a reliable and independent method for measuring core temperature. Trial registration Clinical trial registration number: NCT05595616.
Prevalence and determinants of full vaccination coverage according to the national schedule among children aged 12–35 months in Ghana
Prognostic signature and therapeutic drug identification for dilated cardiomyopathy based on necroptosis via bioinformatics and experimental validation
Photoinduced hidden monoclinic metallic phase of VO2 driven by local nucleation
Exploring transition states of protein conformational changes via out-of-distribution detection in the hyperspherical latent space
Seroconversion and dynamics of IgG anti-SARS-CoV-2 antibodies during the pandemic: A two-month observation cohort study on the population of Sleman in Indonesia
Background This study describes the seroconversion and serodynamics of IgG antibodies against the RBD of SARS-CoV-2 in the general population of Sleman District, Yogyakarta Special Province. We aim to identify possible factors that correlate with the seroconversion and serodynamics of IgG antibodies against the RBD of SARS-CoV-2. Methods We performed a longitudinal study of the population at Health and Demographic Surveillance System (HDSS) Sleman, Yogyakarta, Indonesia. Study subjects were recruited between April and December 2021 using convenience sampling and were followed up 2 times, i.e. 4–5 and 8–9 weeks. The inclusion criteria for subjects were age ≥ 18 years, absence of flu-like symptoms, and negative COVID-19 by using GeNose C19® screening. A community-based survey on demographics, comorbidities and smoking habits were documented at baseline, while a history of vaccination, COVID-19-related symptoms, mobility, and preventive measures, weight and height as well as a venous blood draw, were collected at each visit. The anti-RBD-SARS-CoV-2 IgG antibody concentration from blood plasma was measured using chemiluminescent microplate immunoassay (CMIA). Descriptive analysis was performed based on IgG seropositivity by using chi-squared test or Fisher’s exact test, as appropriate. Logistic regression was subsequently performed to identify factors that were correlated with IgG seropositivity. Further, a grouping of subjects based on IgG seropositivity was done to analyze factors that might correlate with seroconversion and serodynamics of anti-RBD-SARS-CoV-2 IgG antibody. A P value ≤ 0.05 was considered to indicate a significant difference. Results Three hundred eighty-five (385) participants were analyzed. At baseline, 307 out of 385 (79.7%) subjects were seropositive for the IgG antibody against the RBD of SARS-CoV-2. Descriptive analysis showed that sex, marital status, smoking habits, obesity, vaccination status, and preventive measures were different between the IgG anti-RBD-SARS-CoV-2 seropositive and negative individuals (p≤ 0.05). Further analysis showed that, vaccination was the factor most strongly correlated with seropositivity [OR = 20.58; 95% CI 10.82, 39.15]. Based on the correlation, we separated subjects into 4 groups. Group 1 (seronegative-unvaccinated individuals; 50 subjects); Group 2 (seronegative-vaccinated individuals; 27 subjects); Group 3 (seropositive-unvaccinated individuals; 25 subjects); and Group 4 (seropositive-vaccinated individuals; 282 subjects). During monitoring, 27/49 (55.10%), 5/25 (20%), 9/22 (40.91%), and 27/257 (10.51%) of subjects in Group 1, 2, 3, and 4 respectively, received 1 or 2 doses of COVID19 vaccine. When comparing seroconversion at baseline and monitoring 2, positive IgG seroconversion was observed in Group 1 (from 0/51 (0%) to 23/49 (46.94%)) and Group 2 (from 0/27 (0%) to 10/25 (40%)), but negative seroconversion was observed in Group 4 (from 282/0 (100%) to 248/257 (96.50%)); while, all subjects in Group 3 remained seropositive at the end of monitoring. This evidence suggested for hybrid immunity, on which infection and vaccine simultaneously contributes to anti-RBD-SARS-CoV-2 IgG seroconversion. Conclusions A high seroprevalence of the IgG antibody against RBD-SARS-CoV-2 in the Sleman population was found to correlate with COVID-19 vaccination and as infection occurred, thus enhancing hybrid immunity. We also identified nonresponder and rapid antibody decaying individuals, that call for targeted vaccinations in addition to annual universal boosting.