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Ménière's disease (MD) is characterized by loss of balance and hearing disorders. Although there is known to be endolymphatic hydrops involved in the pathological process, the pathogenesis of the disease is still largely unclear. Approximately half of patients with MD suffer from depressive symptoms and high levels of several stress hormones were observed in MD and depression, simultaneously. Recently, gut microbes have been shown to influence the function of the central nervous system in humans through their metabolites. We studied the intestinal microbiota of 10 patients with MD and 11 healthy donors (HD). Significant negative correlations were found between disease duration and alpha diversity indexes of gut microbes in patients with MD. The relative abundance of the species Butyricicoccus ambiguous taxa was increased in patients with MD compared with that of HD. In contrast, Oscillospiraceae UCG-002/UCG-005 ambiguous taxa and Anaerovoracaceae (Eubacterium) brachy group uncultured bacterium were increased in the relative abundance of HD than that of patients with MD. The relative abundance of the Butyricicoccus species was positively correlated with disease duration. Thus, these compositional alterations of gut microbes in patients with MD are associated with inner ear pathologies, such as endolymphatic hydrops, by changing the metabolite profiles in the intestine. [ABSTRACT FROM AUTHOR]

Background: Because of growing concerns regarding repeated head trauma, in 2016, the United States Soccer Federation (USSF) banned headers for athletes aged ≤10 years and limited athletes aged 11 to 13 years to practicing headers for 30 minutes per week. Purpose: To assess whether the USSF header policy was associated with fewer soccer-related concussions after the 2015 season. Study Design: Descriptive epidemiology study. Methods: A retrospective cohort from the National Electronic Injury Surveillance System database was assessed. Age, sex, and injury type were extracted for all soccer-related emergency department visits between January 1, 2012, and December 31, 2023. Univariate and multiple regression analyses were used to assess concussions as a percentage of all soccer-related injuries based on sex, age group (6-9, 10-13, and 14-17 years), and year. The following time frames were assessed: 2012-2015, 2016-2019, and 2020-2023. Results: The proportion of concussions decreased from 8.2% of all soccer-related injuries in 2012-2015 to 6.1% in 2020-2023 (P <.01). The relative risk reduction for soccer-related concussions presenting to an emergency department in 2020-2023 compared with 2012-2015 was 25.6%. Overall, the proportion of concussions among 10- to 13-year-old and 14- to 17-year-old players was higher than for 6- to 9-year-old players (6.6% and 8.9% vs 4.9%, respectively; P <.01). Despite having a lower frequency of soccer-related injuries overall, female players had a greater proportion of concussions than male players (9.6% vs 6.2% of all soccer-related injuries; P <.01). In the multiple regression analysis, injuries that occurred in 2020-2023 were associated with lower odds of concussion compared with 2012-2015 (odds ratio [OR], 0.75 [95% CI, 0.69-0.81]). Compared with 6- to 9-year-old and male players, the 10- to 13-year-old (OR, 1.30 [95% CI, 1.16-1.45]), 14- to 17-year-old (OR, 1.79 [95% CI, 1.61-1.99]), and female players (OR, 1.53 [95% CI, 1.43-1.63]) were associated with higher odds of concussion. Conclusion: A 25.6% reduction in the relative risk of presenting to the emergency department with a soccer-related concussion was found when comparing 2020-2023 (after USSF header policy implementation) with 2012-2015 (before policy implementation). The USSF youth soccer header policy may improve player safety by reducing head impacts in the pediatric population. [ABSTRACT FROM AUTHOR]

Proteolysis-targeting chimeras (PROTACs) have been explored for the degradation of drug targets for more than two decades. However, only a handful of E3 ligase substrate receptors have been efficiently used. Downregulation and mutation of these receptors would reduce the effectiveness of such PROTACs. We recently developed potent ligands for DCAF1, a substrate receptor of EDVP and CUL4 E3 ligases. Here, we focus on DCAF1 toward the development of PROTACs for WDR5, a drug target in various cancers. We report four DCAF1-based PROTACs with endogenous and exogenous WDR5 degradation effects and high-resolution crystal structures of the ternary complexes of DCAF1-PROTAC-WDR5. The structures reveal detailed insights into the interaction of DCAF1 with various WDR5-PROTACs, indicating a significant role of DCAF1 loops in providing needed surface plasticity, and reflecting the mechanism by which DCAF1 functions as a substrate receptor for E3 ligases with diverse sets of substrates. The authors show that DCAF1, a substrate receptor of CUL4 and EDVP E3 ligases, can be recruited by PROTACs to degrade the cancer drug target, WDR5. They also report the crystal structures of PROTAC ternary complexes that reveal a significant role for loops in DCAF1 substrate recognition, a potential mechanism behind the diverse substrate specificity of DCAF1. [ABSTRACT FROM AUTHOR]

Background: Supporting the sleep health of surrogate decision-makers of patients in the intensive care unit is a research priority. However, few studies have approached sleep health as a multidimensional construct, instead focusing on 1 or 2 dimensions in isolation. Objective: To holistically examine the sleep health (satisfaction, timing, efficiency, duration) of surrogate decision-makers of critically ill patients. Methods: This secondary analysis involved surrogate decision-makers of incapacitated intensive care unit patients at a tertiary medical center in northeastern Ohio (n = 19). Sleep-health data were captured by means of a subjective scale (satisfaction) and objectively (timing, efficiency, duration) by means of a wrist-worn accelerometer (Actiwatch Spectrum Plus; Philips Respironics). Upon enrollment, participants completed the satisfaction scale and wore the Actiwatch Spectrum Plus for 3 consecutive days. Descriptive statistics of the study variables were evaluated. Results: A minority (15%) of the sample reported poor sleep satisfaction. Sleep timing variables were comparable to those found in other adult studies. Participants averaged approximately 6 hours of sleep per day with an average sleep efficiency of 83.7%. Conclusions: Despite adequate satisfaction scores, intensive care unit surrogate decision-makers' sleep duration is inadequate and sleep efficiency is suboptimal. Sleep-health interventions may be needed in this at-risk population. Future research should consider the impact of surrogate decision-maker sleep health on their capacity to serve in the surrogate decision-maker role. [ABSTRACT FROM AUTHOR]

Road dust resuspension in urban environments can contribute to high human exposure to metal(loid)s, polycyclic aromatic hydrocarbons, and other potentially toxic organic compounds. However, for many regions, information on loadings, emission factors and chemical profiles is lacking to accurately apply emission inventories and source apportionment models. In the present study, PM10 samples were collected with an in situ road dust sampler from eleven representative streets of Bragança, an inland city of the Iberian Peninsula, and were analysed for organic and elemental carbon by a thermal-optical technique, elemental composition by ICP-MS and ICP-OES, and ecotoxicity by a luminescence inhibition bioassay with Allivibrio fischeri. A global emission factor of 5.36 ± 2.35 mg veh−1 km−1 was obtained but in suburban areas the values reached twice the average. Total carbon accounted for 14.9 ± 6.8% of the PM10 mass, while element oxides represented the largest share (28.6 ± 18.7%). Very high enrichments were found for typical traffic-related elements such as Cu, Zn, S, Pb and Ni. The geochemical index Igeo further confirmed that road dust of the study region is extremely contaminated by elements mainly originated from tyre and brake wear. Although the total non-carcinogenic and carcinogenic risks associated with metal exposure were found to be low for both children and adults, the bioluminescence inhibition assay showed (eco)toxic responses for all samples, indicating that road dust resuspension may pose a significant human health and ecological threat. [ABSTRACT FROM AUTHOR]

Objective: Confined placental mosaicism (CPM) is associated with an increased risk for pregnancy complications, such as fetal growth restriction (FGR), preterm birth and hypertensive disorders. Pregnancies with possible CPM can be identified with non‐invasive prenatal testing (NIPT). We performed a retrospective cohort study to investigate whether the mosaic ratio, as calculated with the Veriseq v2 used for NIPT, can predict adverse pregnancy outcomes in cases of CPM. Method: A mosaic ratio for trisomies detected by NIPT and obstetric data such as fetal growth, structural fetal anomalies and birthweight were retrospectively studied in a cohort of patients with CPM diagnosed between February 2021 and October 2023. Structural and sex chromosomal aberrations were not included in this study. Results: Of 122 CPM cases, 52 cases (42.6%) showed adverse perinatal outcomes, including FGR, low birthweight, hypertensive disorders, or preterm birth. A significantly higher mosaic ratio was found in the adverse outcome group compared to those with normal outcome, but a clear‐cut threshold could not be set, except potentially for trisomy 16. Conclusion: There is an association between the mosaic ratio and adverse pregnancy outcomes in cases of CPM. However, without a clear‐cut threshold, it cannot be used for the individual patient for differentiation between CPM with and without clinical consequences. [ABSTRACT FROM AUTHOR]

Background and Objectives Cross-sectional studies have shown improvements in cognition in later-born cohorts. However, it remains unclear whether these cohort effects extend beyond cognitive levels and are also detectable in the rate of age-related cognitive decline. Additionally, evidence is scarce on the presence and consistency of cohort effects throughout different segments of the distribution of cognitive trajectories. Research Design and Methods This study evaluates the existence and variability of cohort effects across the entire distribution of aging-related trajectories of verbal fluency. With this purpose, we develop sex and education-adjusted longitudinal norms of verbal fluency using data from 9 waves of the English Longitudinal Study of Aging (ELSA) by fitting quantile mixed models. The effect of age was modeled using splines to assess birth cohort effects, after grouping individuals in 5-year groups from 1920 to 1950 according to their age at study entry. To test for possible cohort effects across the 10th, 50th, and 90th quantiles, the coefficients associated with the splines were allowed to vary among cohorts. Results Our results suggest that, consistently across longitudinal quantiles, decline in verbal fluency across age is less pronounced for later-born individuals (p  < .001), supporting the hypothesis of cohort effects. Additionally, we also found that quantiles of verbal fluency at any age are shifted upwards in later-born cohorts compared to those in earlier-born cohorts. Discussion and Implications These results enhance our understanding of cognitive decline in older adults by demonstrating that cohort effects on cognition are observable both cross-sectionally and longitudinally, affecting the entire range of verbal fluency trajectories. [ABSTRACT FROM AUTHOR]

Relational analytics—the leveraging of data on workplace relationships—acts as a complement to traditional people analytics and moves scholars and practitioners closer to an understanding of the realities of the modern workplace. This article serves as a primer for relational analytics by highlighting the potential of the perspective for human resources, the levels of analysis that can be used to study relational analytics, and some of the common theoretical perspectives employed in this area. We introduce the 15 articles in the special issue by positioning them within broader trends we see in the field of relational analytics. Finally, we provide commentary on challenges and future directions in relational analytics with a focus on how the articles in this special issue may serve as examples of best practices and inspiration for future research and practice. [ABSTRACT FROM AUTHOR]

Background: Research on circulating tumor cells (CTCs) offers the opportunity to better understand the initial steps of blood‐borne metastasis as main cause of cancer‐related deaths. Here, we have used the colon cancer CTC‐MCC‐41 and breast cancer CTC‐ITB‐01 lines, which were both established from human CTCs as permanent cell lines as models to further study CTC biology with special emphasis on anchorage‐independent survival and growth. Methods and Results: Both cell lines showed a marked intrinsic plasticity to switch between suspension and adherent in vitro growth, in 2D adherent culture conditions, and established an equilibrium of both growth patterns with predominant adherent cells in the CTC‐MCC‐41 line (77%) and suspension cells in the CTC‐ITB‐01 line (85%). Western blot analysis revealed a higher expression of pERK1/2 in CTC‐ITB‐01 adherent cells compared to the suspension counterpart that suggested the involvement of kinases in this process. Subsequent functional kinome profiling identified several serine/threonine as well as tyrosine kinases that were differentially regulated in adherent and suspension CTCs. In the adherent cells of the breast cancer line CTC‐ITB‐01 the activity of MSK1, Src family kinases and the PKG family was increased compared to the suspension counterpart. In adherent cells of the colorectal CTC‐MCC‐41 line, an increased activity of TYRO3 and JAK2 was detected, whereas p38 MAPK was strongly impaired in the suspension CTC‐MCC‐41 cells. Some of the regulated kinases, which include the Src family, TYRO3, MSK1, JAK2 and p38 MAPK, have been associated with crucial cellular processes including proliferation, migration and dormancy in the past. Conclusions: The investigated CTC lines exhibit a high plasticity, similar to the concept of 'adherent‐to‐suspension transition (AST)' that was recently suggested as a new hallmark of tumor biology by Huh et al. Moreover, we identified differentially regulated kinome profiles that may represent potential targets for future studies on therapeutic interventions. [ABSTRACT FROM AUTHOR]

The endogenous incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) possess neurotrophic, neuroprotective, and anti-neuroinflammatory actions. The dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin reduces degradation of endogenous GLP-1 and GIP, and, thereby, extends the circulation of these protective peptides. The current nonhuman primate (NHP) study evaluates whether human translational sitagliptin doses can elevate systemic and central nervous system (CNS) levels of GLP-1/GIP in naive, non-lesioned NHPs, in line with our prior rodent studies that demonstrated sitagliptin efficacy in preclinical models of Parkinson's disease (PD). PD is an age-associated neurodegenerative disorder whose current treatment is inadequate. Repositioning of the well-tolerated and efficacious diabetes drug sitagliptin provides a rapid approach to add to the therapeutic armamentarium for PD. The pharmacokinetics and pharmacodynamics of 3 oral sitagliptin doses (5, 20, and 100 mg/kg), equivalent to the routine clinical dose, a tolerated higher clinical dose and a maximal dose in monkey, were evaluated. Peak plasma sitagliptin levels were aligned both with prior reports in humans administered equivalent doses and with those in rodents demonstrating reduction of PD associated neurodegeneration. Although CNS uptake of sitagliptin was low (cerebrospinal fluid (CSF)/plasma ratio 0.01), both plasma and CSF concentrations of GLP-1/GIP were elevated in line with efficacy in prior rodent PD studies. Additional cellular studies evaluating human SH-SY5Y and primary rat ventral mesencephalic cultures challenged with 6-hydroxydopamine, established cellular models of PD, demonstrated that joint treatment with GLP-1 + GIP mitigated cell death, particularly when combined with DPP-4 inhibition to maintain incretin levels. In conclusion, this study provides a supportive translational step towards the clinical evaluation of sitagliptin in PD and other neurodegenerative disorders for which aging, similarly, is the greatest risk factor. [ABSTRACT FROM AUTHOR]

Epidemiological studies report an elevated risk of Parkinson's disease (PD) in patients with type 2 diabetes mellitus (T2DM) that is mitigated in those prescribed dipeptidyl peptidase 4 (DPP-4) inhibitors. With an objective to characterize clinically translatable doses of DPP-4 inhibitors (gliptins) in a well-characterized PD rodent model, sitagliptin, PF-00734,200 or vehicle were orally administered to rats initiated either 7-days before or 7-days after unilateral medial forebrain bundle 6-hydroxydopamine (6-OHDA) lesioning. Measures of dopaminergic cell viability, dopamine content, neuroinflammation and neurogenesis were evaluated thereafter in ipsi- and contralateral brain. Plasma and brain incretin and DPP-4 activity levels were quantified. Furthermore, brain incretin receptor levels were age-dependently evaluated in rodents, in 6-OHDA challenged animals and human subjects with/without PD. Cellular studies evaluated neurotrophic/neuroprotective actions of combined incretin administration. Pre-treatment with oral sitagliptin or PF-00734,200 reduced methamphetamine (meth)-induced rotation post-lesioning and dopaminergic degeneration in lesioned substantia nigra pars compacta (SNc) and striatum. Direct intracerebroventricular gliptin administration lacked neuroprotective actions, indicating that systemic incretin-mediated mechanisms underpin gliptin-induced favorable brain effects. Post-treatment with a threefold higher oral gliptin dose, likewise, mitigated meth-induced rotation, dopaminergic neurodegeneration and neuroinflammation, and augmented neurogenesis. These gliptin-induced actions associated with 70–80% plasma and 20–30% brain DPP-4 inhibition, and elevated plasma and brain incretin levels. Brain incretin receptor protein levels were age-dependently maintained in rodents, preserved in rats challenged with 6-OHDA, and in humans with PD. Combined GLP-1 and GIP receptor activation in neuronal cultures resulted in neurotrophic/neuroprotective actions superior to single agonists alone. In conclusion, these studies support further evaluation of the repurposing of clinically approved gliptins as a treatment strategy for PD. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) causes axon tearing and synapse degradation, resulting in multiple neurological dysfunctions and exacerbation of early neurodegeneration; the repair of axonal and synaptic structures is critical for restoring neuronal function. C-C Motif Chemokine Ligand 5 (CCL5) shows many neuroprotective activities. Method: A close-head weight-drop system was used to induce mild brain trauma in C57BL/6 (wild-type, WT) and CCL5 knockout (CCL5-KO) mice. The mNSS score, rotarod, beam walking, and sticker removal tests were used to assay neurological function after mTBI in different groups of mice. The restoration of motor and sensory functions was impaired in CCL5-KO mice after one month of injury, with swelling of axons and synapses from Golgi staining and reduced synaptic proteins-synaptophysin and PSD95. Administration of recombinant CCL5 (Pre-treatment: 300 pg/g once before injury; or post-treatment: 30 pg/g every 2 days, since 3 days after injury for 1 month) through intranasal delivery into mouse brain improved the motor and sensory neurological dysfunctions in CCL5-KO TBI mice. Results: Proteomic analysis using LC-MS/MS identified that the "Nervous system development and function"-related proteins, including axonogenesis, synaptogenesis, and myelination signaling pathways, were reduced in injured cortex of CCL5-KO mice; both pre-treatment and post-treatment with CCL5 augmented those pathways. Immunostaining and western blot analysis confirmed axonogenesis and synaptogenesis related Semaphorin, Ephrin, p70S6/mTOR signaling, and myelination-related Neuregulin/ErbB and FGF/FAK signaling pathways were up-regulated in the cortical tissue by CCL5 after brain injury. We also noticed cortex redevelopment after long-term administration of CCL5 after brain injury with increased Reelin positive Cajal-Rerzius Cells and CXCR4 expression. CCL5 enhanced the growth of cone filopodia in a primary neuron culture system; blocking CCL5's receptor CCR5 by Maraviroc reduced the intensity of filopodia in growth cone and also CCL5 mediated mTOR and Rho signalling activation. Inhibiting mTOR and Rho signaling abolished CCL5 induced growth cone formation. Conclusions: CCL5 plays a critical role in starting the intrinsic neuronal regeneration system following TBI, which includes growth cone formation, axonogenesis and synaptogensis, remyelination, and the subsequent proper wiring of cortical circuits. Our study underscores the potential of CCL5 as a robust therapeutic stratagem in treating axonal injury and degeneration during the chronic phase after mild brain injury. [ABSTRACT FROM AUTHOR]

The ability of morphine to decrease cysteine transport into neurons by inhibition of excitatory amino acid transporter 3 (EAA3) may be a key molecular mechanism underlying the acquisition of physical and psychological dependence to morphine. This study examined whether co-administration of the cell-penetrant antioxidant D-thiol ester, D-cysteine ethyl ester (D-CYSee), with morphine, would diminish the development of physical dependence to morphine in male Sprague Dawley rats. Systemic administration of the opioid receptor antagonist, naloxone (NLX), elicited pronounced withdrawal signs (e.g., wet-dog shakes, jumps, rears, circling) in rats that received a subcutaneous depot of morphine (150 mg/kg, SC) for 36 h and continuous intravenous infusion of vehicle (20 µL/h, IV). The NLX-precipitated withdrawal signs were reduced in rats that received an infusion of D-CYSee, but not D-cysteine, (both at 20.8 µmol/kg/h, IV) for the full 36 h. NLX elicited pronounced withdrawal signs in rats treated for 48 h with morphine (150 mg/kg, SC), plus continuous infusion of vehicle (20 µL/h, IV) that began at the 36 h timepoint of morphine treatment. The NLX-precipitated withdrawal signs were reduced in rats that received a 12 h infusion of D-CYSee, but not D-cysteine, (both at 20.8 µmol/kg/h, IV) that began at the 36 h timepoint of morphine treatment. These findings suggest that D-CYSee may attenuate the development of physical dependence to morphine and reverse established dependence to the opioid in male Sprague Dawley rats. Alternatively, D-CYSee may simply suppress the processes responsible for NLX-precipitated withdrawal. Nonetheless, D-CYSee and analogues may be novel therapeutics for the treatment of opioid use disorders. [ABSTRACT FROM AUTHOR]

Background and Objectives: Clearances and the area under the plasma concentration–time curve extrapolated to infinity (AUC0–∞) of intravenous (IV) and oral midazolam and alfentanil are probes for hepatic and first-pass cytochrome P450 3A (CYP3A) activity, drug interactions, and phenotyping. Single-time plasma concentrations are also used as a proxy for clearance and AUC0–∞. Pupil diameter change is a noninvasive surrogate for plasma alfentanil. An ideal probe should have minimal intrasubject (interday) variability. Despite their widespread use, the intrasubject variability of CYP3A probes is not well characterized. This investigation determined the intrasubject (interday) variability of midazolam and alfentanil metrics of hepatic and first-pass CYP3A. Methods: Twelve volunteers were studied in a four-period protocol, with each period identical and separated by approximately 2 weeks. In each period, participants received 1 mg IV midazolam then 15 μg/kg IV alfentanil 1 h later. The next day, they received 3 mg oral midazolam then 60 μg/kg oral alfentanil. Plasma drug concentrations were determined by liquid chromatography-mass spectrometry (LCMS). Dark-adapted pupil diameters were measured coincident with blood sampling. Plasma concentrations and pupil effects (miosis) were analyzed using noncompartmental methods. The results were the coefficient of variation (%CV, mean ± SD) across four sessions in 12 participants. Results: For IV midazolam: AUC0–∞, clearance, and 5 h concentration, the %CVs were 12 ± 3, 12 ± 3, and 18 ± 8. For IV alfentanil AUC0–∞, clearance, 2 h concentration, and area under the effect curve from time zero to infinity (AUEC0–∞), the %CVs were 16 ± 5, 15 ± 4, 22 ± 7, and 50 ± 28. For oral midazolam AUC0–∞, clearance, and 5 h concentration, %CVs were 19 ± 5, 18 ± 4, and 28 ± 11. For oral alfentanil: AUC0–∞, clearance, 4 h concentration, and AUEC0–∞, %CVs were 20 ± 4, 21 ± 4, 42 ± 26, and 37 ± 14. Conclusions: Midazolam and alfentanil had comparable intrasubject variabilities of clearance and AUC0–∞. Single-time point metrics had greater intrasubject variability than AUC0–∞ and clearance. Miosis was a surrogate for alfentanil concentrations and provided real-time results, but intrasubject variability was greater than that of clearances and AUC0–∞. [ABSTRACT FROM AUTHOR]

Background: Previous biomechanical studies have identified capsular closure, labral repair or reconstruction, and osteochondroplasty as important surgical interventions to improve hip stability. Purpose: To investigate the outcome metrics used to quantify hip stability and assess and measure the relative contributions of the labrum, capsule, and bone to hip stability through a quantitative analysis. Study Design: Systematic review and meta-analysis; Level of evidence, 4. Methods: PubMed and Embase databases were searched using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Included studies evaluated cadaveric hip biomechanics related to capsular, labral, and bony management during hip arthroscopy. Studies were assessed for distraction force and distance, fluid measures, and contact forces used to quantify the suction seal. Exclusion criteria included open surgery, arthroplasty, reorientation osteotomy, or traumatic dislocation. Results: A total of 33 biomechanical studies comprising 322 hips that evaluated 1 or more of the following were included: distraction force or distance (24 studies), fluid measures (10 studies), and contact forces (6 studies). Compared with a capsulotomy or capsulectomy, capsular repair or reconstruction demonstrated greater resistance to distraction (standardized mean difference [SMD], 1.13; 95% CI, 0.46-1.80; P =.0009). Compared with a labral tear, a labral repair or reconstruction demonstrated less resistance to distraction (SMD, −0.67; 95% CI, −1.25 to −0.09; P =.02). Compared with a labral debridement, repair or reconstruction demonstrated greater resistance to distraction (SMD, 1.74; 95% CI, 1.23 to 2.26; P <.00001). No quantitative analysis was feasible from studies evaluating the effect of osseous resection due to the heterogeneity in methodology and outcome metrics assessed. Conclusion: Most biomechanical evidence supports capsulotomy repair or reconstruction to improve hip distractive stability at the end of hip arthroscopic surgery. While the repair of a torn labrum does not improve distractive resistance, it is superior to labral debridement in most biomechanical studies. [ABSTRACT FROM AUTHOR]

The results of experimental research on the acoustic and electrical characteristics of underwater spark discharges facilitated by a preliminary discharge are presented. The latter was produced through the application of a short duration high-voltage pulse formed by a Marx generator. The application of this pulse lead to the formation of a low-density region in the form of a streamer which transformed to an oscillating vapor cavity. It was shown that this method provided a breakdown of a significantly increased interelectrode gap for the same charging voltage of the main capacitor and allowed the generation of stronger shocks. The temporal development of transient discharges in a long gap and the relationships between the hydrodynamic and electrical parameters of such discharges are reported and analyzed. [ABSTRACT FROM AUTHOR]

Inhibitory phosphatases, such as the inositol-5-phosphatase SHIP1 could potentially contribute to B-cell acute lymphoblastic leukemia (B-ALL) by raising the threshold for activation of the autoimmunity checkpoint, allowing malignant cells with strong oncogenic B-cell receptor signaling to escape negative selection. Here, we show that SHIP1 is differentially expressed across B-ALL subtypes and that high versus low SHIP1 expression is associated with specific B-ALL subgroups. In particular, we found high SHIP1 expression in both, Philadelphia chromosome (Ph)-positive and ETV6-RUNX1-rearranged B-ALL cells. As demonstrated by targeted knockdown of SHIP1 by RNA interference, proliferation of B-ALL cells in vitro and their tumorigenic spread in vivo depended in part on SHIP1 expression. We investigated the regulation of SHIP1, as an important antagonist of the AKT signaling pathway, by the B-cell-specific transcription factor Ikaros. Targeted restoration of Ikaros and pharmacological inhibition of the antagonistic casein kinase 2, led to a strong reduction in SHIP1 expression and at the same time to a significant inhibition of AKT activation and cell growth. Importantly, the tumor suppressive function of Ikaros was enhanced by a SHIP1-dependent additive effect. Furthermore, our study shows that all three AKT isoforms contribute to the pro-mitogenic and anti-apoptotic signaling in B-ALL cells. Conversely, hyperactivation of a single AKT isoform is sufficient to induce negative selection by increased oxidative stress. In summary, our study demonstrates the regulatory function of Ikaros on SHIP1 expression in B-ALL and highlights the relevance of sustained SHIP1 expression to prevent cells with hyperactivated PI3K/AKT/mTOR signaling from undergoing negative selection. [ABSTRACT FROM AUTHOR]

Background: The serotonin (5-HT) system can manipulate the processing of exogenous L-DOPA in the DA-denervated striatum, resulting in the modulation of L-DOPA-induced dyskinesia (LID). Objective: To characterize the effects of the serotonin precursor 5-hydroxy-tryptophan (5-HTP) or the serotonin transporter (SERT) inhibitor, Citalopram on L-DOPA-induced behavior, neurochemical signals, and underlying protein expressions in an animal model of Parkinson's disease. Methods: MitoPark (MP) mice at 20 weeks of age, subjected to a 14-day administration of L-DOPA/Carbidopa, displayed dyskinesia, referred to as LID. Subsequent investigations explored the effects of 5-HT-modifying agents, such as 5-HTP and Citalopram, on abnormal involuntary movements (AIMs), locomotor activity, neurochemical signals, serotonin transporter activity, and protein expression in the DA-denervated striatum of LID MP mice. Results: 5-HTP exhibited duration-dependent suppressive effects on developing and established LID, especially related to abnormal limb movements observed in L-DOPA-primed MP mice. However, Citalopram, predominantly suppressed abnormal axial movement induced by L-DOPA in LID MP mice. We demonstrated that 5-HTP could decrease L-DOPA-upregulation of DA turnover rates while concurrently upregulating 5-HT metabolism. Additionally, 5-HTP was shown to reduce the expressions of p-ERK and p-DARPP-32 in the striatum of LID MP mice. The effect of Citalopram in alleviating LID development may be attributed to downregulation of SERT activity in the dorsal striatum of LID MP mice. Conclusions: While both single injection of 5-HTP and Citalopram effectively mitigated the development of LID, the difference in mitigation of AIM subtypes may be linked to the unique effects of these two serotonergic agents on L-DOPA-derived DA and 5-HT metabolism. [ABSTRACT FROM AUTHOR]

This is a case of a woman in her 50s with HIV and uncontrolled diabetes who presented to the emergency department with urinary retention and a painful gluteal cleft lesion, admitted for cellulitis. Since initial CT and soft tissue ultrasound (US) were negative for fluid collection, the care team was surprised to find her symptoms continued to progress despite intravenous antibiotics. Finally, MRI 9 days into her admission demonstrated a 12-cm perirectal horseshoe abscess. The patient was ultimately treated with incision and drainage with Penrose drain placement. This case demonstrates the importance of maintaining a high suspicion for horseshoe abscess, a complex form of ischiorectal fossa abscess which can be missed on CT and US imaging, and which may expand rapidly in immunosuppressed patients. [ABSTRACT FROM AUTHOR]

Anterior cruciate ligament reconstruction (ACLR) is one of the most common orthopedic procedures, and huge variation exists in the surgical technique. Single bundle hamstrings autograft reconstruction is a common method and has good clinical outcomes. A criticism of the hamstrings autograft is a small graft diameter, often less than 8-mm, which has been associated with increased re-rupture rates. Several graft preparation techniques for single bundle hamstrings autograft exist. Perioperative decisions include the number of tendons utilized, number of graft strands, graft configuration, and femoral and tibial fixation methods. Awareness of the minimum tendon and graft length required to produce each graft variation is necessary to avoid common pitfalls. However, intraoperative graft modification is possible to maximize graft diameter, and obtain proper fixation. The objective of this current concepts review is to describe the indications, surgical anatomy, technique, intraoperative tips, clinical outcomes, and complications for single bundle hamstrings autograft preparation techniques in ACLR. [ABSTRACT FROM AUTHOR]

Heterotopic ossification is ectopic lamellar bone formation within soft tissue and can result in significant functional limitations. There are multiple underlying etiologies of HO including musculoskeletal trauma and traumatic brain injury. Intra‐articular HO of the knee is rare and is typically located within the cruciate ligaments. We report a case of a 24‐year‐old female who presented with worsening right knee pain and limited knee extension two and a half years after a motor vehicle crash with multiple lower extremity fractures. Physical examination of the knee revealed anterior pain, limited extension, and a palpable infrapatellar prominence. Imaging showed a retropatellar tendon, intra‐articular excrescence of bone proximal to the anterior tibial plateau. Diagnostic arthroscopy with a 70° arthroscope identified HO at the proximal anterior tibial plateau, which was excised with a high‐speed burr under direct visualization. At the three‐month follow‐up, the patient remained asymptomatic and returned to sport. Retropatellar tendon, intra‐articular anterior knee HO is a rare but debilitating clinical entity that can be successfully and safely managed with excision under direct visualization using a 70° arthroscope. [ABSTRACT FROM AUTHOR]

Over the past century, multichannel fluorescence imaging has been pivotal in myriad scientific breakthroughs by enabling the spatial visualization of proteins within a biological sample. With the shift to digital methods and visualization software, experts can now flexibly pseudocolor and combine image channels, each corresponding to a different protein, to explore their spatial relationships. We thus propose psudo, an interactive system that allows users to create optimal color palettes for multichannel spatial data. In psudo, a novel optimization method generates palettes that maximize the perceptual differences between channels while mitigating confusing color blending in overlapping channels. We integrate this method into a system that allows users to explore multi‐channel image data and compare and evaluate color palettes for their data. An interactive lensing approach provides on‐demand feedback on channel overlap and a color confusion metric while giving context to the underlying channel values. Color palettes can be applied globally or, using the lens, to local regions of interest. We evaluate our palette optimization approach using three graphical perception tasks in a crowdsourced user study with 150 participants, showing that users are more accurate at discerning and comparing the underlying data using our approach. Additionally, we showcase psudo in a case study exploring the complex immune responses in cancer tissue data with a biologist. [ABSTRACT FROM AUTHOR]

Introduction: This study sought to determine the effect of Occupational Safety and Health Administration (OSHA) compliant noise on auditory health and assess whether pre-noise near infrared (NIR) light therapy can mitigate the effects of noise exposure. Methods: Over four visits, participants (n = 30, NCT#: 03834714) with normal hearing completed baseline hearing health assessments followed by exposure to open ear, continuous pink noise at 94 dBA for 15 min. Immediately thereafter, post-noise hearing tests at 3000, 4000, and 6000 Hz and distortion product otoacoustic emissions (DPOAEs) were conducted along with the Modified Rhyme Test (MRT), Masking Level Difference Test (MLD), and Fixed Level Frequency Tests (FLFT) [collectively referred to as the Central and Peripheral Auditory Test Battery (CPATB)] to acquire baseline noise sensitivity profiles. Participants were then randomized to either Active or Sham NIR light therapy for 30 min binaurally to conclude Visit 1. Visit 2 (=24 and = 48 h from Visit 1) began with an additional 30-min session of Active NIR light therapy or Sham followed by repeat CPATB testing and noise exposure. Post-noise testing was again conducted immediately after noise exposure to assess the effect of NIR light therapy. The remaining visits were conducted following =2 weeks of noise rest in a cross-over design (i.e., those who had received Active NIR light therapy in Visits 1 and 2 received Sham therapy in Visits 3 and 4). Results: Recovery hearing tests and DPOAEs were completed at the end of each visit. Participants experienced temporary threshold shifts (TTS) immediately following noise exposure, with a mean shift of 6.79 dB HL (±6.25), 10.61 dB HL (±6.89), and 7.30 dB HL (±7.25) at 3000, 4000, and 6000 Hz, respectively, though all thresholds returned to baseline at 3000, 4000, and 6000 Hz within 75 min of noise exposure. Paradoxically, Active NIR light therapy threshold shifts were statistically higher than Sham therapy at 3000 Hz (p = 0.04), but no other differences were observed at the other frequencies tested. An age sub-analysis demonstrated that TTS among younger adults were generally larger in the Sham therapy group versus Active therapy, though this was not statistically different. There were no differences in CPATB test results across Active or Sham groups. Finally, we observed no changes in auditory function or central processing following noise exposure, suggestive of healthy and resilient inner ears. Conclusion: In this study, locally administered NIR prior to noise exposure did not induce a significant protective effect in mitigating noise-induced TTS. Further exploration is needed to implement effective dosage and administration for this promising otoprotective therapy. [ABSTRACT FROM AUTHOR]

Background: Mitochondria are essential organelles involved in cellular energy production. Changes in mitochondrial function can lead to dysfunction and cell death in aging and age-related disorders. Recent research suggests that mitochondrial dysfunction is closely linked to neurodegenerative diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonist has gained interest as a potential treatment for Parkinson's disease (PD). However, the exact mechanisms responsible for the therapeutic effects of GLP-1R-related agonists are not yet fully understood. Methods: In this study, we explores the effects of early treatment with PT320, a sustained release formulation of the GLP-1R agonist Exenatide, on mitochondrial functions and morphology in a progressive PD mouse model, the MitoPark (MP) mouse. Results: Our findings demonstrate that administration of a clinically translatable dose of PT320 ameliorates the reduction in tyrosine hydroxylase expression, lowers reactive oxygen species (ROS) levels, and inhibits mitochondrial cytochrome c release during nigrostriatal dopaminergic denervation in MP mice. PT320 treatment significantly preserved mitochondrial function and morphology but did not influence the reduction in mitochondria numbers during PD progression in MP mice. Genetic analysis indicated that the cytoprotective effect of PT320 is attributed to a reduction in the expression of mitochondrial fission protein 1 (Fis1) and an increase in the expression of optic atrophy type 1 (Opa1), which is known to play a role in maintaining mitochondrial homeostasis and decreasing cytochrome c release through remodeling of the cristae. Conclusion: Our findings suggest that the early administration of PT320 shows potential as a neuroprotective treatment for PD, as it can preserve mitochondrial function. Through enhancing mitochondrial health by regulating Opa1 and Fis1, PT320 presents a new neuroprotective therapy in PD. [ABSTRACT FROM AUTHOR]

Post vaccine immunity following COVID-19 mRNA vaccination may be driven by extrinsic, or controllable and intrinsic, or inherent health factors. Thus, we investigated the effects of extrinsic and intrinsic on the peak antibody response following COVID-19 primary vaccination and on the trajectory of peak antibody magnitude and durability over time. Participants in a longitudinal cohort attended visits every 3 months for up to 2 years following enrollment. At baseline, participants provided information on their demographics, recreational behaviors, and comorbid health conditions which guided our model selection process. Blood samples were collected for serum processing and spike antibody testing at each visit. Cross-sectional and longitudinal models (linear-mixed effects models) were generated to assess the relationship between selected intrinsic and extrinsic health factors on peak antibody following vaccination and to determine the influence of these predictors on antibody over time. Following cross-sectional analysis, we observed higher peak antibody titers after primary vaccination in females, those who reported recreational drug use, younger age, and prior COVID-19 history. Following booster vaccination, females and Hispanics had higher peak titers after the 3rd and 4th doses, respectively. Longitudinal models demonstrated that Moderna mRNA-1273 recipients, females, and those previously vaccinated had increased peak titers over time. Moreover, drug users and half-dose Moderna mRNA-1273 recipients had higher peak antibody titers over time following the first booster, while no predictive factors significantly affected post-second booster antibody responses. Overall, both intrinsic and extrinsic health factors play a significant role in shaping humoral immunogenicity after initial vaccination and the first booster. The absence of predictive factors for second booster immunogenicity suggests a more robust and consistent immune response after the second booster vaccine administration. [ABSTRACT FROM AUTHOR]

Background: Imaging is vital for assessing rectal cancer, with endoanal ultrasound (EAUS) being highly accurate in large tertiary medical centers. However, EAUS accuracy drops outside such settings, possibly due to varied examiner experience and fewer examinations. This underscores the need for an AI-based system to enhance accuracy in non-specialized centers. This study aimed to develop and validate deep learning (DL) models to differentiate rectal cancer in standard EAUS images. Methods: A transfer learning approach with fine-tuned DL architectures was employed, utilizing a dataset of 294 images. The performance of DL models was assessed through a tenfold cross-validation. Results: The DL diagnostics model exhibited a sensitivity and accuracy of 0.78 each. In the identification phase, the automatic diagnostic platform achieved an area under the curve performance of 0.85 for diagnosing rectal cancer. Conclusions: This research demonstrates the potential of DL models in enhancing rectal cancer detection during EAUS, especially in settings with lower examiner experience. The achieved sensitivity and accuracy suggest the viability of incorporating AI support for improved diagnostic outcomes in non-specialized medical centers. [ABSTRACT FROM AUTHOR]

Purpose: To compare simulated keratometry (SimK) and total corneal power (TCP) in keratoconic eyes, to determine whether the differences are systematic and predictable and to evaluate an adjusted TCP-based formula for intraocular lens (IOL) power calculation. Methods: In a consecutive series of keratoconic eyes, measurements of SimK, TCP, posterior keratometry, and anterior and posterior corneal asphericities (Q-values) were retrospectively collected. The difference between SimK and TCP was linearly correlated to the biometric parameters. In a separate sample of keratoconic eyes that had undergone cataract surgery, IOL power was calculated with the Barrett Universal II, Hoffer QST, Holladay 1, Kane, and SRK/T formulas using the SimK and an adjusted TCP power. The respective prediction errors were calculated. Results: A total of 382 keratoconic eyes (271 patients) were enrolled. An increasing overestimation of SimK by TCP was detected from stage I to III, with a significant correlation between the SimK and TCP difference and SimK in the whole sample (P <.0001, r2 = 0.1322). Approximately 7% of cases presented an underestimation of SimK by TCP. IOL power calculation with the adjusted TCP improved outcomes, achieving a maximum of 80% of eyes with a prediction error within ±0.50 diopters with the Hoffer QST, Holladay 1, and Kane formulas. Conclusions: Overall, SimK overestimated TCP. Such a difference could not be predicted by any variable. The proposed TCP-adjustment formula (TCPadj = TCP + 0.56 diopters) in keratoconic eyes for IOL power calculation might be valuable for improving refractive outcomes. [J Refract Surg. 2024;40(4):e253–e259.] [ABSTRACT FROM AUTHOR]

The bromodomain adjacent to zinc finger 2B (BAZ2B) gene encodes a chromatin remodeling protein that has been shown to perform a variety of regulatory functions. It has been proposed that loss of BAZ2B function is associated with neurodevelopmental phenotypes, and some recurrent structural birth defects and dysmorphic features have been documented among individuals carrying heterozygous loss‐of‐function BAZ2B variants. However, additional evidence is needed to confirm that these phenotypes are attributable to BAZ2B deficiency. Here, we report 10 unrelated individuals with heterozygous deletions, stop‐gain, frameshift, missense, splice junction, indel, and start‐loss variants affecting BAZ2B. These included a paternal intragenic deletion and a maternal frameshift variant that were inherited from mildly affected or asymptomatic parents. The analysis of molecular and clinical data from this cohort, and that of individuals previously reported, suggests that BAZ2B haploinsufficiency causes an autosomal dominant neurodevelopmental syndrome that is incompletely penetrant. The phenotypes most commonly seen in association with loss of BAZ2B function include developmental delay, intellectual disability, autism spectrum disorder, speech delay—with some affected individuals being non‐verbal—behavioral abnormalities, seizures, vision‐related issues, congenital heart defects, poor fetal growth, and an indistinct pattern of dysmorphic features in which epicanthal folds and small ears are particularly common. [ABSTRACT FROM AUTHOR]

Objective: To evaluate which cytogenetic characteristics of confined placental mosaicism (CPM) detected in the first trimester chorionic villi and/or placentas in terms of chromosome aberration, cell lineage involved and trisomy origin will lead to fetal growth restriction and low birthweight. Methods: Cohort study using routinely collected perinatal data and cytogenetic data of non‐invasive prenatal testing, the first trimester chorionic villi sampling and postnatal placentas. Results: 215 CPM cases were found. Fetal growth restriction (FGR) and low birthweight below the 10th percentile (BW < p10) were seen in 34.0% and 23.1%, respectively. Excluding cases of trisomy 16, 29.1% showed FGR and 17.9% had a BW < p10. The highest rate of FGR and BW < p10 was found in CPM type 3, but differences with type 1 and 2 were not significant. FGR and BW < p10 were significantly more often observed in cases with meiotic trisomies. Conclusion: There is an association between CPM and FGR and BW < p10. This association is not restricted to trisomy 16, neither to CPM type 3, nor to CPM involving a meiotic trisomy. Pregnancies with all CPM types and origins should be considered to be at increased risk of FGR and low BW < p10. A close prenatal fetal monitoring is indicated in all cases of CPM. Key points: What's already known about this topic? CPM may have an impact on fetal growth and birthweight.CPM type 3 often involving a meiotic trisomy is associated with an adverse pregnancy outcome. What does this study add? Although fetal growth problems were more often seen in CPM type 3 and those involving a meiotic trisomy, both CPM type 1 and CPM involving a mitotic trisomy were also associated with an increased risk of impaired fetal growth and low birthweight.Irrespective of CPM type, trisomy origin, or involved chromosome aberration, we advocate to closely monitor all pregnancies where CPM is suspected, except for CPM type 2. [ABSTRACT FROM AUTHOR]

Alexander Hamilton's view of law was more than pragmatic. Forward looking, and innovative, it saw law as a creative tool. Often misread, and dismissed, as mere policy preference, it was in fact sophisticated and superbly articulated jurisprudence. In the years between the ratification debate and the proposal for the First Bank of the United States, Hamilton displayed this jurisprudence to great effect. [ABSTRACT FROM AUTHOR]

"The Fiery Test of Critique: A Reading of Kant's Dialectic" by Ian Proops is a comprehensive and detailed analysis of Kant's Transcendental Dialectic in the Critique of Pure Reason. Proops explores Kant's negative assessment of traditional metaphysics and argues that the Dialectic is not solely a critique, but also aims to salvage valuable elements from the tradition. The book provides in-depth reconstructions of Kant's arguments and offers a unifying interpretation of the faculty of reason. Proops also contextualizes Kant's arguments within the historical-intellectual framework, showcasing his command of diverse sources. While the book is highly recommended for those interested in Kant's philosophy, there are some reservations about certain arguments and interpretations. [Extracted from the article]

The illegal burning of solid waste in residential stoves is an existing practice, but until now it has been completely disregarded as an emission source of atmospheric pollutants in many developed countries, including those in eastern Europe. Various types of solid waste (plastics, treated wood, plyboards, tyre, rag) serve as an auxiliary fuel in many households, in particular during the heating season. In this work, for the first time ever in atmospheric pollution studies, specific tracer compounds identified previously in controlled test burnings of different waste types in the laboratory were detected and quantified in ambient PM10 samples collected in five Hungarian and four Romanian settlements. Using the identified tracers and their experimentally determined relative emission factors, the potential contribution of illegal waste burning emissions to ambient PM10 mass concentrations was assessed. Our findings implied that the burning of polyethylene terephthalate (PET)-containing waste (food and beverage packaging, clothes) was predominant at all the locations, especially in north-eastern Hungary and Romania. There is substantial evidence that the burning of scrap furniture is also common in big cities in Hungary and Romania. Back-of-the-envelope calculations based on the relative emission factors of individual tracers suggested that the contribution of solid waste burning particulate emissions to ambient PM10 mass concentrations may be as high as a few percent. This finding, when considering the extreme health hazards associated with particulate emissions from waste burning, is a matter of serious public health concern. [ABSTRACT FROM AUTHOR]

Introduction: Exposure to occupational or recreational loud noise activates multiple biological regulatory circuits and damages the cochlea, causing permanent changes in hearing sensitivity. Currently, no effective clinical therapy is available for the treatment or mitigation of noise-induced hearing loss (NIHL). Here, we describe an application of localized and non-invasive therapeutic hypothermia and targeted temperature management of the inner ear to prevent NIHL. Methods: We developed a custom-designed cooling neck collar to reduce the temperature of the inner ear by 3-4°C post-injury to deliver mild therapeutic hypothermia. Results: This localized and non-invasive therapeutic hypothermia successfully mitigated NIHL in rats. Our results show that mild hypothermia can be applied quickly and safely to the inner ear following noise exposure. We show that localized hypothermia after NIHL preserves residual hearing and rescues noiseinduced synaptopathy over a period of months. Discussion: This study establishes a minimally-invasive therapeutic paradigm with a high potential for rapid translation to the clinic for long-term preservation of hearing health. [ABSTRACT FROM AUTHOR]

Objectives: To assess the safety and efficacy of radiofrequency ablation (RFA) guidance software that incorporated patient-specific physics-based simulation of each ablation volume. Materials and methods: Patients referred for curative ablation of hepatocellular carcinoma (HCC) of 2–5 cm diameter were prospectively enrolled. RFA was performed under general anesthesia. Procedure planning and intraprocedural modifications were guided by computer simulation of each ablation. The segmented target (tumor with 5 mm margin) was registered to and superimposed on subsequent 3D multiplanar images. The applied RF energy was used to calculate a simulated ablation volume which was displayed relative to the electrode and segmented target, to depict any untreated target tissue. After each additional ablation, the software updated the accumulated simulated ablation volume in relation to the target. The primary endpoints were technical efficacy and rate of local tumor progression (LTP). Results: Sixty-eight tumors were ablated during 57 procedures in 52 patients (68.3 ± 9.2 years old, 78.8% male); 15 (26.3%) had multiple lesions and 23 (39.1%) had prior HCC treatment. The mean tumor diameter was 2.73 (±0.64) cm. The intraprocedural simulation directed additional overlapping ablations in 75.9% of tumors. Technical success and efficacy were 100% at 3-month contrast enhanced CT or MRI follow-up after the single treatment session. Cumulative incidence function estimates for 1- and 2-year LTP were 3.9% and 20.2%, respectively. Conclusion: This prospective study found computer-assisted guidance that simulated each ablation was both safe and efficacious. The low rate of LTP was similar to studies that employed stereotactic guidance and ablation confirmation, without requiring a second contrast enhanced study. [ABSTRACT FROM AUTHOR]

Neuronal damage resulting from traumatic brain injury (TBI) causes disruption of neuronal projections and neurotransmission that contribute to behavioral deficits. Cellular generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is an early event following TBI. ROS often damage DNA, lipids, proteins, and carbohydrates while RNS attack proteins. The products of lipid peroxidation 4-hydroxynonenal (4-HNE) and protein nitration 3-nitrotyrosine (3-NT) are often used as indicators of oxidative and nitrosative damages, respectively. Increasing evidence has shown that striatum is vulnerable to damage from TBI with a disturbed dopamine neurotransmission. TBI results in neurodegeneration, oxidative stress, neuroinflammation, neuronal apoptosis, and autophagy in the striatum and contribute to motor or behavioral deficits. Pomalidomide (Pom) is a Food and Drug Administration (FDA)-approved immunomodulatory drug clinically used in treating multiple myeloma. We previously showed that Pom reduces neuroinflammation and neuronal death induced by TBI in rat cerebral cortex. Here, we further compared the effects of Pom in cortex and striatum focusing on neurodegeneration, oxidative and nitrosative damages, as well as neuroinflammation following TBI. Sprague–Dawley rats subjected to a controlled cortical impact were used as the animal model of TBI. Systemic administration of Pom (0.5 mg/kg, intravenous [i.v.]) at 5 h post-injury alleviated motor behavioral deficits, contusion volume at 24 h after TBI. Pom alleviated TBI-induced neurodegeneration stained by Fluoro-Jade C in both cortex and striatum. Notably, Pom treatment reduces oxidative and nitrosative damages in cortex and striatum and is more efficacious in striatum (93% reduction in 4-HNE-positive and 84% reduction in 3-NT-positive neurons) than in cerebral cortex (42% reduction in 4-HNE-positive and 55% reduction in 3-NT-positive neurons). In addition, Pom attenuated microgliosis, astrogliosis, and elevations of proinflammatory cytokines in cortical and striatal tissue. We conclude that Pom may contribute to improved motor behavioral outcomes after TBI through targeting oxidative/nitrosative damages and neuroinflammation. [ABSTRACT FROM AUTHOR]

It is still unclear how the chemical speciation of Cu in surface seawater is impacted by aerosols from various sources deposited on the sea surface, which is surprising, considering the environmental importance of Cu. Therefore, we used voltammetry to investigate Cu complexing capacity (CuCC) in the sea surface microlayer (SML) and in the underlying water (ULW) of the oligotrophic middle Adriatic Sea during February–July 2019. The focus was on the impacts of specific atmospheric processes such as open-fire biomass burning (BB), pollination season and Saharan dust intrusion. The presence of ligand class L2 (19.9–392.0, average 63.8, median 43.1) nM; log K2 (8.3–10.2, average 9.6, median 9.6) was observed in all samples, while ligand class L1 (40.5–76.1, average 53.6, median 48.9) nM; log K1 (10.3–11.1, average 10.6, median 10.5) was found in only 25% of SML samples. Throughout the period, the SML was enriched with organic ligands by a factor of up to 9.1 compared to the ULW, mainly due to the high sensitivity of the SML to specific atmospheric depositions. In addition, measurements with corresponding specific model aerosols were conducted to analyse their impacts on CuCC. Pollen directly affected CuCC in the SML by increasing the concentration of allochthonous ligands such as proteins. The deposition of BB aerosols rich in nutrients and trace metals stimulated the biological production of organic ligands, showing an indirect effect on CuCC delayed by up to two weeks. Finally, Saharan dust had a negligible impact on CuCC. This study illustrates the susceptibility of oligotrophic coastal area to the effects of pollen and open-fire BB aerosols in altering the Cu-binding organic ligands in the SML. [ABSTRACT FROM AUTHOR]

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The current study explored the relation between sexual orientation, masculinity ideology, and sexism among 380 adult heterosexual and bisexual women. Participants completed measures of sexual orientation, masculinity ideology, hostile sexism, and benevolent sexism. Mean-level analyses concluded that heterosexual women scored significantly higher on hostile and benevolent sexism than their bisexual counterparts. Findings from the regression analyses revealed that masculinity ideology predicted both hostile and benevolent sexism. Sexual orientation only moderated the association between masculinity ideology and hostile sexism, such that the effect was stronger for heterosexual women. Sexual orientation did not moderate the association between women's masculinity ideology and benevolent sexism, suggesting that women's relationship with benevolent sexism may be more complex. The current findings suggest that heterosexual women's conceptions of gender-role attitudes toward men and women may be more salient and potentially harmful compared to bisexual women, and heterosexual intimacy may be an important factor to consider. [ABSTRACT FROM AUTHOR]

Background: Imaging is vital for assessing rectal cancer, with endoanal ultrasound (EAUS) being highly accurate in large tertiary medical centers. However, EAUS accuracy drops outside such settings, possibly due to varied examiner experience and fewer examinations. This underscores the need for an AI-based system to enhance accuracy in non-specialized centers. This study aimed to develop and validate deep learning (DL) models to differentiate rectal cancer in standard EAUS images. Methods: A transfer learning approach with fine-tuned DL architectures was employed, utilizing a dataset of 294 images. The performance of DL models was assessed through a tenfold cross-validation. Results: The DL diagnostics model exhibited a sensitivity and accuracy of 0.78 each. In the identification phase, the automatic diagnostic platform achieved an area under the curve performance of 0.85 for diagnosing rectal cancer. Conclusions: This research demonstrates the potential of DL models in enhancing rectal cancer detection during EAUS, especially in settings with lower examiner experience. The achieved sensitivity and accuracy suggest the viability of incorporating AI support for improved diagnostic outcomes in non-specialized medical centers. [ABSTRACT FROM AUTHOR]