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Abstract Sea cucumbers are deposit feeding members of marine benthic communities. The over-exploitation of sea cucumber natural stocks, especially in the Mediterranean basin, is having negative impacts on the marine ecosystem. This concerns had led the Italian government to take legal actions to preserve these important marine resources. The aim of this study was to evaluate the level of genetic diversity and population structures within two sympatric Holothuria sea cucumber species, H. polii and H. tubulosa, across ten Mediterranean areas along Italy. A 323 bp portion of the COI mitochondrial gene was sequenced in a total of 441 holothurians (251 H. polii, 177 H. tubulosa and 13 from other species). Genetic diversity analyses and analysis of molecular variance (AMOVA) suggest that H. polii and H. tubulosa species are distinct, but within and among populations are homogeneous, indicating active gene flows across the Mediterranean areas investigated. H. polii showed a lower genetic diversity than H. tubulosa, probably related to differences in life history traits. Phylogenetic analyses showed a clear differentiation between the two species, even if six specimens morphologically assigned to a species clustered within the other species, indicating a possible occurrence of hybridization events. These data will be useful in implementing conservation actions for these holothurian genetic resources.

Objectives: Moderate daily mocha pot coffee intake has been associated with better mood and cognition in patients with mild vascular cognitive impairment (VCI). Similarly, moderate red wine consumption has shown protective effects on cognitive disorders, including Alzheimer's disease and vascular dementia. The aim of this study was to explore the synergistic relation between red wine and coffee intake on mood and cognitive status in mild VCI patients at risk for dementia. Methods: A total of 300 non-demented older patients with mild VCI were asked for coffee and red wine consumption and administered with the 17-items Hamilton Depression Rating Scale (HDRS), the Mini Mental State Examination (MMSE), and the Stroop Color-Word Interference Test (Stroop T), as well as the Activities of Daily Living (ADL) and the Instrumental ADL to measure their mood status, cognitive performance, and functional independence. Linear regression models were used to test the association between variables. Results: Moderate wine drinkers tended to show the best Stroop T score at any level of coffee consumption; conversely, heavy wine consumers performed worse at the Stroop T, especially in patients reporting high coffee intake. Moderate drinkers of both coffee and wine showed the lowest HDRS scores. Finally, a progressive increase in MMSE score was evident with increasing coffee consumption, which peaks when combined with a moderate wine consumption. Conclusions: Daily mocha pot coffee and red wine intake seem to be synergistically associated with global cognition, executive functioning, and mood status in patients with mild VCI; the association was not linear, resulting in a protective direction for moderate intake and detrimental for heavy consumption. Future studies are needed to further corroborate the present findings and the potential long-term protective effects of these dietary compounds over time.

Ratings of test item relevance were collected from 57 practitioners from a pretest of a medical certifying examination. Ratings were correlated with item difficulty, but the relationship between ratings and item discrimination was less clear. Application of generalizability theory shows that reasonable estimates of item, stem, and total test relevance can be obtained with about 10 raters. (SLD)

Abstract Over the last decades, the Mediterranean diet gained enormous scientific, social, and commercial attention due to proven positive effects on health and undeniable taste that facilitated a widespread popularity. Researchers have investigated the role of Mediterranean-type dietary patterns on human health all around the world, reporting consistent findings concerning its benefits. However, what does truly define the Mediterranean diet? The myriad of dietary scores synthesizes the nutritional content of a Mediterranean-type diet, but a variety of aspects are generally unexplored when studying the adherence to this dietary pattern. Among dietary factors, the main characteristics of the Mediterranean diet, such as consumption of fruit and vegetables, olive oil, and cereals should be accompanied by other underrated features, such as the following: (i) specific reference to whole-grain consumption; (ii) considering the consumption of legumes, nuts, seeds, herbs and spices often untested when exploring the adherence to the Mediterranean diet; (iii) consumption of eggs and dairy products as common foods consumed in the Mediterranean region (irrespectively of the modern demonization of dietary fat intake). Another main feature of the Mediterranean diet includes (red) wine consumption, but more general patterns of alcohol intake are generally unmeasured, lacking specificity concerning the drinking occasion and intensity (i.e., alcohol drinking during meals). Among other underrated aspects, cooking methods are rather simple and yet extremely varied. Several underrated aspects are related to the quality of food consumed when the Mediterranean diet was first investigated: foods are locally produced, minimally processed, and preserved with more natural methods (i.e., fermentation), strongly connected with the territory with limited and controlled impact on the environment. Dietary habits are also associated with lifestyle behaviors, such as sleeping patterns, and social and cultural values, favoring commensality and frugality. In conclusion, it is rather reductive to consider the Mediterranean diet as just a pattern of food groups to be consumed decontextualized from the social and geographical background of Mediterranean culture. While the methodologies to study the Mediterranean diet have demonstrated to be useful up to date, a more holistic approach should be considered in future studies by considering the aforementioned underrated features and values to be potentially applied globally through the concept of a “Planeterranean” diet.

Abstract We introduce a novel technique for designing color filter metasurfaces using a data-driven approach based on deep learning. Our innovative approach employs inverse design principles to identify highly efficient designs that outperform all the configurations in the dataset, which consists of 585 distinct geometries solely. By combining Multi-Valued Artificial Neural Networks and back-propagation optimization, we overcome the limitations of previous approaches, such as poor performance due to extrapolation and undesired local minima. Consequently, we successfully create reliable and highly efficient configurations for metasurface color filters capable of producing exceptionally vivid colors that go beyond the sRGB gamut. Furthermore, our deep learning technique can be extended to design various pixellated metasurface configurations with different functionalities.

In recent years, the search for novel natural-based ingredients by food and related industries has sparked extensive research aimed at discovering new sources of functional molecules. Camellia japonica, traditionally known as an ornamental plant, has gained attention due to its diverse array of bioactive compounds with potential industrial applications. Although C. japonica flowers are edible, their phytochemical profile has not been thoroughly investigated. In this study, a phenolic profile screening through an HPLC–ESI-QQQ-MS/MS approach was applied to C. japonica flower extracts, revealing a total of 36 compounds, including anthocyanins, curcuminoids, dihydrochalcones, dihydroflavonols, flavonols, flavones, hydroxybenzoic acids, hydroxycinnamic acids, isoflavonoids, stilbenes, and tyrosols. Following extract profiling, their bioactivity was assessed by means of in vitro antioxidant, antimicrobial, cytotoxic, and neuroprotective activities. The results showed a multifaceted high correlation of phenolic compounds with all the tested bioactivities according to Pearson’s correlation analysis, unraveling the potential of C. japonica flowers as promising sources of nutraceuticals. Overall, these findings provide insight into the valorization of C. japonica flowers from different unexplored cultivars thus diversifying their industrial outcome.

Abstract Natural climate solutions provide opportunities to reduce greenhouse gas emissions and the United States is among a growing number of countries promoting storage of carbon in agricultural soils as part of the climate solution. Historical patterns of soil organic carbon (SOC) stock changes provide context about mitigation potential. Therefore, our objective was to quantify the influence of climate-smart soil practices on SOC stock changes in the top 30 cm of mineral soils for croplands in the United States using the DayCent Ecosystem Model. We estimated that SOC stocks increased annually in US croplands from 1995 to 2015, with the largest increase in 1996 of 16.6 Mt C (95% confidence interval ranging from 6.1 to 28.2 Mt CO2 eq.) and the lowest increase in 2015 of 10.6 Mt C (95% confidence interval ranging from − 1.8 to 22.2 Mt C). Most climate-smart soil practices contributed to increases in SOC stocks except for winter cover crops, which had a negligible impact due to a relatively small area with cover crop adoption. Our study suggests that there is potential for enhancing C sinks in cropland soils of the United States although some of the potential has been realized due to past adoption of climate-smart soil practices.

Purpose: The present study sought to provide reproducible and patient-oriented metrics to assess the rate of “successful” outcomes (Trifecta) following holmium laser enucleation of the prostate (HoLEP). Clinical and surgical predictors of failure to achieve Trifecta were investigated. Materials and Methods: We queried our prospectively collected database of all patients treated with HoLEP between March 2017 and January 2021. Trifecta was defined as the contemporary presence of: (1) no postoperative complication within 3 months; (2) no urinary incontinence at 3-months follow-up; and (3) 3-month postoperative max flow-rate >15 mL/s. Cases were grouped according to Trifecta achievement. All surgical procedures were carried out by a single surgeon. Surgical experience was divided into two different eras according to the number of procedures conducted (surgical era). Multivariate logistic regression analysis was performed to assess predictors of Trifecta failure. Results: Overall 305 patients were included. Of these, 192 patients (63.0%) achieved Trifecta. Preoperative patient-related features were comparable between the two groups, except for a higher post-void residual (PVR) in non-Trifecta patients (median 180 vs. 130 mL, p=0.003). A significant proportion of Trifecta patients (88.5%) were treated in the second surgical era and in 126 (65.6%) cases an en-bloc enucleation was performed. Multivariate analysis confirmed PVR ≥250 mL, first surgical era and standard three-lobes enucleation technique as independent predictors of Trifecta failure. Conclusions: In our experience the rate of “successful” HoLEP, defined according to our newly introduced Trifecta metric, was 63.0%. We demonstrated that surgical strategy together with rising experience and baseline PVR are key elements to forecast the outcomes.

This study investigates whether humans recognize different emotions conveyed only by the kinematics of a single moving geometrical shape and how this competence unfolds during development, from childhood to adulthood. To this aim, animations in which a shape moved according to happy, fearful, or neutral cartoons were shown, in a forced-choice paradigm, to 7- and 10-year-old children and adults. Accuracy and response times were recorded, and the movement of the mouse while the participants selected a response was tracked. Results showed that 10-year-old children and adults recognize happiness and fear when conveyed solely by different kinematics, with an advantage for fearful stimuli. Fearful stimuli were also accurately identified at 7-year-olds, together with neutral stimuli, while, at this age, the accuracy for happiness was not significantly different than chance. Overall, results demonstrates that emotions can be identified by a single point motion alone during both childhood and adulthood. Moreover, motion contributes in various measures to the comprehension of emotions, with fear recognized earlier in development and more readily even later on, when all emotions are accurately labeled.

Objective When considering proposals to improve diets, it is important to understand how factors like price and income can affect saturated fat (SF) intake and demand. In this study, we examine and estimate the influence of price and income on intake across 160 countries, by age and sex, and derive sensitivity measures (price elasticities) that vary by age, sex and world region.Design We econometrically estimate intake responsiveness to income and prices across countries, accounting for differences by world region, age and sex. Intake data by age, sex and country were obtained from the 2018 Global Dietary Database. These data were then linked to global price data for select food groups from the World Bank International Comparison Programme and income data from the World Development Indicators Databank (World Bank).Results Intake differences due to price were highly significant, with a 1% increase in price associated with a lower SF intake (% energy/d) of about 4.3 percentage points. We also find significant differences across regions. In high-income countries, median (age 40) intake reductions were 1.4, 0.8 and 0.2 percentage points, given a 1% increase in the price of meat, dairy, and oils and fats, respectively. Price elasticities varied with age but not sex. Intake differences due to income were insignificant when regional binary variables were included in the analysis.Conclusion The results of this study show heterogeneous associations among prices and intake within and across countries. Policymakers should consider these heterogeneous effects as they address global nutrition and health challenges.

Abstract The epigenetic role of microRNAs is established at both physiological and pathological levels. Dysregulated miRNAs and their targets appear to be a promising approach for innovative anticancer therapies. In our previous study, circulating miR-197-3p tested dysregulated in workers ex-exposed to asbestos (WEA). Herein, an epigenetic investigation on this circulating miRNA was carried out in sera from malignant pleural mesothelioma (MPM) patients. MiR-197-3p was quantified in MPM (n = 75) sera and comparatively analyzed to WEA (n = 75) and healthy subject (n = 75) sera, using ddPCR and RT-qPCR techniques. Clinicopathological characteristics, occupational, non-occupational information and overall survival (OS) were evaluated in correlation studies. MiR-197-3p levels, analyzed by ddPCR, were significantly higher in MPM than in WEA cohort, with a mean copies/µl of 981.7 and 525.01, respectively. Consistently, RT-qPCR showed higher miR-197-3p levels in sera from MPM with a mean copies/µl of 603.7, compared to WEA with 336.1 copies/µl. OS data were significantly associated with histologic subtype and pleurectomy. Circulating miR-197-3p is proposed as a new potential biomarker for an early diagnosis of the MPM onset. Indeed, miR-197-3p epigenetic investigations along with chest X-ray, computed tomography scan and spirometry could provide relevant information useful to reach an early and effective diagnosis for MPM.

Scientific evidence suggests a relation between dietary factors and sleep. Several studies show that higher adherence to the Mediterranean diet is associated with better sleep quality, but the relation with chronotype has been only recently explored. The aim of this study was to better understand the relation between chronotype and Mediterranean diet adherence. For this purpose, an analysis of 1936 adults (age 18–90 y) living in Italy was performed to investigate the association between chronotype (assessed with a short form of the morningness-eveningness questionnaire) and adherence to the Mediterranean diet (assessed through a 110-item food frequency questionnaire and the Medi-Lite literature-based Mediterranean adherence score). A multivariate logistic regression analysis was conducted to calculate odds ratios (OR) and 95 % confidence intervals (CIs) describing the association between chronotypes and high adherence to the Mediterranean diet (>14 points). Moreover, a systematic review of other observational studies published so far was performed. Individuals reporting having intermediate (n = 614) and evening (n = 173) chronotypes were less likely to have high adherence to the Mediterranean diet compared to morning chronotype (OR = 0.28, 95 % CI: 0.18, 0.42 and OR = 0.08, 95 % CI: 0.03, 0.27, respectively). When the analysis was conducted in subgroups of age, the results were similar in mid-age (>50 y) participants (for intermediate and evening chronotypes, OR = 0.21, 95 % CI: 0.10, 0.43 and OR = 0.92, 95 % CI: 0.01, 0.69, respectively) while the association with high adherence to the Mediterranean diet of evening compared to morning chronotype lost significance in older (>60 y) participants (for intermediate and evening chronotypes, OR = 0.27, 95 % CI: 0.09, 0.82 and OR = 0.22, 95 % CI: 0.02, 1.92, respectively). Out of 10 studies (date range of publication 2020–2022) included in the systematic review, there was a general consistence of findings showing higher adherence to the Mediterranean diet among morning chronotypes, although few studies reported null results. In conclusion, current evidence suggests that an intermediate and evening chronotype could be associated with lower adherence to a Mediterranean diet, but the association could be modified by other factors when considering older individuals.

Abstract Vascular endothelial growth factor-A (VEGF) physiologically regulates both angiogenesis and osteogenesis, but its application in bone tissue engineering led to contradictory outcomes. A poorly understood aspect is how VEGF dose impacts the coordination between these two processes. Taking advantage of a unique and highly tunable platform, here we dissected the effects of VEGF dose over a 1,000-fold range in the context of tissue-engineered osteogenic grafts. We found that osteo-angiogenic coupling is exquisitely dependent on VEGF dose and that only a tightly defined dose range could stimulate both vascular invasion and osteogenic commitment of progenitors, with significant improvement in bone formation. Further, VEGF dose regulated Notch1 activation and the induction of a specific pro-osteogenic endothelial phenotype, independently of the promotion of vascular invasion. Therefore, in a therapeutic perspective, fine-tuning of VEGF dose in the signaling microenvironment is key to ensure physiological coupling of accelerated vascular invasion and improved bone formation.

Abstract The aim of this study was to assess the relationship of clinical characteristics to the rate of retinal thinning in eyes with diabetic macular edema (DME) treated with anti-vascular endothelial growth factor (VEGF) therapy. We analyzed subjects with a long-term follow-up (≥ 3 years) and evidence of resolved DME after the initiation of anti-VEGF therapy (baseline visit). To measure the long-term rate of retinal thinning during treatment, a second visit (first visit with evidence of resolved DME after 3 years) was also considered. A longitudinal quantitative topographical assessment of the inner and outer retinal thicknesses was provided. Clinical characteristics were associated with the rate of longitudinal retinal thinning. We included 56 eyes (50 patients) in the analysis. A significant longitudinal thinning in the inner and outer retina was detected in all the analyzed regions (p values between 0.027 and

Abstract Filter-feeding mussels blend suspended particles into faeces and pseudo-faeces enhancing organic matter flows between the water column and the bottom, and strengthening benthic-pelagic coupling. Inside operating farms, high bivalve densities in relatively confined areas result in an elevated rate of organic sinking to the seabed, which may cause a localized impact in the immediate surrounding. Deposit-feeding sea cucumbers are potentially optimal candidates to bioremediate mussel organic waste, due to their ability to process organic-enriched sediments impacted by aquaculture waste. However, although the feasibility of this polyculture has been investigated for a few Indo-Pacific species, little is known about Atlanto-Mediterranean species. Hence, for the first time, in the present study, we conducted a comparative investigation on the suitability of different Mediterranean sea cucumber species, to be reared in Integrated Multitrophic Aquaculture (IMTA) with mussels. A pilot-scale experiment was accomplished operating within a mussel farm where two sea cucumbers species, Holothuria tubulosa and Holothuria polii, were caged beneath the long-line mussel farm of Mytilus galloprovincialis. After four months, H. tubulosa showed high survivorship (94%) and positive somatic growth (6.07%); conversely H. polii showed negative growth (− 25.37%), although 92% of specimens survived. Furthermore, sea cucumber growth was size-dependent. In fact, smaller individuals, independently from the species, grew significantly faster than larger ones. These results evidenced a clear difference in the suitability of the two sea cucumber species for IMTA with M. galloprovincialis, probably due to their different trophic ecology (feeding specialization on different microhabitats, i.e. different sediment layers). Specifically, H. tubulosa seems to be an optimal candidate as extractive species both for polycultures production and waste bioremediation in M. galloprovincialis operating farms.

Objective This qualitative study aimed to identify person-centred domains that would contribute to the definition and measurement of abortion quality of care based on the perceptions, experiences and priorities of people seeking abortion.Methods We conducted interviews with people seeking abortion aged 15–41 who obtained care in Argentina, Bangladesh, Ethiopia or Nigeria. Participants were recruited from hospitals, clinics, pharmacies, call centres and accompaniment models. We conducted thematic analysis and quantified key domains of quality identified by the participants.Results We identified six themes that contributed to high-quality abortion care from the clients’ perspective, with particular focus on interpersonal dynamics. These themes emerged as participants described their abortion experience, reflected on their interactions with providers and defined good and bad care. The six themes included (1) kindness and respect, (2) information exchange, (3) emotional support, (4) attentive care throughout the process, (5) privacy and confidentiality and (6) prepared for and able to cope with pain.Conclusions People seeking abortion across multiple country contexts and among various care models have confirmed the importance of interpersonal care in quality. These findings provide guidance on six priority areas which could be used to sharpen the definition of abortion quality, improve measurement, and design interventions to improve quality.

Acropora palmata is a foundational yet endangered Caribbean reef-building coral species. The lack of recovery after a disease outbreak and low recruitment has led to widespread use of fragmentation to restore populations. Another option is the production of sexual recruits (settlers) via assisted reproduction to improve the genetic diversity of depleted populations; however, the viability of this approach has not been tested over the long term. In 2011 and 2012, A. palmata larvae were cultured, settled, and the sexual recruits raised in an ex-situ nursery. Survival and growth were monitored over time. In 2014, these two F1 cohorts were moved to an in-situ nursery and after one year, a subset (29 colonies) was outplanted onto Cuevones Reef in the Mexican Caribbean. Growth and survival of these colonies were monitored periodically and compared to colonies that remained in the in-situ nursery. In 2019, samples were collected and analyzed for fertility and fecundity. 53% of the colonies were gravid and fecundity was 5.61 ± 1.91 oocytes and 3.04 ± 0.26 spermaries per polyp. A further 14 colonies from these two cohorts were outplanted in 2020 onto Picudas Reef and monitored during the subsequent spawning seasons. Two years after outplanting onto Picudas Reef, all colonies were alive and spawning of three of these colonies was recorded in 2022 in synchrony with the wild population. Gametes were collected from two colonies and crossed, with 15% fertilization success. Spermatozoa from wild colonies were then added and fertilization success increased to 95%. The resultant larvae followed normal development and symbiont uptake was visible within two weeks. The F2 generation was settled, maintained in an ex-situ nursery, and monitored for survival and growth. Both F1 and F2 generations followed a Type III survival curve with high initial mortality while in the ex-situ nursery and low later-stage mortality. The growth rates of these colonies increased three-fold after outplanting when compared to their growth rates in the ex-situ and in-situ nurseries. All colonies survived while in the in-situ nursery and for an additional nine years after outplanting onto Cuevones Reef. Overall, our results show that colonies produced by assisted breeding, once outplanted, may contribute to the genetic diversity and establishment of self-sustaining sexually-reproducing populations, which is an overarching goal of coral restoration programs.

Objective The objective of this study was to identify trajectories of depressive symptoms (DSs) during the first half of drug-sensitive pulmonary tuberculosis (PTB) treatment and examine their association with loss to follow-up (LTFU) in the second half.Design This study involved a secondary analysis of longitudinal data to identify potential trajectories of DS and their relationship with LTFU.Setting The study was conducted in first and second-level health centres located in San Juan de Lurigancho, Lima, Peru.Participants Anonymised data from 265 individuals, including monthly measures of DSs from diagnosis to the completion of treatment, initiation of treatment for multidrug resistant TB, LTFU or death, were collected.Results Three trajectories were identified: ‘declining’, ‘growth’ and ‘high’. These trajectories were observed in 182 (68.7%), 53 (20%) and 30 (11.3%) of the 265 individuals, respectively, during the first half of PTB treatment. Compared with those with a ‘declining’ trajectory, individuals with a ‘growth’ trajectory had a higher likelihood of experiencing LTFU during the second half of PTB treatment, after controlling for sociodemographic factors and at least weekly alcohol use (OR 3.9; 95% CI 1.09 to 13.97, p=0.036).Conclusions The findings suggest that a trajectory of increasing DSs during the first half of PTB treatment is associated with a higher risk of LTFU during the second half.

Stony coral tissue loss disease (SCTLD) has caused high mortality of at least 25 coral species across the Caribbean, with Pseudodiploria strigosa being the second most affected species in the Mexican Caribbean. The resulting decreased abundance and colony density reduces the fertilization potential of SCTLD-susceptible species. Therefore, larval-based restoration could be of great benefit, though precautionary concerns about disease transmission may foster reluctance to implement this approach with SCTLD-susceptible species. We evaluated the performance of offspring obtained by crossing gametes of a healthy P. strigosa colony (100% apparently healthy tissue) with that of a colony affected by SCTLD (>50% tissue loss) and compared these with prior crosses between healthy parents. Fertilization and settlement were as high as prior crosses among healthy parents, and post-settlement survivorship over a year in outdoor tanks was 7.8%. After thirteen months, the diseased-parent recruits were outplanted to a degraded reef. Their survivorship was ∼44% and their growth rate was 0.365 mm ± 1.29 SD per month. This study shows that even diseased parent colonies can be effective in assisted sexual reproduction for the restoration of species affected by SCTLD.

Olive leaves are consumed as an extract or as a whole herbal powder with several potential therapeutic benefits attributed to polyphenols, tocopherol’s isomers, and flavonoids, among others. This study assessed the potential variance in the functional features presented by olive leaves from three different Portuguese cultivars—Cobrançosa, Madural, and Verdeal—randomly mix-cultivated in the geographical area of Vale de Salgueiros. Inorganic analysis determined their mineral profiles while an organic analysis measured their total phenolic and flavonoid content, and scanned their phenolic and tocopherol and fatty acid composition. The extracts’ biological activity was tested by determining their antimicrobial and antioxidant power as well as their ability to inhibit acetylcholinesterase, butyrylcholinesterase, MAO-A/B, and angiotensin-I-converting enzyme. The inorganic profiles showed them to be an inexpensive source able to address different mineral deficiencies. All cultivars appear to have potential for use as possible antioxidants and future alternative antibiotics against some multidrug-resistant microorganisms, with caution regarding the arsenic content in the Verdeal cultivar. Madural’s extract displayed properties to be considered a natural multitarget treatment for Alzheimer’s and Parkinson’s diseases, depression, and cardiometabolic and dual activity for blood pressure modulation. This work indicates that randomly cultivating different cultivars significantly modifies the leaves’ composition while keeping their multifaceted therapeutic value.

Isoflavones are a group of (poly)phenols, also defined as phytoestrogens, with chemical structures comparable with estrogen, that exert weak estrogenic effects. These phytochemical compounds have been targeted for their proven antioxidant and protective effects. Recognizing the increasing prevalence of cardiovascular diseases (CVD), there is a growing interest in understanding the potential cardiovascular benefits associated with these phytochemical compounds. Gut microbiota may play a key role in mediating the effects of isoflavones on vascular and endothelial functions, as it is directly implicated in isoflavones metabolism. The findings from randomized clinical trials indicate that isoflavone supplementation may exert putative effects on vascular biomarkers among healthy individuals, but not among patients affected by cardiometabolic disorders. These results might be explained by the enzymatic transformation to which isoflavones are subjected by the gut microbiota, suggesting that a diverse composition of the microbiota may determine the diverse bioavailability of these compounds. Specifically, the conversion of isoflavones in equol—a microbiota-derived metabolite—seems to differ between individuals. Further studies are needed to clarify the intricate molecular mechanisms behind these contrasting results.

Healthy successful aging with preserved mental and cognitive health is expected to be one of the most important challenges of the growing old population globally. Studies investigating these multi-dimensional aspects of senescence are important to identify potential targets for early prevention. The aim of this study was to investigate the relation between adherence to the Mediterranean diet and mental and cognitive health, quality of life, and successful aging in middle-age and older adults living in Sicily, southern Italy. Data from a sample of 883 individuals was collected including information on food intake (through a 110-item food frequency questionnaire), sleep quality (through the Pittsburgh sleep quality index) depressive symptoms (through the Center for the Epidemiological Studies of Depression Short Form), quality of life (through the Manchester Short Assessment of Quality of Life), cognitive status (through the Short Portable Mental Status Questionnaire), and overall successful aging (through the Successful Aging Index). Multivariate logistic regression analyses were conducted to assess the association between adherence to the Mediterranean diet and the outcomes investigated. After adjustment for potential confounding factors, individuals in the highest quartile of adherence to the Mediterranean diet were less likely to have cognitive impairment (OR = 0.19, 95 % CI: 0.04, 0.86), depressive symptoms (OR = 0.19, 95 % CI: 0.08, 0.46) and more likely to have good quality of life (OR = 14.04, 95 % CI: 6.81, 28.93); significant results were also found for individuals in the third quartile of Mediterranean diet adherence and good sleep quality (OR = 1.65, 95 % CI: 1.03, 2.64). Moreover, individuals in the highest quartile of adherence were more likely to have a successful aging (OR = 1.65, 95 % CI: 1.01, 2.68). In conclusion, this study supports the hypothesis that adherence to the Mediterranean diet provides a positive trajectory toward a healthy successful aging, with major potential benefits toward mental and cognitive health.

Objective: We report the results of a panel of Brazilian experts and provide recommendations for the management of these patients. Material and Methods: The panel convened composed by 28 local opinion leaders, addressed 59 multiple-choice questions taking into account the published scientific literature and their own clinical experience. The level of agreement among panel members was qualified as (1) consensus, when at least 75% of the voting panel members; (2) majority vote (50%-74.9%); or (3) less than majority vote. Results: There was at least majority vote for eight of 10 questions on staging and follow-up; for 14 of 23 questions on the treatment of early-stage disease; for 12 of 14 questions related to the treatment of locally-advanced disease; and for seven of the 12 questions related to the treatment of recurrent/metastatic disease. Conclusion: The current recommendations may help practitioners from Brazil and other countries to improve the care they provide to patients.

This review summarizes the recent findings on the development of different types of single and multitarget nanoparticles for disease detection and drug delivery to the brain, focusing on promising active principles encapsulated and nanoparticle surface modification and functionalization. Functionalized nanoparticles have emerged as promising tools for the diagnosis and treatment of brain disorders, offering a novel approach to addressing complex neurological challenges. They can act as drug delivery vehicles, transporting one or multiple therapeutic agents across the blood–brain barrier and precisely releasing them at the site of action. In diagnostics, functionalized nanoparticles can serve as highly sensitive contrast agents for imaging techniques such as magnetic resonance imaging and computed tomography scans. By attaching targeting ligands to the nanoparticles, they can selectively accumulate in the affected areas of the brain, enhancing the accuracy of disease detection. This enables early diagnosis and monitoring of conditions like Alzheimer’s or Parkinson’s diseases. While the field is still evolving, functionalized nanoparticles represent a promising path for advancing our ability to diagnose and treat brain disorders with greater precision, reduced invasiveness, and improved therapeutic outcomes.

BackgroundIndividuals diagnosed with melanoma before the age of 40 years (young-onset melanoma survivors) and their first-degree relatives (FDRs) are a growing population at risk for developing recurrent melanoma or new melanomas. Regular surveillance using clinical skin examination (CSE) and skin self-examination (SSE) and engagement in preventive behaviors including sun protection are recommended. Given the growing population of survivors and their families who are at increased risk, it is surprising that no behavioral interventions have been developed and evaluated to improve risk-reduction behaviors. ObjectiveWe describe the rationale and methodology for a randomized controlled trial evaluating the efficacy of a Facebook intervention providing information, goal setting, and peer support to increase CSE, SSE, and sun protection for young-onset melanoma survivors and their FDRs. MethodsOverall, 577 survivors and 577 FDRs will be randomly assigned to either the Young Melanoma Family Facebook Group or the Melanoma Family Healthy Lifestyle Facebook Group condition. Participants will complete measures of CSE, SSE, and sun protection, and mediator measures of attitudes and beliefs before and after the intervention. The primary aim is to evaluate the impact of the Young Melanoma Family Facebook intervention versus the Melanoma Family Healthy Lifestyle Facebook intervention on CSE, SSE frequency and comprehensiveness, and sun protection among FDRs. The secondary aims examine the efficacy of the Young Melanoma Family Facebook intervention on survivors’ SSE frequency and comprehensiveness and sun protection behaviors and mechanisms of intervention efficacy for intervention impact on FDR and survivor outcomes. The exploratory aim is to evaluate the efficacy of the 2 interventions on perceived stress, physical activity, and healthy eating. ResultsThis project was funded by the National Institutes of Health (R01CA221854). The project began in May 2018, and recruitment started in January 2019. We anticipate completing enrollment by November 2023. Power calculations recommended a sample size of 577 survivors and 577 FDRs. Multilevel modeling treating family as the upper-level sampling unit and individual as the lower-level sampling unit will be the primary data analytic approach. Fixed effect predictors in these models will include condition, role, sex, all 2- and 3-way interactions, and covariates. ConclusionsThe Young Melanoma Family Facebook intervention aims to improve primary and secondary skin cancer prevention for young-onset melanoma survivors and their family members. The intervention’s delivery via a popular, freely available social media platform increases its impact because of the potential for dissemination in many contexts. If efficacious, this program could be disseminated by dermatologist practices, public health or nonprofit organizations focused on melanoma, and existing melanoma and skin cancer Facebook groups, thereby expanding its reach. This project will produce a content library of posts and a moderation guide for others. Trial RegistrationClinicalTrials.gov NCT03677739; https://clinicaltrials.gov/ct2/show/NCT03677739 International Registered Report Identifier (IRRID)DERR1-10.2196/39640

Introduction: Latency and resistance of acyclovir-resistant strains of Herpes simplex virus type 1 (HSV-1) have been associated with serious sequelae in immunocompromised individuals, such as AIDS patients. Consequently, the search for new substances with anti-HSV activity is both necessary and urgent. Objective: To investigate whether extracts obtained from Plexaurella spp can be used in preclinical studies of drugs against herpes simplex virus type 1. Methods: Cell viability and inhibitory drug concentrations as screening tests were used to investigate ethyl acetate and dichloromethane extracts from Plexaurella spp as antivirals. Results: The results of viability assays demonstrated that extracts from Plexaurella regia and Plexaurella grandiflora showed less cytotoxicity, but only Plexaurella regia reached a very expressive CC50 value. In antiviral assays, Plexaurella regia showed an even more significant result of effective concentration (EC50) and therapeutic index (

Introduction: The olfactory neuro-epithelium has an intrinsic capability of renewal during lifetime provided by the existence of globose and horizontal olfactory precursor cells. Additionally, mesenchymal stromal olfactory cells also support the homeostasis of the olfactory mucosa cell population. Under in vitro culture conditions with Dulbecco modified eagle/F12 medium supplemented with 10% fetal bovine serum, tissue biopsies from upper turbinate have generated an adherent population of cells expressing mainly mesenchymal stromal phenotypic markers. A closer examination of these cells has also found co-expression of olfactory precursors and ensheathing cell phenotypic markers. These results were suggestive of a unique property of olfactory mesenchymal stromal cells as potentially olfactory progenitor cells. Objective: To study whether the expression of these proteins in mesenchymal stromal cells is modulated upon neuronal differentiation. Materials and methods: We observed the phenotype of olfactory stromal cells under DMEM/F12 plus 10% fetal bovine serum in comparison to cells from spheres induced by serum-free medium plus growth factors inducers of neural progenitors. Results: The expression of mesenchymal stromal (CD29+, CD73+, CD90+, CD45-), horizontal basal (ICAM-1/CD54+, p63+, p75NGFr+), and ensheathing progenitor cell (nestin+, GFAP+) proteins was determined in the cultured population by flow cytometry. The determination of Oct 3/4, Sox-2, and Mash-1 transcription factors, as well as the neurotrophins BDNF, NT3, and NT4 by RT-PCR in cells, was indicative of functional heterogeneity of the olfactory mucosa tissue sample. Conclusions: Mesenchymal and olfactory precursor proteins were downregulated by serum-free medium and promoted differentiation of mesenchymal stromal cells into neurons and astroglial cells.

Background Nutritional status impacts quality of life and prognosis of patients with respiratory diseases, including idiopathic pulmonary fibrosis (IPF). However, there is a lack of studies performing an extensive nutritional assessment of IPF patients. This study aimed to investigate the nutritional status and to identify nutritional phenotypes in a cohort of IPF patients at diagnosis. Methods Patients underwent a thorough pulmonary and nutritional evaluation including questionnaires on nutritional status, and physical activity, anthropometry, body impedance, dynamometry, 4-m gait speed and blood tests. Results 90 IPF patients (78.9% males, mean age 72.7 years) were enrolled. The majority of patients were classified as Gender-Age-Physiology Index stage 2 (47, 52.2%) with an inactive lifestyle according to International Physical Activity Questionnaire score (39, 43.3%), and had mean forced vital capacity and diffusing capacity for carbon monoxide 86.5% and 54.2%, respectively. In regards to nutritional phenotypes, the majority of patients were normally nourished (67.8%, 95% CI 58.6–77.7%), followed by non-sarcopenic obese (25.3%, 95% CI 16.1–35.2%), sarcopenic (4.6%, 95% CI 0.0–14.5%) and sarcopenic obese (2.3%, 95% CI 0.0–12.2%). Among the normally nourished, 49.2% showed early signs of nutritional and physical performance alterations, including body mass index ≥30 kg·m−2 in 4.3%, history of weight loss ≥5% in 11.9%, and reduction of gait speed and hand grip strength in 11.9% and 35.6%, respectively. Low vitamin D values were observed in 56.3% of cases. Conclusions IPF patients at diagnosis are mainly normally nourished and obese, but early signs of nutritional and physical performance impairment can already be identified at this stage.

Background For people with symptomatic COVID-19, the relative risks of hospital admission, death without hospital admission and recovery without admission, and the times to those events, are not well understood. We describe how these quantities varied with individual characteristics, and through the first wave of the pandemic, in Milan, Italy.Methods A cohort study of 27 598 people with known COVID-19 symptom onset date in Milan, Italy, testing positive between February and June 2020 and followed up until 17 July 2020. The probabilities of different events, and the times to events, were estimated using a mixture multistate model.Results The risk of death without hospital admission was higher in March and April (for non-care home residents, 6%–8% compared with 2%–3% in other months) and substantially higher for care home residents (22%–29% in March). For all groups, the probabilities of hospitalisation decreased from February to June. The probabilities of hospitalisation also increased with age, and were higher for men, substantially lower for healthcare workers and care home residents, and higher for people with comorbidities. Times to hospitalisation and confirmed recovery also decreased throughout the first wave. Combining these results with our previously developed model for events following hospitalisation, the overall symptomatic case fatality risk was 15.8% (15.4%–16.2%).Conclusions The highest risks of death before hospital admission coincided with periods of severe burden on the healthcare system in Lombardy. Outcomes for care home residents were particularly poor. Outcomes improved as the first wave waned, community healthcare resources were reinforced and testing became more widely available.

DNA oxidation by ten-eleven translocation (TET) family enzymes is essential for epigenetic reprogramming. The conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) initiates developmental and cell-type-specific transcriptional programs through mechanisms that include changes in the chromatin structure. Here, we show that the presence of 5hmC in the transcribed gene promotes the annealing of the nascent RNA to the template DNA strand, leading to the formation of an R-loop. Depletion of TET enzymes reduced global R-loops in the absence of gene expression changes, whereas CRISPR-mediated tethering of TET to an active gene promoted the formation of R-loops. The genome-wide distribution of 5hmC and R-loops shows a positive correlation in mouse and human stem cells and overlap in half of all active genes. Moreover, R-loop resolution leads to differential expression of a subset of genes that are involved in crucial events during stem cell proliferation. Altogether, our data reveal that epigenetic reprogramming via TET activity promotes co-transcriptional R-loop formation, disclosing new mechanisms of gene expression regulation.

We herein report an innovative antisense approach based on Peptide Nucleic Acids (PNAs) to down-modulate CD5 expression levels in chronic lymphocytic leukemia (CLL). Using bioinformatics tools, we selected a 12-mer tract of the CD5 mRNA as the molecular target and synthesized the complementary and control PNA strands bearing a serine phosphate dipeptide tail to enhance their water solubility and bioavailability. The specific recognition of the 12-mer DNA strand, corresponding to the target mRNA sequence by the complementary PNA strand, was confirmed by non-denaturing polyacrylamide gel electrophoresis, thermal difference spectroscopy, circular dichroism (CD), and CD melting studies. Cytofluorimetric assays and real-time PCR analysis demonstrated the downregulation of CD5 expression due to incubation with the anti-CD5 PNA at RNA and protein levels in Jurkat cell line and peripheral blood mononuclear cells from B-CLL patients. Interestingly, we also observed that transfection with the anti-CD5 PNA increases apoptotic response induced by fludarabine in B-CLL cells. The herein reported results suggest that PNAs could represent a potential candidate for the development of antisense therapeutic agents in CLL.

In recent years, 4-phenylbutyric acid (4-PBA), an FDA-approved drug, has increasingly been used as a nonspecific chemical chaperone in vitro and in vitro, but its pharmacodynamics is still not clear. In this context, we developed and validated a Liquid Chromatography–High Resolution Mass Spectrometry (LC-HRMS) method to quantify 4-PBA in NeuroBasal-A and Dulbecco’s Modified Eagle widely used cell culture media. Samples were injected on a Luna® 3 µm PFP(2) 100 Å (100 × 2.0 mm) column maintained at 40 °C. Water and methanol both with 0.1% formic acid served as mobile phases in a step gradient mode. The mass acquisition was performed by selected ion monitoring (SIM) in negative mode for a total run time of 10.5 min at a flow rate of 0.300 mL/min. The analogue 4-(4-Nitrophenyl)-Butyric Acid served as internal standard. Validation parameters were verified according to FDA and EMA guidelines. The quantification ranges from 0.38–24 µM. Inter and intraday RSDs (Relative Standard Deviations) were within 15%. The developed LC-HRMS method allowed the estimation of 4-PBA absorption and adsorption kinetics in vitro in two experimental systems: (i) 4-PBA improvement of protein synthesis in an Alzheimer’s disease astrocytic cell model; and (ii) 4-PBA reduction of endoplasmic reticulum stress in thapsigargin-treated melanoma cell lines.

Introduction A range of barriers deter or prevent people from accessing facility-based abortion care. As a result, people are obtaining and using abortifacient medications to end their pregnancies outside of the formal healthcare system, without clinical supervision. One model of self-managed abortion has come to be known as the ‘accompaniment’ model, in which grassroots organisations provide pregnant people with evidence-based counselling and support through the medication abortion process. Data are needed to understand the safety and effectiveness of this increasingly common model of abortion care.Methods and analysis This is a large, prospective, observational study in Argentina and Nigeria. All people who contact one of two accompaniment groups seeking information for their own self-managed medication abortion, are ages 13 years and older, have no contraindications for medication abortion, are within the gestational range supported by the group (up to 12 weeks’ gestation for the primary outcome) and are willing to be contacted for follow-up will be recruited. Participants will respond to an interviewer-administered baseline survey at enrolment, and 1–4 additional surveys over 6 weeks to ascertain whether they obtain medications for abortion, dosing and route of administration of medications, physical and emotional experience of medication abortion self-management, and effectiveness and safety outcomes. Analyses will include estimates of the primary outcome: the proportion of participants that report a complete abortion without surgical intervention at last recorded follow-up; as well as secondary outcomes including a pseudo-experimental test of non-inferiority of the effectiveness of self-managed medication abortion as compared with clinical medication abortion.Ethics and dissemination We describe the ethical considerations and protections for this study, as well the creation of a study-specific Data Monitoring and Oversight Committee. We describe dissemination plans to ensure that study results are shared widely with all relevant audiences, particularly researchers, advocates, policymakers and clinicians.Trial registration number ISRCTN95769543.

Regulation of protein synthesis makes a major contribution to post-transcriptional control pathways. During disease, or under stress, cells initiate processes to reprogramme protein synthesis and thus orchestrate the appropriate cellular response. Recent data show that the elongation stage of protein synthesis is a key regulatory node for translational control in health and disease. There is a complex set of factors that individually affect the overall rate of elongation and, for the most part, these influence either transfer RNA (tRNA)- and eukaryotic elongation factor 1A (eEF1A)-dependent codon decoding, and/or elongation factor 2 (eEF2)-dependent ribosome translocation along the mRNA. Decoding speeds depend on the relative abundance of each tRNA, the cognate:near-cognate tRNA ratios and the degree of tRNA modification, whereas eEF2-dependent ribosome translocation is negatively regulated by phosphorylation on threonine-56 by eEF2 kinase. Additional factors that contribute to the control of the elongation rate include epigenetic modification of the mRNA, coding sequence variation and the expression of eIF5A, which stimulates peptide bond formation between proline residues. Importantly, dysregulation of elongation control is central to disease mechanisms in both tumorigenesis and neurodegeneration, making the individual key steps in this process attractive therapeutic targets. Here, we discuss the relative contribution of individual components of the translational apparatus (e.g. tRNAs, elongation factors and their modifiers) to the overall control of translation elongation and how their dysregulation contributes towards disease processes.

Asthma often remains uncontrolled, despite the fact that the pharmacological treatment has undergone large changes. We studied changes in the treatment of asthma over a 20-year period and identified factors associated with the regular use of inhaled corticosteroid (ICS) treatment. Changes in the use of medication were determined in 4617 randomly selected subjects, while changes in adults with persistent asthma were analysed in 369 participants. The study compares data from three surveys in 24 centres in 11 countries. The use of ICSs increased from 1.7% to 5.9% in the general population and the regular use of ICSs increased from 19% to 34% among persistent asthmatic subjects. The proportion of asthmatic subjects reporting asthma attacks in the last 12 months decreased, while the proportion that had seen a doctor in the last 12 months remained unchanged (42%). Subjects with asthma who had experienced attacks or had seen a doctor were more likely to use ICSs on a regular basis. Although ICS use has increased, only one-third of subjects with persistent asthma take ICSs on a regular basis. Less than half had seen a doctor during the last year. This indicates that underuse of ICSs and lack of regular healthcare contacts remains a problem in the management of asthma.

The growing number of known venomous marine invertebrates indicates that chemical warfare plays an important role in adapting to diversified ecological niches, even though it remains unclear how toxins fit into the evolutionary history of these animals. Our case study, the Polychaeta Eulalia sp., is an intertidal predator that secretes toxins. Whole-transcriptome sequencing revealed proteinaceous toxins secreted by cells in the proboscis and delivered by mucus. Toxins and accompanying enzymes promote permeabilization, coagulation impairment and the blocking of the neuromuscular activity of prey upon which the worm feeds by sucking pieces of live flesh. The main neurotoxins (“phyllotoxins”) were found to be cysteine-rich proteins, a class of substances ubiquitous among venomous animals. Some toxins were phylogenetically related to Polychaeta, Mollusca or more ancient groups, such as Cnidaria. Some toxins may have evolved from non-toxin homologs that were recruited without the reduction in molecular mass and increased specificity of other invertebrate toxins. By analyzing the phylogeny of toxin mixtures, we show that Polychaeta is uniquely positioned in the evolution of animal venoms. Indeed, the phylogenetic models of mixed or individual toxins do not follow the expected eumetazoan tree-of-life and highlight that the recruitment of gene products for a role in venom systems is complex.