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BACKGROUND: Tau is aberrantly acetylated in various neurodegenerative conditions, including Alzheimers disease, frontotemporal lobar degeneration (FTLD), and traumatic brain injury (TBI). Previously, we reported that reducing acetylated tau by pharmacologically inhibiting p300-mediated tau acetylation at lysine 174 reduces tau pathology and improves cognitive function in animal models. METHODS: We investigated the therapeutic efficacy of two different antibodies that specifically target acetylated lysine 174 on tau (ac-tauK174). We treated PS19 mice, which harbor the P301S tauopathy mutation that causes FTLD, with anti-ac-tauK174 and measured effects on tau pathology, neurodegeneration, and neurobehavioral outcomes. Furthermore, PS19 mice received treatment post-TBI to evaluate the ability of the immunotherapy to prevent TBI-induced exacerbation of tauopathy phenotypes. Ac-tauK174 measurements in human plasma following TBI were also collected to establish a link between trauma and acetylated tau levels, and single nuclei RNA-sequencing of post-TBI brain tissues from treated mice provided insights into the molecular mechanisms underlying the observed treatment effects. RESULTS: Anti-ac-tauK174 treatment mitigates neurobehavioral impairment and reduces tau pathology in PS19 mice. Ac-tauK174 increases significantly in human plasma 24 h after TBI, and anti-ac-tauK174 treatment of PS19 mice blocked TBI-induced neurodegeneration and preserved memory functions. Anti-ac-tauK174 treatment rescues alterations of microglial and oligodendrocyte transcriptomic states following TBI in PS19 mice. CONCLUSIONS: The ability of anti-ac-tauK174 treatment to rescue neurobehavioral impairment, reduce tau pathology, and rescue glial responses demonstrates that targeting tau acetylation at K174 is a promising neuroprotective therapeutic approach to human tauopathies resulting from TBI or genetic disease.

Abstract Background Self-directed violence (SDV) comprises both suicide and self-injury and represents a pressing problem among incarcerated persons. Negative impacts of SDV in correctional settings also extend to behavioral health clinicians (BHCs) (e.g., job turnover). Correctional SDV risk assessment and management standards include staff training as part of the comprehensive approach. The Core Competency Model for Corrections (CCM-C) is a novel, evidence-informed training program for BHCs covering both clinician self-management and clinical care skills. Methods This pilot trial is a type 3 hybrid implementation–effectiveness approach. It will employ a wait-list control sequential cross-over design. Participants (N = 50–100) will be BHCs employed by the North Carolina Department of Adult Corrections. Following stratification for years of clinical experience, BHCs will be randomly assigned to (1) a training group that receives CCM-C immediately and (2) a wait-list control receiving CCM-C approximately 6 weeks later. Electronically administrated survey evaluation will occur across baseline and two follow-up (i.e., 2 weeks after each training session) time points. Discussion The primary outcome is feasibility assessed through collaboration with a Corrections Advisory Panel and feedback from BHCs. Secondary effectiveness outcomes that will be evaluated over time include SDV-related knowledge, attitudes, stigma, and intent to use training content. We will examine a tertiary outcome, namely compassion fatigue. Clinical trial limitations and impacts are discussed. Trial registration Clinicaltrials.gov, NCT06359574. This study was registered on 04/05/2024.

Abstract Background Adverse childhood experiences (ACEs) are important factors for population mental and physical health. While considerable public health literature demonstrates the global relevance of ACEs, more recent research shows that benevolent childhood experiences (BCEs) might be important to consider in their direct and mitigating roles for psychological distress and other mental health outcomes. There is little evidence of latent class examinations involving both ACEs and BCEs among adults in western nations. The present study sought to replicate and extend prior literature by: (1) assessing the extent to which past latent class groupings reproduce in present samples, and (2) analyzing the association of latent classes of childhood experiences with psychological distress and suicidal thoughts and behaviours (STBs). We examined psychological distress (i.e., depression, anxiety, post-traumatic stress, general wellbeing) and STBs (i.e., suicidal ideation, self-harm ideation and behaviour, entrapment, and defeat). Method Data were drawn from two nationwide cross-sectional online survey studies in the United Kingdom. The first sample (N = 488) was drawn from a study on suicidal behaviour, and the second sample (N = 447) was from a study concerning risk for interpersonal violence. Results Results largely replicated an existing four class solution of childhood experiences: Class 1 (Moderate ACEs/High BCEs; 17.6%), Class 2 (High ACEs/Moderate BCEs; 15.3%), Class 3 (Low ACEs/High BCEs; 48.3%), and Class 4 (Low ACEs/Moderate BCEs; 18.8%). Class 2 (High ACEs/Moderate BCEs) was associated with consistently worse psychological distress and STBs. Classes containing high BCEs (1 and 3) were characterized by generally lower levels of psychological distress and STBs. Conclusions Results affirm the potential value for jointly considering ACEs and BCEs to understand psychological distress and STBs. ACEs and BCEs may serve foundational roles in theories of suicide. The protective role of BCEs hypothesized in resiliency theory may be supported. Prevention practice and research implications are discussed.

Abstract Background Surfactant is a well-established therapy for preterm neonates affected by respiratory distress syndrome (RDS). The goals of different methods of surfactant administration are to reduce the duration of mechanical ventilation and the severity of bronchopulmonary dysplasia (BPD); however, the optimal administration method remains unknown. This study compares the effectiveness of the INtubate-RECruit-SURfactant-Extubate (IN-REC-SUR-E) technique with the less-invasive surfactant administration (LISA) technique, in increasing BPD-free survival of preterm infants. This is an international unblinded multicenter randomized controlled study in which preterm infants will be randomized into two groups to receive IN-REC-SUR-E or LISA surfactant administration. Methods In this study, 382 infants born at 24+0–27+6 weeks’ gestation, not intubated in the delivery room and failing nasal continuous positive airway pressure (nCPAP) or nasal intermittent positive pressure ventilation (NIPPV) during the first 24 h of life, will be randomized 1:1 to receive IN-REC-SUR-E or LISA surfactant administration. The primary outcome is a composite outcome of death or BPD at 36 weeks’ postmenstrual age. The secondary outcomes are BPD at 36 weeks’ postmenstrual age; death; pulse oximetry/fraction of inspired oxygen; severe intraventricular hemorrhage; pneumothorax; duration of respiratory support and oxygen therapy; pulmonary hemorrhage; patent ductus arteriosus undergoing treatment; percentage of infants receiving more doses of surfactant; periventricular leukomalacia, severe retinopathy of prematurity, necrotizing enterocolitis, sepsis; total in-hospital stay; systemic postnatal steroids; neurodevelopmental outcomes; and respiratory function testing at 24 months of age. Randomization will be centrally provided using both stratification and permuted blocks with random block sizes and block order. Stratification factors will include center and gestational age (24+0 to 25+6 weeks or 26+0 to 27+6 weeks). Analyses will be conducted in both intention-to-treat and per-protocol populations, utilizing a log-binomial regression model that corrects for stratification factors to estimate the adjusted relative risk (RR). Discussion This trial is designed to provide robust data on the best method of surfactant administration in spontaneously breathing preterm infants born at 24+0–27+6 weeks’ gestation affected by RDS and failing nCPAP or NIPPV during the first 24 h of life, comparing IN-REC-SUR-E to LISA technique, in increasing BPD-free survival at 36 weeks’ postmenstrual age of life. Trial registration ClinicalTrials.gov NCT05711966. Registered on February 3, 2023.

Abstract Background Tau is aberrantly acetylated in various neurodegenerative conditions, including Alzheimer’s disease, frontotemporal lobar degeneration (FTLD), and traumatic brain injury (TBI). Previously, we reported that reducing acetylated tau by pharmacologically inhibiting p300-mediated tau acetylation at lysine 174 reduces tau pathology and improves cognitive function in animal models. Methods We investigated the therapeutic efficacy of two different antibodies that specifically target acetylated lysine 174 on tau (ac-tauK174). We treated PS19 mice, which harbor the P301S tauopathy mutation that causes FTLD, with anti-ac-tauK174 and measured effects on tau pathology, neurodegeneration, and neurobehavioral outcomes. Furthermore, PS19 mice received treatment post-TBI to evaluate the ability of the immunotherapy to prevent TBI-induced exacerbation of tauopathy phenotypes. Ac-tauK174 measurements in human plasma following TBI were also collected to establish a link between trauma and acetylated tau levels, and single nuclei RNA-sequencing of post-TBI brain tissues from treated mice provided insights into the molecular mechanisms underlying the observed treatment effects. Results Anti-ac-tauK174 treatment mitigates neurobehavioral impairment and reduces tau pathology in PS19 mice. Ac-tauK174 increases significantly in human plasma 24 h after TBI, and anti-ac-tauK174 treatment of PS19 mice blocked TBI-induced neurodegeneration and preserved memory functions. Anti-ac-tauK174 treatment rescues alterations of microglial and oligodendrocyte transcriptomic states following TBI in PS19 mice. Conclusions The ability of anti-ac-tauK174 treatment to rescue neurobehavioral impairment, reduce tau pathology, and rescue glial responses demonstrates that targeting tau acetylation at K174 is a promising neuroprotective therapeutic approach to human tauopathies resulting from TBI or genetic disease.

Objective: To compare the safety profile and clinical outcomes of Altieri-modified Nesbit corporoplasty using two different anesthesia methods including spinal anesthesia and local anesthesia. Materials and methods: A total of 40 patients with congenital penile curvature (CPC) and Peyronie’s disease (PD) underwent Altieri-modified Nesbit corporoplasty. Group 1 (n = 20) received spinal anesthesia, and Group 2 (n = 20) received local anesthesia. The patients were categorized into age groups (< 30 years, 31-45 years, 46-60 years, and 61-75 years) for analysis. Clinical outcomes, post-operative complications, hospital stay, pain levels, and other parameters were assessed. Results: The results showed that 2 patients (10%) reported postoperative complications, including headache, arterial hypotension, and penile foreskin necrosis from the spinal anesthesia group. Whereas, in the local anesthesia group, 1 patient (5%) reported scar phimosis. Further, post-operative pain was predominantly very mild, with 16 patients (80%) in the spinal anesthesia group and 14 patients (70%) in the local anesthesia group experiencing minimal discomfort. Age did not significantly impact hospital stay, post-operative intestinal disorders, constipation, lower urinary tract symptoms, voiding burning, or dysuria. Conclusions: Spinal anesthesia may lead to more post-operative complications and longer hospital stays compared to local anesthesia. Age does not significantly affect most clinical outcomes but can influence post-operative pain in patients receiving local anesthesia.

Infertility is usually defined as the inability of a couple to conceive even after 1 year of unprotected, frequent sexual intercourse. The male is solely responsible in about 20% of cases. Several risk factors as well as urogenital abnormalities,endocrinological disease,enviromental toxines,genetic disorders,immunological factors,urogenitaly infections,sexual dysfunction have been identified as causes of male infertility. Nowadays different studies reported mithocoldrial dysfunction as cause of male infertility and alteration of semen parameters.

Abstract The distribution of earthquakes in stable intracontinental tectonic settings is typically far more diffuse than along plate boundaries and the causative mechanisms underlying some recognizable clustering are not understood. Here we show that seismicity in intraplate western and central Europe is largely limited to regions that exhibit a low-density layer in the uppermost lithospheric mantle and preferentially clustered above lateral gradients in upper mantle effective viscosity. The basis for these new insights into the thermal and density configuration of the upper mantle is provided by a shear-wave tomographic model. We propose that the spatial correlations between mantle low-density bodies and crustal seismicity reflect the importance of buoyancy forces within the mantle lithosphere. In addition, under the interaction of forces due to mantle gravitational instabilities, plate tectonics and postglacial rebound, the variably hot and strong mantle lithosphere responds by localized deformation which imposes differential loading on the overlying crust.

Abstract Cellular senescence is a stress response mechanism that induces proliferative arrest. Hypoxia can bypass senescence and extend the lifespan of primary cells, mainly by decreasing oxidative damage. However, how hypoxia promotes these effects prior to malignant transformation is unknown. Here we observed that the lifespan of mouse embryonic fibroblasts (MEFs) is increased when they are cultured in hypoxia by reducing the expression of p16 INK4a , p15 INK4b and p21 Cip1 . We found that proliferating MEFs in hypoxia overexpress Tfcp2l1, which is a main regulator of pluripotency and self-renewal in embryonic stem cells, as well as stemness genes including Oct3/4, Sox2 and Nanog. Tfcp2l1 expression is lost during culture in normoxia, and its expression in hypoxia is regulated by Hif1α. Consistently, its overexpression in hypoxic levels increases the lifespan of MEFs and promotes the overexpression of stemness genes. ATAC-seq and Chip-seq experiments showed that Tfcp2l1 regulates genes that control proliferation and stemness such as Sox2, Sox9, Jarid2 and Ezh2. Additionally, Tfcp2l1 can replicate the hypoxic effect of increasing cellular reprogramming. Altogether, our data suggest that the activation of Tfcp2l1 by hypoxia contributes to immortalization prior to malignant transformation, facilitating tumorigenesis and dedifferentiation by regulating Sox2, Sox9, and Jarid2.

The seismogenesis of rocks is mainly affected by their mineral composition and in situ conditions (temperature and state of stress). Diverse laboratory experiments have explored the frictional behaviour of the rocks and rock-forming minerals most common in the crust and uppermost mantle. However, it is debated how to “upscale” these results to the lithosphere. In particular, most earthquakes in the crust nucleate down to the crustal seismogenic depth (CSD), which is a proxy for the maximum depth of crustal earthquake ruptures in seismic hazard assessments. In this study we propose a workflow to upscale and validate those laboratory experiments to natural geological conditions relevant for crustal and upper-mantle rocks. We used the southern Caribbean and northwestern South America as a case study to explore the three-dimensional spatial variation of the CSD (mapped as D90, the 90 % percentile of hypocentral depths) and the temperatures at which crustal earthquakes likely occur. A 3D steady-state thermal field was computed for the region with a finite-element scheme using the software GOLEM, considering the uppermost 75 km of a previously published 3D data-integrative lithospheric configuration, lithology-constrained thermal parameters, and appropriate upper and lower boundary conditions. The model was validated using additional, independent measurements of downhole temperatures and heat flow. We found that the majority of crustal earthquakes nucleate at temperatures less than 350 ∘C, in agreement with frictional experiments of typical crustal rocks. A few outliers with larger hypocentral temperatures evidence nucleation conditions consistent with the seismogenic window of olivine-rich rocks, and can be due to either uncertainties in the Moho depths and/or in the earthquake hypocentres or the presence of ultramafic rocks within different crustal blocks and allochthonous terranes accreted to this complex margin. Moreover, the spatial distribution of crustal seismicity in the region correlates with the geothermal gradient, with no crustal earthquakes occurring in domains with low thermal gradient. Finally, we find that the largest earthquake recorded in the region (Mw=7.1, Murindó sequence, in 1992) nucleated close to the CSD, highlighting the importance of considering this lower-stability transition for seismogenesis when characterizing the depth of seismogenic sources in hazard assessments. The approach presented in this study goes beyond a statistical approach in that the local heterogeneity of physical properties is considered in our simulations and additionally validated by the observed depth distribution of earthquakes. The coherence of the calculated hypocentral temperatures with those expected from laboratory measurements provides additional support to our modelling workflow. This approach can be applied to other tectonic settings worldwide, and it could be further refined as new, high-quality hypocentral locations and heat flow and temperature observations become available.

BACKGROUND: Epidural analgesia may cause maternal hypotension and changes in the fetal heart rate. The implications of such side effects on the course of labor and delivery are incompletely understood. OBJECTIVE: This study aimed to assess whether the occurrence of maternal or fetal side effects associated with labor epidural analgesia increased the risk for cesarean delivery. STUDY DESIGN: This was a cohort study of all women who underwent epidural analgesia during labor for the period October 1, 2020 to December 31, 2020. Excluded were cases of multiples, fetal death, noncephalic presentation, and gestational age at birth 20% below the last value before epidural analgesia was administered, was related to changes in the fetal heart rate category. The principal outcome was cesarean delivery rate; binary logistic regression analysis was used to control for confounders, and mediation model analysis was used to quantify the extent to which significant variables participated in the causation pathway to cesarean delivery (SPSS version 28 was used for the analyses). RESULTS: A total of 439 women met the study criteria. Significant adverse reactions owing to epidural occurred in 184 of 439 women (41.9%) and included severe maternal hypotension in 159 of 439 participants (36.2%) and worsening fetal heart rate category in 50 of 439 participants (11.4%). The logistic regression analysis revealed that cervical dilation at epidural (P=.03), the duration of labor after epidural (P

Studies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, and cognitive decline have heightened the allure of tau and tau-related mechanisms as therapeutic targets. In February 2020, leading tau experts from around the world convened for the first-ever Tau2020 Global Conference in Washington, DC, co-organized and cosponsored by the Rainwater Charitable Foundation, the Alzheimer's Association, and CurePSP. Representing academia, industry, government, and the philanthropic sector, presenters and attendees discussed recent advances and current directions in tau research. The meeting provided a unique opportunity to move tau research forward by fostering global partnerships among academia, industry, and other stakeholders and by providing support for new drug discovery programs, groundbreaking research, and emerging tau researchers. The meeting also provided an opportunity for experts to present critical research-advancing tools and insights that are now rapidly accelerating the pace of tau research.

Abstract Continental deformation is known to be controlled by the interplay between tectonic and gravitational forces modulated by thermal relaxation-controlled lithospheric strength leading to oscillations around an equilibrium state, or to runaway extension. Using data-driven thermomechanical modelling of the Alpine Himalayan Collision Zone, we demonstrate how deviations from an equilibrium between mantle dynamics, plate-boundary forces, and the thermochemical configuration of the lithosphere control continental deformation. We quantify such balance between the internal energy of the plate and tectonic forces in terms of a critical crustal thickness, that match the global average of present-day continental crust. It follows that thicker intraplate domains than the critical crust (orogens) must undergo weakening due to their increased internal energy, and, in doing so, they dissipate the acquired energy within a diffused zone of deformation, unlike the localized deformation seen along plate boundaries. This evolution is controlled by a dissipative thermodynamic feedback loop between thermal and mechanical relaxation of the driving energy in the orogenic lithosphere. Exponentially growing energy states, leading to runaway extension are efficiently dampened by enhanced dissipation from radioactive heat sources. This ultimately drives orogens with their thickened radiogenic crust towards a final equilibrium state. Our results suggest a genetic link between the thermochemical state of the crust and the tectonic evolution of silicate Earth-like planets.

Abstract We analyzed the inclusion of sex and/or gender (S/G) in Head and Neck Cancer (HNC) clinical studies, through inspecting ClinicalTrials.gov (AACT) and the mention of Human Papilloma Virus (HPV) on a specific subgroup, namely oral cavity, larynx and oropharynx. Only 5% of HNC studies mention S/G as a planned analytical variable. Proportionally more observational studies treated S/G as an analytical variable than interventional studies (10% vs 5%, P-value ≤ 0.001), 8% of studies that mentioned S/G involved more than 100 subjects while 4% less than 100 (P-value ≤ 0.001). In randomized protocols, S/G was mentioned more in studies with a planned sample of more than 100 patients and including HPV status (P-value

The objective of this study is to demonstrate the potential of a multicompartmental mathematical model to simulate the activity of the gastrointestinal system after the intake of drugs, with a limited number of parameters. The gastrointestinal system is divided into five compartments, modeled as both continuous systems with discrete events (stomach and duodenum) and systems with delay (jejunum, ileum, and colon). The dissolution of the drug tablet occurs in the stomach and is described through the Noyes–Whitney equation, with pH dependence expressed through the Henderson–Hasselbach relationship. The boluses resulting from duodenal activity enter the jejunum, ileum, and colon compartments, where drug absorption takes place as blood flows countercurrent. The model includes only three parameters with assigned physiological meanings. It was tested and validated using data from in vivo experiments. Specifically, the model was tested with the concentration profiles of nine different drugs and validated using data from two drugs with varying initial concentrations. Overall, the outputs of the model are in good agreement with experimental data, particularly with regard to the time of peak concentration. The primary sources of discrepancy were identified in the concentration decay. The model’s main strength is its relatively low computational cost, making it a potentially excellent tool for in silico assessment and prediction of drug adsorption in the intestine.

The use of reclaimed wastewater for irrigation could result in the release of pharmaceutically active compounds (PhACs) and their metabolites into the agroecosystem. In this study, we investigated the fate of carbamazepine (CBZ) and its metabolites, with the aim of clarifying their behavior in a soil–plant system in a greenhouse experiment. The research was carried out using irrigation water especially fortified with high doses of CBZ (200 or 600 ppb) in order to evaluate the dynamics of CBZ and its metabolites in the soil and basil organs. The results of the study showed that CBZ is easily absorbed by the aerial part of the basil plant. The soil contained two metabolites of CBZ, namely acridine and carbamazepine-10,11-epoxide, as revealed by high-resolution mass spectrometry analyses. In addition, acridine was found in the aerial parts of basil plants. Furthermore, the greater presence of CBZ and its metabolites in bulk soil indicated a positive role of the basil rhizosphere in the degradation of such compounds or a positive role of the plant in the removal of the contaminant by uptake. Considering the observed morphological parameters and the mean CBZ content in wastewater, significantly lower than that used in the experiment, basil can be considered resistant to the application of irrigation water contaminated with CBZ.