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Curcumin has been proposed as a potential treatment for Alzheimer's disease (AD) due to its ability to inhibit amyloid-β (Aβ) peptide aggregates and to destabilise pre-formed ones. Derivative 27 was synthesized to improve low-dose efficacy in the context of AD. Its anti-inflammatory, antioxidant and anti-amyloidogenic activities were evaluated in chemico, in vitro using AD and neuroinflammation cell models, and in vivo using the double-transgenic APP/PS1 mice. In vitro, this curcumin derivative significantly reduced nitric oxide (NO) production and levels of pro-inflammatory proteins, inducible NO synthase, pro-interleukin-1β (Pro-IL-1β) and cyclooxygenase-2. Furthermore, Derivative 27 activated nuclear factor erythroid 2-related factor 2 transcription factor (Nrf2) and significantly increased Nrf2 and heme-oxygenase-1 protein levels in the nucleus and in the cytoplasm, respectively. In one-year-old APP/PS1 mice, orally administered-Derivative 27 (50 mg/Kg/day) for 28 days improved spatial short-term memory and significantly decreased hippocampal Pro-IL-1β and amyloid precursor protein levels, as well as Aβ levels in the hippocampus and plasma. This study supports developing new chemical approaches to alter curcumin molecule, enabling lower doses, while increasing the effectiveness in AD treatment., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background : The profile of metal(loid)s in human milk is essential for infant growth and development, yet its impact on the development of the infant microbiota remains unclear. Elements, such as manganese, zinc, iron or copper, play crucial roles in influencing infant health. Aim : To investigate the metal(loid) content within human milk and its influence on the infant's gut microbiota within the first 2 months after birth. Methods : Human milk samples and infant stool samples from 77 mother-infant dyads in the MAMI cohort were collected at two time points: the early transitional stage and the mature stage. Metallomic profiling of human milk was conducted using inductively coupled plasma-mass spectrometry (ICP-MS). The infant gut microbiota was profiled through 16S rRNA amplicon sequencing and maternal-infant clinical data were available. Spearman's rank correlation coefficientsprovided insights into metal(loid)-microbiota relationships. Results : Independent cross-sectional analyses of mother-infant pairs at two time points, significant variations in metal concentrations and differences in microbial abundances and diversities were observed. Notably, Bifidobacterium genus abundance was higher during the mature lactation stage. During early lactation, we found a significant positive correlation between infant gut Corynebacterium and human milk nickel concentrations, and negative correlations between Veillonella spp. and antimony, and Enterobacter spp. and copper. Additionally, Simpson's diversity was negatively correlated with iron. In the mature lactation stage, we identified eleven significant correlations between metals and microbiota. Notably, Klebsiella genus showed multiple negative correlations with iron, antimony, and vanadium. Conclusion : Our study highlights the significance of metal(loid)-microbiota interactions in early infant development, indicating that infant gut Klebsiella genus may be particularly vulnerable to fluctuations in metal(loid) levels present in human milk, when compared to other genera. Future research should explore these interactions at a strain level and the implications on infant health and development. This trial was registered as NCT03552939.

Introduction: While HTN is widely seen as a primary threat to cardiovascular conditions worldwide, it is essential to recognize that not all HTN is identical., Objective: To determine the prevalence, trend, and factors associated with each type of HTN: isolated systolic (ISH), isolated diastolic (IDH), and systolic-diastolic (SDH)., Methods: A secondary analysis of data from the Demographic and Family Health Survey from 2014 to 2022 was conducted. For the analysis of associated factors, a Poisson regression model with robust variance was implemented to calculate adjusted prevalence ratios (aPR) along with their 95% confidence intervals., Results: The prevalence was 7.02%, 1.55%, and 3.28% for ISH, IDH, and SDH, respectively. ISH showed a decline in 2022, unlike the other two types, which seem to be on the rise. A statistically significant association was found in men and an increased risk with age for ISH and SDH, unlike IDH, where age acts as a protective factor. Additional factors identified include smoking and excessive alcohol consumption, while a high intake of fruits/vegetables offers a protective effect. Obesity and diabetes were associated with a higher risk, and significant variations by region and altitude, as well as among ethnic groups, were observed., Conclusions: Significant differences in the prevalence of HTN subtypes have been found, underscoring the heterogeneity of this chronic condition, both in related factors and in trends over the years., (Copyright © 2024 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background/objectives: Mesothelioma is an aggressive cancer with limited treatment options. Mesothelioma therapy often involves a multimodal approach including surgery, radiotherapy and chemotherapy. However, the prognosis for patients remains poor. Difficult diagnosis, late symptoms when the tumor is in an advanced stage and the onset of chemotherapy resistance make mesothelioma difficult to treat. For this reason, it is essential to discover new pharmacological approaches. Capsaicin (CAPS) is the active compound of chili peppers. Based on CAPS's anticancer properties on various tumor lines and its chemo-sensitizing action on resistant cells, in this study, we evaluated the effects of CAPS on mesothelioma cells to assess its potential use in mesothelioma therapy., Methods: To evaluate antiproliferative effects of CAPS, we performed MTS assays on various mesothelioma cells, representative of all major mesothelioma subtypes. Transwell migration and wound-healing assays were used to examine the effect of CAPS on mesothelioma cell migration. We also determined the effects of CAPS on oncogenic signaling pathways by assessing the levels of AKT and MAPK activation., Results: In this study, we show that CAPS significantly reduces proliferation of both parental and cisplatin-resistant mesothelioma cells. CAPS promotes S-phase cell cycle arrest and inhibits lateral motility and migration of mesothelioma cells. Accordingly, CAPS suppresses AKT and ERK1/2 activation in MSTO-211H and NCI-H2052 cells. Our results support an antitumor effect of CAPS on cisplatin-resistant mesothelioma cells, suggesting that it may reduce resistance to cisplatin., Conclusions: Our results could pave the way for further studies to evaluate the use of CAPS for mesothelioma treatment.

The abundance of micro (MPs) and nano (NPs) sized plastic particles in the ocean is concerning due to their harmful effects on marine life. The interactions between MPs and NPs in the marine environment and their impact on marine biota remain not fully understood. This study contributes with new insights into the interaction between polystyrene NPs (PSNPs) and polyethylene MPs (PEMPs) on the clam Ruditapes decussatus. Results showed ingestion of MPs and NPs by clams, with PSNPs demonstrating higher toxicity in hemolymph. While no genotoxicity was observed, clams treated with MPs and the mixture showed increased acetylcolinesterase (AchE) activity over time. Additionally, the antioxidant defense system mitigated oxidative stress, suggesting effective neutralization of reactive oxygen species. Hazard assessment indicated the greatest impact on clam digestive glands after ten days of exposure, with an antagonistic interaction between MPs and NPs noted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

For many years researchers believed that hydrocarbons only contain covalent bonds. However, since 1985 Okamoto et al. demonstrated the formation of hydrocarbon salts in several systems, demolishing the structural principle that hydrocarbons only contain covalent bonds. Despite the great importance of this outcome to the study of chemical bonds, quantum chemical calculations on these systems are essentially nonexistent. The stability of the hydrocarbon ions along with the steric hindrance associated with the formation of the covalent bond contribute to their occurrence either in solution (dissociated) or in the solid state. These facts along with the common formation of ion pairs in solvents of low polarity motivated us to search for hydrocarbon ion pairs in the gas phase. Its energetics has also been studied in four nonprotic solvents, through a continuum solvation model (CPCM). DFT and CASSCF calculations indicate a metastable and highly polar ion pair between the tricyclopropylcyclopropenylium cation and a simplified Kuhn's anion. The barrier to the covalent structure varies from ∼4.8 to 14.4 kcal/mol, while the energy difference between the ion pair and the covalent form varies from ∼4.3 to 25.4 kcal/mol. The obtained theoretical results along with previous experimental results suggest the following strategy to obtain kinetically and thermodynamically stable hydrocarbon ion pairs: choose very stable hydrocarbon ions and systematically increase the steric hindrance between them., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Introduction: Although obesity substantially influences public health owing to related comorbidities, it has been discovered that the incidence of such issues is not directly related to obesity but to the patient's unhealthy metabolic status (MUS) independent of the body mass index (BMI)., Objectives: To describe the prevalence of UMS overall and according to BMI and determine the factors associated with it., Methods: A cross-sectional analytical study was used based on the analysis of secondary databases called the Life Stage Nutritional Surveillance Survey (VIANEV). Participants were selected in two stages, finally obtaining 885 participants. UMS was defined based on the criteria of the Adult Treatment Panel III used to define metabolic status in a set of 5 parameters, if the subject presented two or more alterations it was considered UMS. Six groups were formed according to BMI: metabolically healthy, average weight (MHNW) and unhealthy (MUNW), metabolically healthy, overweight (MHOW) and unhealthy (MUOW), metabolically healthy, obese (MHO) and unhealthy (MUO).)., Results: The total prevalence of UMS was 73.11%, with MUNW, MUOW, and MUO being 47.90%, 80.34%, and 96.44%, respectively. Only 5.31% did not present any metabolic alteration. The multivariable analysis found variations globally according to sex, age, marital status, geographical region, smoking habit, and altitude., Conclusions: A high prevalence of UMS was observed in Peru, indicating that BMI alone is not a sufficient indicator of metabolic status. These findings suggest that strategies should be prioritized to address the growing problem of UMS, considering the particularities of each subpopulation and using a multifaceted approach that addresses modifiable and non-modifiable risk factors., (© 2024. The Author(s).)

Plastic pollution in the form of microplastics (MPs), poses a significant threat to natural ecosystems, with detrimental ecological, social, and economic impacts. This review paper aims to provide an overview of the existing research on the interaction between microbial biofilms and MPs in natural environments. The review begins by outlining the sources and types of MPs, emphasizing their widespread presence in marine, freshwater, and terrestrial ecosystems. It then discusses the formation and characteristics of microbial biofilms on MPs surfaces, highlighting their role in altering the physicochemical properties of MPs and facilitating processes such as vertical transport, biodegradation, dispersion of microorganisms, and gene transfer. Different methods used to assess these interactions are discussed, including microbiological and physicochemical characterization. Current gaps and challenges in understanding the complex relationships between biofilms and MPs are identified, highlighting the need for further research to elucidate the mechanisms underlying these complex interactions and to develop effective mitigation strategies. Innovative solutions, including bioremediation techniques and their combination with other strategies, such as nanotechnology, advanced filtration technologies, and public awareness campaigns, are proposed as promising approaches to address the issue of MPs pollution. Overall, this review underscores the urgent need for a multidisciplinary approach to combating MPs pollution, combining scientific research, technological innovation, and public engagement to safeguard the health and integrity of natural ecosystems., (© 2024. The Author(s).)

Although CH 2 FCl (HCFC-31) recently became of great atmospheric importance, studies concerning its excited states are almost nonexistent. Several excited singlet states were studied (valence nσ* and Rydberg n3s, n3p, σ3s, and σ3p) through highly correlated multireference configuration interaction with singles and doubles, including extensivity correction. Comparison with the states of CH 3 Cl indicates a strong influence of the F atom. Potential energy curves suggest formation of an electrostatically bound complex that relaxes to a hydrogen-bonded contact ion-pair (HBCIP) which can decay yielding CH 2 F + Cl or to the ground state minimum of CH 2 FCl. The HBCIP has a dipole moment of 9.57 D, a CI wavefunction described as 0.65ionic + 0.20biradical and it is strongly bonded by 4.72 eV. Its H bond has characteristics of moderate and strong H bonds. The simulated absorption spectrum confirms the nσ* assignment for the first and suggests the n3s + n3p σ assignment for the second band., (© 2023 Wiley Periodicals LLC.)

This study investigates the genealogical and demographic trends of the Massese sheep breed in Tuscany from 2001 to 2021. The Herd Book kept by the Italian Sheep and Goat Breeders Association (Asso.Na.Pa) provided the data. The descriptive statistics were analyzed using JMP software. The pedigree parameters of a total of 311,056 animals (whole population-WP) were analyzed using CFC, ENDOG, and Pedigree viewer software. A total of 24,586 animals born in the period 2007-2021 represented the Reference Population (RP), and 18,554 animals the Base Population (BP). The demographic results showed an inconsistent trend of offspring registration. This study showed a short period of productivity for both ewes and rams, with means of 1.47 and 19.2 registered newborn ewes and rams, respectively. The genealogical analysis revealed incomplete data, highlighting inaccurate assessments of the relationships among the animals, and inbreeding with large differences among provinces. The average inbreeding coefficient in the WP was 1.16%, and it was 2.26% in the RP. The total number of inbreds was 2790 in the WP, with an average F PED of 13.56%, and 2713 in the RP, with an average F PED of 12.82%. The use of pedigree data is a key and economical approach to calculating inbreeding and relationship coefficients. It is the primary step in genetic management, playing a crucial role in the preservation of a breed. The regular updating of genealogical data is the first step to ensuring the conservation of animal genetic resources, and this study is compromised by the lack of such updates.

Here, we explored the vast potential of microbiome-based interventions in preventing and managing non-communicable diseases including obesity, diabetes, allergies, celiac disease, inflammatory bowel diseases, malnutrition, and cardiovascular diseases across different life stages. We discuss the intricate relationship between microbiome and non-communicable diseases, emphasizing on the "window of opportunity" for microbe-host interactions during the first years after birth. Specific biotics and also live biotherapeutics including fecal microbiota transplantation emerge as pivotal tools for precision medicine, acknowledging the "one size doesn't' fit all" aspect. Challenges in implementation underscore the need for advanced technologies, scientific transparency, and public engagement. Future perspectives advocate for understanding maternal-neonatal microbiome, exploring the maternal exposome and delving into human milk's role in the establishment and restoration of the infant microbiome and its influence over health and disease. An integrated scientific approach, employing multi-omics and accounting for inter-individual variance in microbiome composition and function appears central to unleash the full potential of early-life microbiome interventions in revolutionizing healthcare.

Progranulin is a growth factor with pro-tumorigenic activity. We recently demonstrated that in mesothelioma, progranulin regulates cell migration, invasion, adhesion, and in vivo tumor formation by modulating a complex signaling network involving multiple receptor tyrosine kinase (RTK)s. Progranulin biological activity relies on epidermal growth factor receptor (EGFR) and receptor-like tyrosine kinase (RYK), a co-receptor of the Wnt signaling pathway, which are both required for progranulin-induced downstream signaling. However, the molecular mechanism regulating the functional interaction among progranulin, EGFR, and RYK are not known. In this study, we demonstrated that progranulin directly interacted with RYK by specific enzyme-linked immunosorbent assay (ELISA) (K D  = 0.67). Using immunofluorescence and proximity ligation assay, we further discovered that progranulin and RYK colocalized in mesothelioma cells in distinct vesicular compartments. Notably, progranulin-dependent downstream signaling was sensitive to endocytosis inhibitors, suggesting that it could depend on RYK or EGFR internalization. We discovered that progranulin promoted RYK ubiquitination and endocytosis preferentially through caveolin-1-enriched pathways, and modulated RYK stability. Interestingly, we also showed that in mesothelioma cells, RYK complexes with the EGFR, contributing to the regulation of RYK stability. Collectively, our results suggest a complex regulation of RYK trafficking/activity in mesothelioma cells, a process that is concurrently regulated by exogenous soluble progranulin and EGFR. NEW & NOTEWORTHY The growth factor progranulin has pro-tumorigenic activity. In mesothelioma, progranulin signaling is mediated by EGFR and RYK, a co-receptor of the Wnt signaling. However, the molecular mechanisms regulating progranulin action are not well defined. Here, we demonstrated that progranulin binds RYK and regulates its ubiquitination, internalization, and trafficking. We also uncovered a role for EGFR in modulating RYK stability. Overall, these results highlight a complex modulation of RYK activity by progranulin and EGFR in mesothelioma.

An active environment is any atomic or molecular system changing a chromophore's nonadiabatic dynamics compared to the isolated molecule. The action of the environment on the chromophore occurs by changing the potential energy landscape and triggering new energy and charge flows unavailable in the vacuum. Surface hopping is a mixed quantum-classical approach whose extreme flexibility has made it the primary platform for implementing novel methodologies to investigate the nonadiabatic dynamics of a chromophore in active environments. This Perspective paper surveys the latest developments in the field, focusing on charge and energy transfer processes.

Progranulin is a pleiotropic growth factor with important physiological roles in embryogenesis and maintenance of adult tissue homeostasis. While-progranulin deficiency is associated with a broad range of pathological conditions affecting the brain, such as frontotemporal dementia and neuronal ceroid lipofuscinosis, progranulin upregulation characterizes many tumors, including brain tumors, multiple myeloma, leiomyosarcoma, mesothelioma and epithelial cancers such as ovarian, liver, breast, bladder, adrenal, prostate and kidney carcinomas. The increase of progranulin levels in tumors might have diagnostic and prognostic significance. In cancer, progranulin has a pro-tumorigenic role by promoting cancer cell proliferation, migration, invasiveness, anchorage-independent growth and resistance to chemotherapy. In addition, progranulin regulates the tumor microenvironment, affects the function of cancer-associated fibroblasts, and modulates tumor immune surveillance. However, the molecular mechanisms of progranulin oncogenic function are not fully elucidated. In bladder cancer, progranulin action relies on the activation of its functional signaling receptor EphA2. Notably, more recent data suggest that progranulin can also modulate a functional crosstalk between multiple receptor-tyrosine kinases, demonstrating a more complex and context-dependent role of progranulin in cancer. Here, we will review what is currently known about the function of progranulin in tumors, with a focus on its molecular mechanisms of action and regulation.

Background: Mesothelioma is an aggressive disease with limited therapeutic options. The growth factor progranulin plays a critical role in several cancer models, where it regulates tumor initiation and progression. Recent data from our laboratories have demonstrated that progranulin and its receptor, EphA2, constitute an oncogenic pathway in bladder cancer by promoting motility, invasion and in vivo tumor formation. Progranulin and EphA2 are expressed in mesothelioma cells but their mechanisms of action are not well defined. In addition, there are no data establishing whether the progranulin/EphA2 axis is tumorigenic for mesothelioma cells., Methods: The expression of progranulin in various mesothelioma cell lines derived from all major mesothelioma subtypes was examined by western blots on cell lysates, conditioned media and ELISA assays. The biological roles of progranulin, EphA2, EGFR, RYK and FAK were assessed in vitro by immunoblots, human phospho-RTK antibody arrays, pharmacological (specific inhibitors) and genetic (siRNAs, shRNAs, CRISPR/Cas9) approaches, motility, invasion and adhesion assays. In vivo tumorigenesis was determined by xenograft models. Focal adhesion turnover was evaluated biochemically using focal adhesion assembly/disassembly assays and immunofluorescence analysis with focal adhesion-specific markers., Results: In the present study we show that progranulin is upregulated in various mesothelioma cell lines covering all mesothelioma subtypes and is an important regulator of motility, invasion, adhesion and in vivo tumor formation. However, our results indicate that EphA2 is not the major functional receptor for progranulin in mesothelioma cells, where progranulin activates a complex signaling network including EGFR and RYK. We further characterized progranulin mechanisms of action and demonstrated that progranulin, by modulating FAK activity, regulates the kinetic of focal adhesion disassembly, a critical step for cell motility., Conclusion: Collectively, our results highlight the complexity of progranulin oncogenic signaling in mesothelioma, where progranulin modulate functional cross-talks between multiple RTKs, thereby suggesting the need for combinatorial therapeutic approaches to improve treatments of this aggressive disease., (© 2022. The Author(s).)

Introduction/aims: Hourglass-like constrictions (HGCs) occur in neuralgic amyotrophy (NA), but the earliest time at which they can be recognized by imaging is poorly understood. We aimed to determine the prevalence of abnormal imaging findings in the acute phase of NA., Methods: Magnetic resonance neurography (MRN) and high-resolution ultrasound (US) examinations were performed at five sites. The investigation included 39 patients with acute NA who underwent imaging within 31 days of symptom onset. Correlation between imaging and electromyography (EMG) findings was measured., Results: US was performed in 29 patients and MRN in 23; 16 patients underwent US only, 10 MRN only, and 13 had both. US and MRN showed nerve abnormalities within 1 mo from NA onset in 90% of patients. HGCs were found in 74% (29/39) of the patients: 4 within 1 wk, 8 within 2 wk, 5 within 3 wk, and 12 within 4 wk. The earliest HGC on US was found within 12 h, and on MRN within 3 days from symptom onset. MRN demonstrated a denervation edema pattern of affected muscles in 91% of the patients. The shortest time to observe an edema pattern on MRN was 8 days. EMG was performed in 30 patients and revealed fibrillation potentials in affected muscles in 22 (73%). A denervation edema pattern on MRN was significantly associated with the presence of HGCs both on MRN and US, and with fibrillation potentials on EMG., Discussion: In the early phase of NA, US and MRN are useful diagnostic techniques for demonstrating nerve abnormalities., (© 2022 Wiley Periodicals LLC.)

The benefits of sport activity on cognition and especially on executive function development are well-known, and in recent years, several kinds of cognitive-motor training (CMT) have been proven effective in adults and older people. Less is known about possible CMT benefits in children. This study aims to confirm the positive influence played by CMTs on specific executive functions (planning abilities and visual search) in young soccer players. Twenty-four 10-year-old athletes were recruited and randomly assigned to the experimental (Exp) and control (Con) groups of 12 players. Both groups were trained for 10 weeks, twice a week (90 min per training), following standard soccer training (technical-tactical exercises). The Exp group, during the first training session of the week, in the last 22 min, performed the experimental treatment, which consisted of a psychokinetic CMT. Both groups were examined before and after the ten-week training using the Tower of London and WISC-IV cancellation tests. Results revealed that the Exp group, following treatment, reported significantly better scores than the Con group in all the cognitive measures. We concluded that the proposed CMT is more effective than motor training alone at improving planning abilities and visual search abilities, even in children.

Organic molecules are a potential source of prebiotic chemistry in the interstellar medium (ISM). Methanol (MetOH) is a very important source of more complex molecules. H 3 O + (aq) and Cl - (aq) are fundamental to living organisms and can be generated in the ISM from the dissociation of HCl with just four water molecules, yielding the (H 3 O) + (H 2 O) 3 Cl - ion-pair. Here, a detailed mechanism, based on density functional theory (DFT) and ab-initio (2 nd order Mϕller-Plesset perturbation theory, MP2) calculations, is suggested for the substitution reactions of these water molecules by MetOH. The time required for formation of an appreciable amount of the product ((H 3 O) + (MetOH) 3 Cl - ) can be only few years. Such reaction can take place in Sagittarius B2, where HCl, H 2 O and MetOH have already been identified and it can be an important source for the formation of more complex prebiotic structures., (© 2022 Wiley-VCH GmbH.)

Pyrene fluorescence after a high-energy electronic excitation exhibits a prominent band shoulder not present after excitation at low energies. The standard assignment of this shoulder as a non-Kasha emission from the second-excited state (S 2 ) has been recently questioned. To elucidate this issue, we simulated the fluorescence of pyrene using two different theoretical approaches based on vertical convolution and nonadiabatic dynamics with nuclear ensembles. To conduct the necessary nonadiabatic dynamics simulations with high-lying electronic states and deal with fluorescence timescales of about 100 ns of this large molecule, we developed new computational protocols. The results from both approaches confirm that the band shoulder is, in fact, due to S 2 emission. We show that the non-Kasha behavior is a dynamic-equilibrium effect not caused by a metastable S 2 minimum. However, it requires considerable vibrational energy, which can only be achieved in collisionless regimes after transitions into highly excited states. This strict condition explains why the S 2 emission was not observed in some experiments.

Importance: Most ocular lesions have been described for children with congenital Zika syndrome. The frequency of finding ocular abnormalities is unknown among children exposed to Zika virus (ZIKV) during pregnancy. This study was conducted on newborns whose mothers were positive for ZIKV, confirmed with reverse-transcription polymerase chain reaction (RT-PCR) testing., Objective: To report ocular fundus manifestations in newborns with congenital ZIKV exposure in French Guiana, Martinique, and Guadeloupe, French West Indies, to assess its prevalence. Risk factors, such as the presence of extraocular fetopathies and the gestational term at infection, were sought., Design, Setting, and Participants: This was a cross-sectional multicentric study, conducted from August 1, 2016, to April 30, 2019, for which data were collected prospectively. The study inception was at the beginning of 2016 from the onset of the ZIKV epidemic in the French West Indies. Newborns whose mothers tested positive (by RT-PCR) for ZIKV during pregnancy were included., Interventions: Fundus examination was performed using widefield retinal imaging after pupil dilation. Infection date, delivery mode, and newborn measurements were collected., Main Outcomes and Measures: Anomalies of the vitreous, choroid, retina, and optic disc., Results: A total of 330 children (mean [SD] age, 68 [IQR, 22-440] days; 170 girls [51.5%]) were included. Eleven children (3.3%) had perivascular retinal hemorrhages, and 3 (0.9%) had lesions compatible with congenital ZIKV infection: 1 child had torpedo maculopathy, 1 child had a chorioretinal scar with iris and lens coloboma, and 1 child had a chorioretinal scar. Retinal hemorrhages were found at childbirth during early screening. Lesions compatible with congenital ZIKV infection were not associated with the presence of extraocular fetopathy. Microcephaly was not associated with lesions compatible with congenital ZIKV infection (odds ratio [OR], 9.1; 95% CI, 0.8-105.3; P = .08), but severe microcephaly was associated with an OR of 81 (95% CI, 5.1-1297.8; P = .002)., Conclusions and Relevance: Results of this cross-sectional study suggest that the ocular anomalies found may be associated with ZIKV in 0.9% of the exposed population. Ocular lesions were rare, affected mostly the choroid and retina, and seemed to be associated with choroiditis-related scarring that developed during fetal growth.

Purpose: CT-guided percutaneous procedures involving the skull base and atlanto-axial cervical spine pose particular challenges due to high density of vital vascular and nervous structures and because the ideal needle trajectory often has a cranio-caudal obliquity different from the axial scan plane. We describe how the variable CT gantry tilt, combined with gantry-needle-target alignment technique, is used to obtain precise and safe needle placement in conventional and non-conventional approaches to the skull base and the atlanto-axial spine., Methods: We retrospectively analyzed consecutive CT-guided needle accesses to the skull base and atlanto-axial spine performed for tissue sampling through fine-needle aspirates and core biopsies, cementoplasty of neoplastic lytic lesions of atlanto-axial spine, pain management injections, and dural puncture for cerebro-spinal fluid sampling. All the accesses were performed with the gantry-needle-target alignment technique. Procedural complications were recorded., Results: Thirty-nine CT-guided procedures were analyzed. Paramaxillary approach was used in 15 cases, postero-lateral in 11, subzygomatic in 3. Nine non-conventional approach were performed: submastoid in 3 cases, suprazygomatic in 2, trans-nasal in 2, trans-mastoid in 1, and trans-auricular in 1. Two peri-procedural complications occurred: one asymptomatic and one resolved within 24 h. All the procedures were successfully completed with successful needle access to the target., Conclusion: The gantry tilt and gantry-needle-target alignment technique allows to obtain double-oblique needle accesses for CT-guided procedures involving the skull base and atlanto-axial cervical spine, minimizing uncertainty of needle trajectory and obtaining safe needle placement in conventional and non-conventional approaches., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Determine whether an association exists between access barriers reported by women aged 15-49 years and the use of essential health services for women and children in Latin America., Methods: Cross-sectional study using multivariate logistic regression models based on the demographic and health surveys of Bolivia, the Dominican Republic, Guatemala, Guyana, Haiti, Honduras, Nicaragua, and Peru., Results: Geographical and financial barriers, the need to obtain permission to visit the doctor, or not wanting to go alone to a health facility significantly reduced the likelihood of completing prenatal checkups and having an assisted delivery. Women who reported difficulties obtaining permission to visit the doctor were less likely to have had a Pap smear in the past two or three years, to complete vaccination of their children, and to seek care for children with acute respiratory infection. Not wanting to go to a health center alone reduced the likelihood of using modern contraceptives., Conclusions: Women who reported barriers to access had a statistically significant lower probability of using essential health services for themselves and their children. Strategies aimed at removing barriers should focus not only on improving the range of services offered, but also address issues related to norms, gender roles, and women's empowerment if sustainable progress toward universal access is to be made.

The heating of a chromophore due to internal conversion and its cooling down due to energy dissipation to the solvent are crucial phenomena to characterize molecular photoprocesses. In this work, we simulated the ab initio nonadiabatic dynamics of cytosine, a prototypical chromophore undergoing ultrafast internal conversion, in three solvents-argon matrix, benzene, and water-spanning an extensive range of interactions. We implemented an analytical energy-transfer model to analyze these data and extract heating and cooling times. The model accounts for nonadiabatic effects, and excited- and ground-state energy transfer, and can analyze data from any dataset containing kinetic energy as a function of time. Cytosine heats up in the subpicosecond scale and cools down within 25, 4, and 1.3 ps in argon, benzene, and water, respectively. The time constants reveal that a significant fraction of the benzene and water heating occurs while cytosine is still electronically excited.

The Hebbian unlearning algorithm, i.e., an unsupervised local procedure used to improve the retrieval properties in Hopfield-like neural networks, is numerically compared to a supervised algorithm to train a linear symmetric perceptron. We analyze the stability of the stored memories: basins of attraction obtained by the Hebbian unlearning technique are found to be comparable in size to those obtained in the symmetric perceptron, while the two algorithms are found to converge in the same region of Gardner's space of interactions, having followed similar learning paths. A geometric interpretation of Hebbian unlearning is proposed to explain its optimal performances. Because the Hopfield model is also a prototypical model of the disordered magnetic system, it might be possible to translate our results to other models of interest for memory storage in materials.

Background: Progressive familial intrahepatic cholestasis (PFIC) is a spectrum of rare genetic diseases characterized by inadequate bile secretion that requires substantial ongoing care, though little research is published in this area. We report health-related quality of life (HRQoL) and work productivity outcomes from the retrospective, cross-sectional PICTURE study investigating the burden of PFIC on caregivers. Information from caregivers of patients with PFIC 1 or 2 in Germany, the United Kingdom and the United States from September 2020 to March 2021 was included., Results: The PICTURE study sample comprised HRQoL responses from 22 PFIC caregivers. Patients were on average 8.2 years old; most caregivers were 30-49 years old (68%) and mothers (77%). Median CarerQoL-7D score was 67.7/100; mean CarerQoL-VAS score for general happiness was 5.7/10 (SD 2.1). Most caregivers reported fulfilment in their caregiving responsibilities, but problems with mental and physical health, finances, and relationships. When stratified by patient's PFIC type, mean CarerQoL-7D and CarerQoL-VAS scores suggested worse HRQoL outcomes with PFIC2 versus PFIC1 (59.4 vs. 71.2, and 5.3 vs. 6.5, respectively). Additionally, more caregivers reported impact on sleep in the PFIC2 versus PFIC1 subgroup (93% vs. 75%). When stratified by history of PFIC-related surgeries, mean CarerQoL-7D and VAS scores were higher among those whose children had no specified surgeries (67.7 vs. 59.0/100 and 6.2 vs. 5.2/10, respectively). Nearly all caregivers reported an impact of caregiving responsibilities on sleeping (86%) and on personal relationships (82%). No caregivers reported having formal care support. Most caregivers were employed (73%); a third reported mean productivity loss of 12.9 days (SD 19.3) over the last 3 months, and a mean of 2.8 (SD 9.5) missed years of employment during their career. A higher number of workdays were missed by PFIC 2 caregivers compared to PFIC1 over last 3 months (16 days vs. 3 days)., Conclusions: The PICTURE study has demonstrated the prevalent, comprehensive, and meaningful burden that caring for an individual with PFIC has on caregivers. Despite fulfilment from caregiving, the breadth and depth of these responsibilities reduced caregiver reported HRQoL including mental and physical health, productivity, career prospects, sleep, relationships and finances., (© 2022. The Author(s).)

Background: Premature loss of deciduous teeth is the exfoliation or extraction before physiological replacement with < 50% or < 75% of the root of the substitute tooth formed or if there is > 1 mm of alveolar bone covering the permanent successor tooth organ. This study aimed to estimate the prevalence of premature tooth loss in children and identify associated factors in a health center in Acapulco, Guerrero., Methods: We conducted a cross-sectional study in which we collected information from 109 clinical records of children examined from January 2019 to August 2021. Sociodemographic data of the children and parents were collected: socioeconomic level, non-pathological personal history, and the history of premature deciduous tooth loss. Multivariate analysis to identify factors associated with premature deciduous tooth loss was performed with CIETmap statistical software. Odds ratio (OR) and 95% confidence interval (CI) were calculated to estimate the strength of the association., Results: The prevalence of premature loss of primary teeth was 40% (43/109). The leading cause was caries (84%, 36/43). The tooth organ with the highest loss occurrence was the lower right second molar (33%, 14/43). Gender was identified as an associated factor, with males having a higher risk of loss (ORa = 2.97; CI95% = 1.33-6.65)., Conclusions: Our results were similar to those reported in other studies. Strategies aimed at health promotion directed at parents and children should be reinforced., (Copyright: © 2022 Permanyer.)

Superionic solid electrolytes have widespread use in energy devices, but the fundamental motivations for fast ion conduction are often elusive. In this Perspective, we draw upon atomistic simulations of a wide range of superionic conductors to illustrate some ways frustration can lower diffusion cation barriers in solids. Based on our studies of halides, oxides, sulfides and hydroborates and a survey of published reports, we classify three types of frustration that create competition between different local atomic preferences, thereby flattening the diffusive energy landscape. These include chemical frustration, which derives from competing factors in the anion-cation interaction; structural frustration, which arises from lattice arrangements that induce site distortion or prevent cation ordering; and dynamical frustration, which is associated with temporary fluctuations in the energy landscape due to anion reorientation or cation reconfiguration. For each class of frustration, we provide detailed simulation analyses of various materials to show how ion mobility is facilitated, resulting in stabilizing factors that are both entropic and enthalpic in origin. We propose the use of these categories as a general construct for classifying frustration in superionic conductors and discuss implications for future development of suitable descriptors and improvement strategies. This article is part of the Theo Murphy meeting issue 'Understanding fast-ion conduction in solid electrolytes'.

Background: Dissociative symptoms are under recognized and scarcely studied by clinicians and researchers in patients with bipolar disorder (BD). We examined the relationship between dissociative symptoms and the psychotic features in patients with BD and assessed clinical and socio-demographic characteristics more frequently associated with dissociative symptoms and treatment response. Methods: Participants were 100 adult outpatients with BD. They were screened with semi-structured interview to collect socio-demographic and clinical characteristics; the Dissociative Experiences Scale-II (DES-II) and the ALDA scale were used to assess dissociative psychopathologies and response to treatment with mood stabilizers, respectively. Results: DES score (mean 31.7 ± 21.7) correlated with clinical variables, BD features, and course of illness. Psychotic symptoms, mixed features, and previous suicide attempts significantly predicted DES score [ F (3, 47) = 39.880, p < 0.001, R 2 corrected = 0.713]. Dissociative symptoms were inversely correlated with poor response to treatment ( r = -0.593; p < 0.001). Limitations: Cross-sectional design with a small sample and backward clinical assessment of psychotic symptoms. Conclusions: Dissociative phenomena are closely related to the presence of psychotic symptoms, mixed features, and previous suicide attempts in BD, especially in BD-I. Given the close association between dissociative and psychotic symptoms, this association could represent a diagnostic indicator of BD-I that may guide the clinician to plan the most appropriate treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Steardo, Carbone, Ventura, de Filippis, Luciano, Segura-Garcia and De Fazio.)

Primary acinic cell carcinoma arising in the nose is exceptionally rare. In this report, we present a unique case of an acinic cell carcinoma of the nasal lateral wall, and it is only the second such case to be reported. We also engage in a systematic review of all 18 cases of acinic cell carcinoma of the nose reported in the literature in English so far., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Dionísio et al.)

The members of the retinoblastoma (RB) protein family, RB1/p105, retinoblastoma-like (RBL)1/p107 and RBL2/p130 are critical modulators of the cell cycle and their dysregulation has been associated with tumor initiation and progression. The activity of RB proteins is regulated by numerous pathways including oncogenic signaling, but the molecular mechanisms of these functional interactions are not fully defined. We previously demonstrated that RBL2/p130 is a direct target of AKT and it is a key mediator of the apoptotic process induced by AKT inhibition. Here we demonstrated that RBL1/p107 levels are only minorly modulated by the AKT signaling pathway. In contrast, we discovered that RBL1/p107 levels are regulated by multiple pathways linked directly or indirectly to Ca 2+ -dependent signaling. Inhibition of the multifunctional calcium/calmodulin-dependent kinases (CaMKs) significantly reduced RBL1/p107 expression levels and phosphorylation, increased RBL1/p107 nuclear localization and led to cell cycle arrest in G0/G1. Targeting the Ca 2+ -dependent endopeptidase calpain stabilized RBL1/p107 levels and counteracted the reduction of RBL1/p107 levels associated with CaMKs inhibition. Thus, these novel observations suggest a complex regulation of RBL1/p107 expression involving different components of signaling pathways controlled by Ca 2+ levels, including CaMKs and calpain, pointing out a significant difference with the mechanisms modulating the close family member RBL2/p130.

The effect of water molecule on the excited states of CH 3 Cl(H 2 O), as compared to those of the isolated chloromethane, has been studied at the multireference configuration interaction with singles and doubles (MR-CISD), including extensivity corrections. Eight new Rydberg states are due to the water molecule but the common states of both systems are not severely altered. Potential energy curves of 23 singlet states along the C-Cl coordinate have also been computed at the MR-CISD level. The dissociation energy of the C-Cl bond decreases from ∼0.4 to 0.5 eV due to the water molecule. As for CH 3 Cl (de Medeiros, V. C., J. Am. Chem. Soc. 2016, 138, 272-280), a stable ion-pair has also been characterized. However, for CH 3 Cl(H 2 O), this ion-pair is better described as a solvent-shared semi-ion-pair, CH 3 +δ (H 2 O)Cl -δ . This species is connected with three ionic dissociation channels, with two being due to the water molecule. The presence of these new ionic channels, particularly the lowest energy one, [H 3 C-O] + + Cl - , raises a very important question of atmospheric relevance: can the interaction of chloroalkanes with water decrease its deleterious effect on the ozone layer? Several potentially new competing dissociation channels are also studied. The latter results can help to set up the most important states to be included in nonadiabatic dynamic calculations to study how the yields of the ionic channels change due to the water molecule.

The mining-metallurgical industry in the central Andes of Peru is a source of lead (Pb) and cadmium (Cd) contamination in milk, and there are no studies on the impact of their ingestion. Using flame atomic absorption spectrometry, we quantified the concentration of these metals in raw milk produced in agroecological zones near these industries, and estimated the exposure and dietary risk in people aged 2-85 yr with minimum, average and maximum daily milk intake. In 2018, 40 raw milk samples were collected from 20 cows at two times of the year. The mean Pb and Cd concentrations were 577 ± 18.2 and 18.35 ± 5.4 μg/kg, all samples exceeded the maximum limits (ML). Children aged 2-5 and 6-15 yr, with average milk consumption, had Pb weekly intakes (WI) of 2019 and 2423 μg, exceeding the risk value; values for Cd 64 and 77 μg were below the risk values. In those older than 20 years the WI for both metals are below the risk values. The Dietary Risk Coefficient (DRC) to Pb in children younger than 8 years was >3 due to higher milk consumption in relation to body weight; for children aged 9-19 years it was 1.7 and 2.9, being <1 for those older than 20 yr. Cd RDCs were <1 at all ages, with the exception of 2-year-olds in the high milk consumption scenario (RDC > 1). There was notable evidence of Pb and Cd exposure risk from consumption of milk produced near mining-metallurgical activities, predominantly for children under 19-year-olds. In Peru there are no regulations for Pb and Cd in fresh milk and milk products, we recommended that ML for heavy metals in food be established., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The pharmacological approach to eating disorders (ED) is effective in a few conditions, and to date, no treatment has shown certain efficacy in treating patients with this disorder. Furthermore, attempts to regulate hunger and satiety through modulation pharmacological effects of neurotransmitters and neuropeptides have shown only short-term benefit. However, in light of the serious impact of DCA on patients and the scarcity of non-pharmacological therapeutic approaches, research in this area should not be abandoned, also because new generation "molecules" become increasingly available. Many studies looked at efficacy of antipsychotics, Tryciclics, SSRI, mood stabilizers in the treatment of ED. Gabaergic circuit, the opioid one are extremely involved in the neurohormonal mechanisms of regulation of dietary behaviors and that molecules that influence these circuits could be used in the pharmacological treatment of ED as already happens in the case of Naltrexone, gabapentine or gabaergic drugs.

Introduction The purpose of this study was to clarify the role of inflammatory blood markers in the management of early-stage (T1-T2) oral squamous cell carcinoma (OSCC) of the tongue in patients with a clinically negative neck.  Materials and methods We undertook a retrospective chart review of 102 patients with early-stage OSCC of the tongue, subjected to tumor resection and elective neck dissection. Based on postsurgical histopathological examination results, we divided our cohort into pN+ and pN0 groups. Afterwards, we analyzed the role of pretreatment inflammatory blood markers in predicting occult neck metastasis. We also evaluated neutrophil-lymphocyte ratio (NLR) association with the depth of invasion (DOI) of the primary tumor. Results We found a significant association of NLR (p=0.001) and monocyte-lymphocyte ratio (p=0.011) with neck status on univariate analysis. Multivariate analysis showed that only NLR (p=0.02) was an independent risk factor for occult metastasis among inflammatory blood markers. Receiver Operating Characteristic curve analysis and Younden's Index determined the NLR value of 2.96 as the most adequate cut-off value for neck status prediction. NLR values of pretreatment workup also had a significant association with the DOI of the primary tumor (p=0.018). Conclusion Our study supports the role of pretreatment NLR in predicting occult neck metastasis in early-stage OSCC of the tongue. It also sheds some light over the potential of NLR as a predictor of the primary tumor's DOI., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Ventura et al.)

We describe the distinctive features (with images and video) of a case of chronic inflammatory demyelinating polyneuropathy (CIDP) with giant nerves. The main clinical findings were insidious onset, gait ataxia and sensory symptoms. Electrodiagnostic studies showed very slow nerve conduction velocities, multiple conduction blocks, distal CMAP duration increase and absence of F-waves. The protein level in the cerebrospinal fluid was very high. Nerve ultrasound showed swelling of all peripheral nerves outside entrapment sites, with significant variability within different segments of the same nerve; nerves were massively enlarged (up to 10-fold normal values). Brain MRI showed hypertrophic cranial nerves, with gadolinium-enhancement. Spinal MRI showed hypertrophy of spinal roots and cauda equine, with gadolinium enhancement. Genetic test (PMP22 duplication/deletion, Whole Exome Sequencing panel for neuropathies) resulted negative. The patient had a relapsing-remitting course and responded to immunoglobulin treatment. In CIDP with hypertrophic nerves, there is discrepancy between severe nerve hypertrophy and mild clinical symptoms. Nerve enlargement seems inversely related to nerve conduction velocity and directly correlated with disease duration, but not associated with disease severity., (© 2021 Peripheral Nerve Society.)

Microvascular proliferation is a key feature of glioblastoma and neovascularization has been implicated in tumor progression. Glioblastomas use pro-angiogenic factors such as vascular endothelial growth factor (VEGF) for new blood vessel formation. Yet, anti-VEGF therapy does not prolong overall survival so that alternative angiogenic pathways may need to be explored as drug targets. Both glioma cells and glioma-associated endothelial cells produce TGF-β superfamily ligands which bind TGF-β receptors (TGF-βR). The TGF-βR type III endoglin (CD105), is a marker of proliferating endothelium that has already been studied as a potential therapeutic target. We studied endoglin expression in glioblastoma tissue and in glioma-associated endothelial cells in a cohort of 52 newly diagnosed and 10 recurrent glioblastoma patients by immunohistochemistry and by ex vivo single-cell gene expression profiling of 6 tumors. Endoglin protein levels were similar in tumor stroma and endothelium and correlated within tumors. Similarly, endoglin mRNA determined by ex vivo single-cell gene expression profiling was expressed in both compartments. There was positive correlation between endoglin and proteins of TGF-β superfamily signaling. No prognostic role of endoglin expression in either compartment was identified. Endoglin gene silencing in T98G glioma cells and in human cerebral microvascular endothelial cells (hCMEC) did not affect constitutive or exogenous TGF-β superfamily ligand-dependent signaling, except for a minor facilitation of pSmad1/5 signaling in hCMEC. These observations challenge the notion that endoglin might become a promising therapeutic target in glioblastoma.

Background : Progressive familial intrahepatic cholestasis (PFIC) is an ultra-rare disease with a considerable burden on pediatric patients and their caregivers, impacting quality of life (QoL). The mortality rates highlight a significant need for efficacious treatments. Real-world data on associated costs and QoL are needed to gauge the potential impact of new pharmacological treatments. Methods : Clinical and socio-economic burden of PFIC on patients/caregivers, health systems, and society will be assessed. Patient/caregiver- and physician-level retrospective cross-sectional data will be collected from the US, UK, France, and Germany, for PFIC types 1, 2, 3.A representative sample of physicians will provide clinical and resource utilization information using an electronic Case Report Form (eCRF). Patient/caregiver surveys will collect socio-economic and QoL data, enabling assessment of PFIC impact on QoL. Mean costs (direct medical/non-medical, indirect) will be calculated.The study materials were reviewed by medical professionals and patient representatives and received ethical approval from the University of Chester. Discussion : The study aims to reveal the unmet medical need, disease burden, resource utilization, and costs of PFIC, to raise awareness with policymakers and healthcare professionals, and provide support for the patient/caregiver community. As novel PFIC therapies recently emerged, this study will yield quantifiable data for health technology assessments.

Understanding the mechanism responsible for peroxides decomposition is essential to explain several biochemical processes. The mechanisms of the intrinsic reactions between the superoxide radical anion (O2˙-) and methyl, ethyl, and tert-butyl hydroperoxides (ROOH, with R = Me, Et, and t-Bu) have been characterized to understand the mechanism responsible for peroxides decomposition. The reaction energy diagrams suggest a competition between the spin-allowed and spin-forbidden electron transfer (ET), and base-induced elimination (ECO2) mechanisms. In all cases, the spin-allowed ET mechanism describes formation of the ozonide anion radical (O3˙-), either complexed with an alcohol molecule or separated. For the O2˙-/MeOOH(EtOOH) reactions, HCO2- (MeCO2-) + H2O + HO˙ and OH- + CH2O(MeCHO) + HO2˙ products are associated with the spin-forbidden ET and ECO2 channels, respectively. On the other hand, for the reaction between O2˙- and t-BuOOH, the spin-forbidden ET route describes formation of the MeCOCH2- enolate (either separated or hydrated) along with the methyl peroxyl (MeO2˙) radical. In addition, the regeneration of O2˙-via spin-forbidden ET and ECO2 channels was also characterized from the decomposition of ROOH, yielding diols (CH2(OH)2 and MeCH(OH)2), aldehydes (CH2O and MeCHO), and oxirane (cyc-CH2CMe2O).

Cerebral peri-aneurysmal edema (PE) is typically associated with giant partially-thrombosed aneurysms and less frequently with smaller aneurysms treated with endovascular embolization. An understanding of the pathophysiologic mechanism of PE is still limited. We report 3 cases of cerebral aneurysms associated with PE. We describe 2 cases of giant partially thrombosed aneurysms surrounded by vasogenic edema with apposition of an intramural and juxtamural thrombus. Our third case is a smaller aneurysm inciting vasogenic edema several years after coil embolization. Vessel-wall magnetic resonance imaging (MRI) showed avid wall enhancement and an enhancing thrombus embedded within the coils, reflecting inflammation of the aneurysm wall and proliferation of the vasa vasorum. Thrombosis within the aneurysmal sac and walls, both in native and treated aneurysms, may promote inflammatory changes and sustain the occurrence of PE. Vessel-wall MRI has a potential role in the evaluation process of this subgroup of aneurysms.

Objective: Hearing loss is a highly disabling condition. Cochlear implantation is an established remedy if conventional hearing aids have failed to alleviate the level of disability. Unfortunately, cochlear implant (CI) performance varies dramatically. This study aims to examine the effects of duration of deafness (DoD) prior to cochlear implantation and the postoperative duration of implant experience with resulting hearing performance in postlingually deaf patients., Methods: A systematic literature review and two meta-analyses were conducted using the search terms cochlear implant AND duration deafness . Included studies evaluate the correlation between the DoD and auditory performance after cochlear implantation using monosyllabic and sentence tests. Correlation coefficients were determined using Pearson's correlation and Spearman rho., Results: A total of 36 studies were identified and included data on cochlear implantations following postlingual deafness and postoperative speech testing of hearing outcomes for 1802 patients. The mean age ranged from 44 to 68 years with a DoD of 0.1 to 77 years. Cochlear implant use varied from 3 months to 14 years of age. Speech perception, which was assessed by sentence and monosyllabic word perception, was negatively correlated with DoD. Subgroup analyses revealed worse outcomes for longer DoD and shorter postoperative follow-up., Conclusion: DoD is one of the most important factors to predict speech perception after cochlear implantation in postlingually deaf patients. The meta-analyses revealed a negative correlation between length of auditory deprivation and postoperative sentence and monosyllabic speech perception. Longer DoD seems to lead to worse CI performance, whereas more experience with CI mitigates the effect., Competing Interests: The authors have no conflict of interest to declare., (© 2021 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC. on behalf of The Triological Society.)

So far, no conclusive evidence of a ground-state contact ion-pair containing a hydrocarbon carbocation has been given in the gas phase. Due to the very high stability of the 1,2:4,5-dibenzotropylium (or dibenzo[ a , d ]tropylium) carbocation, we suggest (supported by DFT and MP2 calculations) the formation of a contact ion pair between this carbocation and chloride, occurring during the reaction between 1,2:4,5-dibenzotropyl (also named dibenzo[ a , d ]tropyl or dibenzo[ a , d ]cycloheptenyl) radical and chlorine atom at very low temperatures, through the harpoon mechanism. This is the first modeling study to find computational evidence for the possibility of a gas-phase contact ion pair (containing a hydrocarbon carbocation) formed in the ground state. Identification of this metastable species can be carried out by trapping it in He nanodroplets, along with infrared laser spectroscopy routinely coupled with this technique., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

HIV reverse transcriptases (RTs) convert viral genomic RNA into double-stranded DNA. During reverse transcription, polypurine tracts (PPTs) resilient to RNase H cleavage are used as primers for plus-strand DNA synthesis. Nonnucleoside RT inhibitors (NNRTIs) can interfere with the initiation of plus-strand DNA synthesis by enhancing PPT removal, while HIV RT connection subdomain mutations N348I and N348I/T369I mitigate this effect by altering RNase H cleavage specificity. Now, we demonstrate that among approved nonnucleoside RT inhibitors (NNRTIs), nevirapine and doravirine show the largest effects. The combination N348I/T369I in HIV-1 BH10 RT has a dominant effect on the RNase H cleavage specificity at the PPT/U3 site. Biochemical studies showed that wild-type HIV-1 and HIV-2 RTs were able to process efficiently and accurately all tested HIV PPT sequences. However, the cleavage accuracy at the PPT/U3 junction shown by the HIV-2 EHO RT was further improved after substituting the sequence YQEPFKNLKT of HIV-1 BH10 RT (positions 342-351) for the equivalent residues of the HIV-2 enzyme (HQGDKILKV). Our results highlight the role of β-sheets 17 and 18 and their connecting loop (residues 342-350) in the connection subdomain of the large subunit, in determining the RNase H cleavage window of HIV RTs.

Glioblastoma is an invariably deadly disease. A subpopulation of glioma stem-like cells (GSCs) drives tumor progression and treatment resistance. Two recent studies demonstrated that neurons form oncogenic glutamatergic electrochemical synapses with post-synaptic GSCs. This led us to explore whether glutamate signaling through G protein-coupled metabotropic receptors would also contribute to the malignancy of glioblastoma. We found that glutamate metabotropic receptor (Grm)3 is the predominantly expressed Grm in glioblastoma. Associations of GRM3 gene expression levels with survival are confined to the proneural gene expression subtype, which is associated with enrichment of GSCs. Using multiplexed single-cell qRT-PCR, GSC marker-based cell sorting, database interrogations, and functional assays in GSCs derived from patients' tumors, we establish Grm3 as a novel marker and potential therapeutic target in GSCs. We confirm that Grm3 inhibits adenylyl cyclase and regulates extracellular signal-regulated kinase. Targeting Grm3 disrupts self-renewal and promotes differentiation of GSCs. Thus, we hypothesize that Grm3 signaling may complement oncogenic functions of glutamatergic ionotropic receptor activity in neuroglial synapses, supporting a link between neuronal activity and the GSC phenotype. The novel class of highly specific Grm3 inhibitors that we characterize herein have been clinically tested as cognitive enhancers in humans with a favorable safety profile., (© 2020 The Authors.)

Selective androgen receptor modulators (SARMs) are a group of anabolic enhancer drugs posing threats to the integrity of animal sports and the safety of animal-derived foods. The current research describes for the first time the development of a semi-quantitative assay for the monitoring of SARM family compounds in blood and establishes the relative stability of these analytes under various storage conditions prior to analysis. The presented screening method validation was performed in line with current EU legislation for the inspection of livestock and produce of animal origin, with detection capability (CCβ) values determined at 0.5 ng/mL (Ly2452473), 1 ng/mL (AC-262536 and PF-06260414), 2 ng/mL (bicalutamide, GLPG0492, LGD-2226, ostarine, S-1, S-6, and S-23), and 5 ng/mL (andarine, BMS-564929, LGD-4033, RAD140, and S-9), respectively. The applicability of the developed assay was demonstrated through the analysis of blood samples from racehorses and cattle. The developed method presents a high-throughput cost-effective tool for the routine screening for a range of SARM compounds in sport and livestock animals., (© 2020 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.)

Background: Ferritin, a crucial element for iron homeostasis, is associated with chronic diseases characterized by subclinical inflammation such as essential arterial hypertension and type 2 diabetes mellitus (T2DM), showing a prognostic value in different clinical settings. We investigated whether ferritin is associated with arterial stiffness (AS), an early indicator of atherosclerosis, and if it could act as effect modifier on the relationship between inflammation and AS in hypertensive patients with different glucose tolerance., Methods: We enrolled 462 newly diagnosed untreated hypertensive (HT) patients. All subjects underwent an oral glucose tolerance test. Insulin sensitivity was assessed by MATSUDA index and ferritin levels were estimated by immunoradiometric assay. AS was defined by carotid-femoral pulse wave velocity (PWV)., Results: Out of 462 patients, 271 showed normal glucose tolerance (HT/NGT), 146 impaired glucose tolerance (HT/IGT) and 45 were diabetic (HT/T2DM). Iron levels significantly decreased and transferrin and ferritin significantly increased from the first to the third group. PWV values were significantly higher in HT/IGT and HT/T2DM patients. PWV was related directly with ferritin, high sensitivity C reactive protein (hs-CRP), transferrin, and inversely with MATSUDA index. Ferritin resulted the strongest determinant of PWV explaining a 14.9% of its variation; moreover it was a strong modifier of the relationship between hs-CRP and PWV. The estimated augmentation in PWV portended by a fixed increase in hs-CRP, was higher across increasing values of ferritin., Conclusion: Ferritin represents an independent risk factor of arterial stiffness in our study population and a strong effect modifier on the relationship between inflammation and PWV. However, further studies are needed to fully elucidate the potential role of this biomarker in human atherosclerosis.

Selective androgen receptor modulators (SARMs) are a class of new emerging "designer" steroid compounds gaining popularity over more well established anabolic-androgenic steroids (AAS) amongst both non-professional and elite athletes. Moreover, due to their anabolic activity, SARM compounds may also potentially be abused in livestock animals to increase meat production. Consequently, SARM residues should be monitored as a part of routine testing employed within both anti-doping and drug residue laboratories. Since only a limited amount of information on SARM compound stability is currently available within the peer-reviewed literature, this study reports a practical approach to assess optimal storage conditions for 15 SARM compounds in solvent solutions (standard stock and intermediate mixed standard solutions) stored at -20°C for up to 1 year, as well as in a range of urine test matrices (bovine, equine, canine and human) under frozen (-20°C, -80°C) storage for up to 20 weeks and post freeze-thaw cycles. Moreover, SARM storage stability within solvent extracts was assessed at -20°C (0-4 weeks) and 4°C (0-2 weeks). Findings demonstrate that SARM analytes are stable in reference solutions when stored at -20°C, apart from PF-06260414 (stock solution) which should be stored at lower temperatures (e.g. -80°C). A limited degree of compound instability was observed for a number of SARM analytes in urine both when stored at -20°C, and after repeated freeze-thaw cycles. Moreover, SARM compounds within reconstituted urine solvent extracts were found to be effectively stable when stored for up to 4 weeks at -20°C and for 2 weeks at 4°C. The long-term stability testing data reported here will inform the more timely and effective development and validation of analytical methods for SARM residue detection and analysis, ensuring confidence in findings from monitoring of livestock animals and anti-doping processes.

Purpose: Circulating IGF-1 concentrations have been associated with higher cancer risk, particularly prostate, breast and colorectal cancer. There is evidence from observational and intervention studies that milk and dairy products intake is associated with higher IGF-1 concentrations, but results were not always consistent. The purpose of this study was to examine the relationship between dairy intake and circulating IGF-1 concentrations in participants of the Second Bavarian Food Consumption Survey, thereby providing data for a German population for the first time., Methods: In this cross-sectional study of 526 men and women aged 18-80 years, in contrast to most previous investigations, dietary intake was assessed with a more detailed instrument than food frequency questionnaires (FFQs), i.e., by three 24-h dietary recalls conducted on random days close in time to the blood collection. Circulating IGF-1 concentrations were measured in blood samples. Multivariable linear regression models were used to examine the association of dairy intake with IGF-1 concentrations., Results: Each 400 g increment in daily dairy intake was associated with 16.8 µg/L (95% CI 6.9, 26.7) higher IGF-1 concentrations. Each 200 g increment in milk per day was associated with 10.0 µg/L (95% CI 4.2, 15.8) higher IGF-1. In contrast, we observed no association between cheese or yogurt intake and IGF-1 concentrations., Conclusions: Our findings are in line with most previous investigations and support the hypothesis that dairy and milk intake are associated with higher IGF-1 concentrations.