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Improving early detection, management, and treatment of comorbid conditions to dementia in residential care could slow down cognitive and functional decline, and increase residents' quality of life. We conducted a Delphi study comprising three rounds (two surveys and an interview) to identify the most difficult dementia comorbidities to deal with in residential care and related issues. Participants were 15 UK-based experts including academics, residential care workers, geriatricians, and neuropsychologists. In the first-round of the Delphi, experts mentioned 15 comorbid health conditions to dementia and 19 issues. In the following rounds of the Delphi mental illnesses, delirium, and sensory impairments were identified as the most difficult comorbidities to dementia to deal with. Medication management, symptom management, shortage of staff, lack of training among staff, and limited resources from the broader healthcare system were identified as the most difficult issues when dealing with dementia comorbidities., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The Indo-European languages are among the most widely spoken in the world, yet their early diversification remains contentious 1-5 . It is widely accepted that the spread of this language family across Europe from the 5th millennium BP correlates with the expansion and diversification of steppe-related genetic ancestry from the onset of the Bronze Age 6,7 . However, multiple steppe-derived populations co-existed in Europe during this period, and it remains unclear how these populations diverged and which provided the demographic channels for the ancestral forms of the Italic, Celtic, Greek, and Armenian languages 8,9 . To investigate the ancestral histories of Indo-European-speaking groups in Southern Europe, we sequenced genomes from 314 ancient individuals from the Mediterranean and surrounding regions, spanning from 5,200 BP to 2,100 BP, and co-analysed these with published genome data. We additionally conducted strontium isotope analyses on 224 of these individuals. We find a deep east-west divide of steppe ancestry in Southern Europe during the Bronze Age. Specifically, we show that the arrival of steppe ancestry in Spain, France, and Italy was mediated by Bell Beaker (BB) populations of Western Europe, likely contributing to the emergence of the Italic and Celtic languages. In contrast, Armenian and Greek populations acquired steppe ancestry directly from Yamnaya groups of Eastern Europe. These results are consistent with the linguistic Italo-Celtic 10,11 and Graeco-Armenian 1,12,13 hypotheses accounting for the origins of most Mediterranean Indo-European languages of Classical Antiquity. Our findings thus align with specific linguistic divergence models for the Indo-European language family while contradicting others. This underlines the power of ancient DNA in uncovering prehistoric diversifications of human populations and language communities.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are associated with a high prevalence of type 2 diabetes (T2D). Individuals with MASLD exhibit insulin resistance (IR) and hyperglycemia, but it is unclear whether hepatic glucose production (HGP) is increased with MASLD severity. We evaluated HGP in a cohort of histologically characterized individuals with MASL/MASH using stable isotope infusion (6,6- 2 H 2 -glucose, U- 2 H 5 -glycerol) and liver-specific genome-scale metabolic models (GEMs). Tracer-measured HGP is increased with liver fibrosis and inflammation, but not steatosis, and is associated with lipolysis and IR. The GEM-derived gluconeogenesis is elevated due to high glucogenic/energy metabolite uptakes (lactate, glycerol, and free fatty acid [FFA]), and the expression of insulin action genes (IRS1, IRS2, and AKT2) is reduced in MASH with fibrosis F2-F4, with/without T2D, suggesting these as putative mechanisms for increased fasting HGP and hyperglycemia. In conclusion, elevated HGP, lipolysis, and IR help to explain the mechanisms for the increased risk of hyperglycemia and T2D in MASH., Competing Interests: Declaration of interests G.M. reports consulting fees from Novo Nordisk, Fractyl Inc, and Recor Inc. She is also scientific advisor of Metadeq Inc, Keyron Ltd, GHP Scientific Ltd, and Jemyll Ltd. G.M. reports receiving research grants from Metadeq Inc and Fractyl Inc. A.G. has served as a consultant for: Boehringer Ingelheim, Eli Lilly and Company, Metadeq Diagnostics, and Fractyl Health; has participated in advisory boards for Boehringer Ingelheim, Merck Sharp & Dohme, Novo Nordisk, Metadeq Diagnostics, and Pfizer; and has received speaker’s honorarium and other fees from Eli Lilly and Company, Merck Sharp & Dohme, and Novo Nordisk. Q.M.A. reports grants and/or personal fees from Allergan/Tobira, E3Bio, Eli Lilly & Company Ltd, Galmed, Genfit SA, Gilead, Grunthal, Imperial Innovations, Intercept Pharma Europe Ltd, Inventiva, Janssen, Kenes, MedImmune, NewGene, Pfizer Ltd, Raptor Pharma, Novartis Pharma AG, AbbVie, BMS, GSK, NGMBio, Madrigal, Servier, EcoR1, 89Bio, Altimmune, AstraZeneca, Axcella, Blade, BNN Cardio, Celgene, Cirius, CymaBay, Genentech, HistoIndex, Indalo, IQVIA,Metacrine, North Sea Therapeutics, Novo Nordisk, Poxel, Terns, Viking Therapeutics, Glympse Bio, and PathAI, outside the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Dementia is a leading cause of disability and death globally. Individuals with diseases such as cardiovascular, cardiometabolic and cerebrovascular disease are often at increased dementia risk. However, while numerous models have been developed to predict dementia, they are often not tailored to disease-specific groups. Yet, different disease groups may have unique risk factor profiles and tailored models that account for these differences may have enhanced predictive accuracy. In this review, we synthesise findings from three previous systematic reviews on dementia risk model development and testing to present an overview of the literature on dementia risk prediction modelling in people with a history of disease. Nine studies met the inclusion criteria. Currently, disease-specific models have only been developed in people with a history of diabetes where demographic, disease-specific and comorbidity data were used. Some existing risk models, including CHA 2 DS 2 -VASc and CHADS 2 , have been externally validated for dementia outcomes in those with atrial fibrillation and heart failure. One study developed a dementia risk model for their whole population, which had similar predictive accuracy when applied in a sub-sample with stroke. This emphasises the importance of considering disease status in identifying key predictors for dementia and generating accurate prediction models for dementia.

Background: Vaccination is one of the most important public health interventions to combat infectious disease. However, vaccine hesitancy prevents us reaching the global target of vaccine uptake (e.g., 75 % of influenza vaccination in at-risk groups). This review summarises all interventions designed to reduce vaccine hesitancy and increase vaccine uptake for all types of vaccines offered to adults (≥18 years) since 2000, in the United Kingdom (UK)., Methods: PubMed, Cochrane Reviews, CINAHL EBSCO, and Scopus were searched (September 19, 2023). The PRISMA Checklist 2020 was used for quality checking. Data from randomised-controlled trials (RCTs) were analysed with a meta-analysis and narrative analysis. In all included studies, a narrative synthesis was undertaken to summarise, evaluate and characterisethe reported behaviour change interventions into four categories: organisational-level, public demand, provider-level, and multidimensional interventions. Findings are evaluated based on the MINDSPACE framework to understand the possible psychological mechanisms underpinning the interventions., Findings: A total of 9,842 articles were identified, 50 met the inclusion criteria. Interventions aimed to boost vaccine uptake or reduce hesitancy of influenza (50 %), COVID-19 (32 %), hepatitis B (6 %), and other vaccines. A meta-analysis was conducted for nine RCTs evaluating various interventions impact on vaccine uptake. The pooled effect was statistically significant (OR with 95 % CI = 1.23 [1.07 to 1.41]). Providing certain and understandableinformation and using a reminder system with personal messages or letters were the most frequently documented and effective interventions to enhance public demand (enhance information salience). Organisational level interventions intended to make vaccinations more accessible (e.g., providing vaccination at alternative places or times). Provider-oriented interventions encouraged healthcare workers to focus on reducing vaccine hesitancy or enhancing vaccine uptake., Interpretation: Among the main MINDSPACE techniques, enhancing the salience of vaccine information and priming vaccination by improving access were identified as the most applied and effective interventions in the UK., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Aysegul Humeyra Kafadar reports financial support was provided by Republic of Turkey Ministry of National Education. If there are other authors, they 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 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Influenza viruses (IV) are single-stranded RNA viruses with a negative-sense genome and have the potential to cause pandemics. While vaccines exist for influenza, their protection is only partial. Additionally, there is only a limited number of approved anti-IV drugs, which are associated to emergence of drug resistance. To address these issues, for years we have focused on the development of small-molecules that can interfere with the heterodimerization of PA and PB1 subunits of the IV RNA-dependent RNA polymerase (RdRP). In this study, starting from a cycloheptathiophene-3-carboxamide compound that we recently identified, we performed iterative cycles of medicinal chemistry optimization that led to the identification of compounds 43 and 45 with activity in the nanomolar range against circulating A and B strains of IV. Mechanistic studies demonstrated the ability of 43 and 45 to interfere with viral RdRP activity by disrupting PA-PB1 subunits heterodimerization and to bind to the PA C-terminal domain through biophysical assays. Most important, ADME studies of 45 also showed an improvement in the pharmacokinetic profile with respect to the starting hit., 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 Masson SAS. All rights reserved.)

Objectives: This study investigates factors associated with the person with dementia and the caregiver to identify those associated with an increased risk of transition to a care home., Method: IDEAL data were collected at baseline and at 12- and 24-month follow-up for 1545 people with dementia and 1305 caregivers. Modified Poisson regressions with an offset for 'person years at risk' were used. Person with dementia factors explored were personal characteristics, cognition, health, self- and informant-rated functional ability, and neuropsychiatric symptoms. Caregiver factors explored were personal characteristics, stress, health, and quality of the dyadic relationship., Results: A 5% people moved into care. Risk of moving into a care home was higher among people with dementia who were ≥80 years, among people with Parkinson's disease dementia or dementia with Lewy bodies, and among those without a spousal caregiver. Poorer cognition and more self-rated or informant-rated functional difficulties increased the risk of moving into care., Conclusion: Factors related to increased dementia severity and greater disability are the primary influences that place people with dementia at greater risk of moving into a care home. Strategies that help to maintain everyday functional ability for people with dementia could help delay people with dementia moving into care.

Aim: A workshop on concordance and oral hygiene was held in February 2024. To address the topic, a systematic review aimed at investigating the effectiveness of motivational interventions in improving oral hygiene and focusing on periodontal clinical indices outcomes was designed. Materials and Methods: A comprehensive literature search was conducted across PubMed and Scopus electronic databases to identify relevant articles published up to 2024. Inclusion criteria encompassed studies comparing motivational interventions targeting oral hygiene behaviours, with a focus on periodontal clinical indices. Twelve articles meeting the eligibility criteria were selected for analysis. Quality assessment and data extraction were performed systematically. Results: The synthesis of findings from the selected studies revealed a consistent positive effect of motivational interventions on periodontal clinical indices. These interventions encompassed various strategies, including educational sessions, personalized feedback and motivational interviewing. Improvement in indices such as plaque index (PI), gingival index (GI) and periodontal probing depth was observed following motivational interventions, despite the variety of motivational protocols employed. Conclusion: Motivational interventions are effective in enhancing oral hygiene practices and improving periodontal clinical indices. Tailored motivational approaches can serve as valuable tools in promoting oral health behaviours among individuals, potentially reducing the risk of periodontal diseases. Further research is warranted to explore the long-term sustainability and scalability of motivational interventions in diverse populations and settings., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Antonia Abbinante et al.)

Nontuberculous mycobacteria (NTM), which include the Mycobacterium avium complex, are classified as difficult-to-treat pathogens due to their ability to quickly develop drug resistance against the most common antibiotics used to treat NTM infections. The overexpression of efflux pumps (EPs) was demonstrated to be a key mechanism of clarithromycin (CLA) resistance in NTM. Therefore, in this work, 24 compounds from an in-house library, characterized by chemical diversity, were tested as potential NTM EP inhibitors (EPIs) against Mycobacterium smegmatis mc 2  155 and M. avium clinical isolates. Based on the acquired results, 12 novel analogs of the best derivatives 1b and 7b were designed and synthesized to improve the NTM EP inhibition activity. Among the second set of compounds, 13b emerged as the most potent NTM EPI. At a concentration of 4 µg/mL, it reduced the CLA minimum inhibitory concentration by 16-fold against the clinical isolate M. avium 2373 overexpressing EPs as primary mechanism of CLA resistance., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Treatment with glucagon-like peptide 1 receptor agonists reduces liver steatosis and cardiometabolic risk (CMR). Few data are available on lipid metabolism, and no information is available on the postprandial lipidomic profile. Thus, we investigated how exenatide treatment changes lipid metabolism and composition during fasting and after a mixed-meal tolerance test (MMTT) in adults with severe obesity without diabetes. Thirty individuals (26 females and 4 males, 30-60 years old, BMI >40 kg/m2, HbA1c 5.76%) were assigned (1:1) to diet with exenatide 10 μg twice daily treatment (n = 15) or without treatment as control (n = 15) for 3 months. Fasting and postprandial lipidomic profile (by liquid chromatography quadrupole time-of-flight mass spectrometry) and fatty acid metabolism (following a 6-h MMTT/tracer study) and composition (by gas chromatography-mass spectrometry) were evaluated before and after treatment. Both groups had slight weight loss (-5.5% vs. -1.9%, exenatide vs. control; P = 0.052). During fasting, exenatide, compared with control, reduced some ceramides (CERs) and lysophosphatidylcholines (LPCs) previously associated with CMR, while relatively increasing unsaturated phospholipid species (phosphatidylcholine [PC], LPC) with protective effects on CMR, although concentrations of total lipid species were unchanged. During MMTT, both groups showed suppressed lipolysis equal to baseline, but exenatide significantly lowered free fatty acid clearance and postprandial triacyclglycerol (TAG) concentrations, particularly saturated TAGs with 44-54 carbons. Exenatide also reduced some postprandial CERs, PCs, and LPCs previously linked to CMR. These changes in lipidomic profile remained statistically significant after adjusting for weight loss. Exenatide improved fasting and postprandial lipidomic profiles associated with CMR mainly by reducing saturated postprandial TAGs and CERs independently of weight loss and diabetes., (© 2024 by the American Diabetes Association.)

We examined how physical pain impacts the developmental construct of Awareness of Age-Related Change (AARC-gains and AARC-losses) and, in turn, how AARC mediates and moderates the association between pain and subsequent physical activity. We used longitudinal data from 434 participants of the UK PROTECT Study (mean age = 65.5 years; SD = 6.94 years). We found that pain in 2019 predicted higher AARC-losses ( β  = .07; p  = .036) and less physical activity ( β  = -.13; p -value = .001) in 2020. Additionally, we found that AARC-losses partially mediated, but did not moderate, the association of pain in 2019 and physical activity in 2020. AARC-losses may explain physical inactivity in middle-aged and older adults experiencing pain. Incorporating developmental constructs such as AARC into theories and empirical studies on pain and pain management may be necessary to more fully capture people's responses to pain., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

MicroRNAs (miRNAs) play a crucial role in ovarian cancer (OC) pathogenesis and miRNA processing can be the object of pharmacological intervention. By exploiting our in-house quinolone library, we combined a cell-based screening with medicinal chemistry efforts, ultimately leading to derivative 33 with anti-OC activity against distinct cell lines (GI 50 values 13.52-31.04 μM) and CC 50 Wi-38 = 142.9 μM. Compound 33 retained anticancer activity against additional cancer cells and demonstrated a synergistic effect with cisplatin against cisplatin-resistant A2780 cells. Compound 33 bound TRBP by SPR ( K D = 4.09 μM) and thermal shift assays and its activity was TRBP-dependent, leading to modulation of siRNA and miRNA maturation. Derivative 33 exhibited augmented potency against OC cells and a stronger binding affinity for TRBP compared to enoxacin, the sole quinolone identified as a modulator of miRNA maturation. Consequently, 33 represents a promising template for developing novel anti-OC agents with a distinctive mechanism of action., Competing Interests: 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., (This journal is © The Royal Society of Chemistry.)

Dementia is a leading cause of death and disability with over 60% of cases residing in low- and middle-income countries (LMICs). Therefore, new strategies to mitigate risk are urgently needed. However, despite the high burden of disease associated with dementia in LMICs, research into dementia risk profiling and risk prediction modelling is limited. Further, dementia risk prediction models developed in high income countries generally do not transport well to LMICs suggesting that context-specific models are instead needed. New prediction models have been developed, in China and Mexico only, with varying predictive accuracy. However, none has been externally validated or incorporated variables that may be important for predicting dementia risk in LMIC settings such as socio-economic status, literacy, healthcare access, nutrition, stress, pollutants, and occupational hazards. Since there is not yet any curative treatment for dementia, developing a context-specific dementia prediction model is urgently needed for planning early interventions for vulnerable groups, particularly for resource constrained LMIC settings., 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., (© 2024 Alshahrani, Sabatini, Mohan, Brain, Pakpahan, Tang, Robinson, Siervo, Naheed and Stephan.)

Metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH) is recognised as a metabolic disease characterised by excess intrahepatic lipid accumulation due to lipid overflow and synthesis, alongside impaired oxidation and/or export of these lipids. But where do these lipids come from? The main pathways related to hepatic lipid accumulation are de novo lipogenesis and excess fatty acid transport to the liver (due to increased lipolysis, adipose tissue insulin resistance, as well as excess dietary fatty acid intake, in particular of saturated fatty acids). Not only triglycerides but also other lipids are secreted by the liver and are associated with a worse histological profile in MASH, as shown by lipidomics. Herein, we review the role of lipid metabolism in MASLD/MASH and discuss the impact of weight loss (diet, bariatric surgery, GLP-1RAs) or other pharmacological treatments (PPAR or THRβ agonists) on hepatic lipid metabolism, lipidomics, and the resolution of MASH., (© 2024 The Authors.)

Background & Aims: Among the reprogrammed metabolic pathways described in cancer stem cells, aberrant lipid metabolism has recently drawn increasing attention. Our study explored the contribution of fatty acids (FA) in the regulation of stem-like features in intrahepatic cholangiocarcinoma (iCCA)., Methods: We previously identified a functional stem-like subset in human iCCA by using a three-dimensional sphere (SPH) model in comparison to parental cells grown as monolayers (MON). In this study, quantification of intracellular free FA and lipidomic analysis (triacylglycerol [TAG] composition, de novo synthesis products) was performed by Liquid chromatography-mass spectrometry (LC-MS); quadrupole time-of-flight liquid chromatography/mass spectrometry (Q-TOF LC/MS), respectively, in both SPH and MON cultures., Results: Stem-like SPH showed a superior content of free FA (citric, palmitic, stearic, and oleic acids) and unsaturated TAG. Molecularly, SPH showed upregulation of key metabolic enzymes involved in de novo FA biosynthesis (AceCS1, ACLY, ACAC, FASN, ACSL1) and the mTOR signalling pathway. In patients with iCCA (n = 68), tissue expression of FASN , a key gene involved in FA synthesis, correlated with 5-year overall survival. Interference with FASN activity in SPH cells through both specific gene silencing (siRNA) or pharmacological inhibition (orlistat) decreased sphere-forming ability and expression of stem-like markers. In a murine xenograft model obtained by injection of iCCA-SPH cells, FASN inhibition by orlistat or injection of FASN -silenced cells significantly reduced tumour growth and expression of stem-like genes., Conclusion: Altered FA metabolism contributes to the maintenance of a stem-like phenotype in iCCA. FASN inhibition may represent a new approach to interfere with the progression of this deadly disease., Impact and Implications: Recent evidence indicates that metabolic disorders correlate with an increased susceptibility to intrahepatic cholangiocarcinoma (iCCA). Our investigation emphasises the pivotal involvement of lipid metabolism in the tumour stem cell biology of iCCA, facilitated by the upregulation of crucial enzymes and the mTOR signalling pathway. From a clinical perspective, this underscores the dual role of FASN as both a prognostic indicator and a therapeutic target, suggesting that FASN inhibitors could enhance patient outcomes by diminishing stemness and tumour aggressiveness. These findings pave the way for novel therapeutic strategies for iCCA and shed light on its relationship with metabolic disorders such as diabetes, obesity, metabolic syndrome, and metabolic dysfunction-associated steatotic liver disease., (© 2024 The Author(s).)

Background/Objectives : Several psychological conditions, including stress and depression, can adversely affect oral health; in fact, antidepressants, commonly used to treat depressive disorders, may have conflicting effects on the periodontal status of individuals. The aim of this review was to determine the effects of antidepressants on the periodontium. Methods: A literature search was conducted using electronic databases, Pubmed/MEDLINE, Cochrane Library, focusing on the use of antidepressants and their effects on periodontal health in animals or humans. Results : Seventeen articles have been included with the use of amitriptyline (two studies), desipramine (one study), imipramine (two studies), desvenlafaxine (one study), fluoxetine (six studies), venlafaxine (three studies) and tianeptine (two studies). One study evaluated several categories of antidepressants, such as selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), tricyclic, atypical and monoamine oxidase inhibitors (MAO). Most trials showed improvements in periodontal health, especially with fluoxetine, but also with imipramine, desipramine, desvenlafaxine and tianeptine; on the contrary, worsening of clinical periodontal indices and increased loss of alveolar bone were reported with venlafaxine. Conclusions : This review suggests that in the presence of comorbidity between periodontitis and depression, pharmacological treatment with SNRIs, SSRIs and mixed antidepressants is associated with improvement in periodontal parameters, except for venlafaxine. Healthcare professionals (especially oral and mental health professionals) should investigate proper adherence to medication therapy in patients with a history of periodontitis and depression. Further clinical trials are needed to confirm these results.

Objectives: Evidence suggests spouses influence each other's subjective views on aging. Aligned with the Theory of Dyadic Illness Management, we investigated for the first time similarities in felt age (how old people feel relative to their chronological age) between people with dementia and their spousal caregivers, and how each partner's felt age was related to psychological correlates in the other partner., Methods: We used baseline (2014-2016) data from 1,001 people with dementia and their spousal caregivers who participated in the British Improving the experience of Dementia and Enhancing Active Life study. We ran linear regressions to analyze the extent to which the felt age of people with dementia and their caregivers were similar, and whether relationship quality was associated with the similarity. We utilized actor-partner interdependence models to analyze whether the felt age of people with dementia and their caregivers were associated with each other's well-being, satisfaction with life, and self-efficacy., Results: The felt age of people with dementia was associated with the felt age of their caregivers (β = 0.10; p = .001). Caregivers and people with dementia reported a more similar felt age when caregivers rated the caregiving relationship more positively (β = 0.07; p = .04). Caregivers' felt age was associated with well-being (β = 0.07; p = .02) and satisfaction with life (β = 0.06; p = .04), but not with self-efficacy, in people with dementia., Discussion: Felt age in caregivers and people with dementia may be interwoven, and important psychological variables in people with dementia are related to caregivers' felt age. Findings offer empirical evidence on dementia caregiving dynamics and how family relationships are related to views on aging., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Weight loss and lifestyle intervention improve glucose tolerance delaying the onset of type 2 diabetes (T2D), but individual responses are highly variable. Determining the predictive factors linked to the beneficial effects of weight loss on glucose tolerance could provide tools for individualized prevention plans. Thus, the aim was to investigate the relationship between pre-intervention values of insulin sensitivity and secretion and the improvement in glucose metabolism after weight loss., Methods: In the DEXLIFE cohort (373 individuals at high risk of T2D, assigned 3:1 to a 12-week lifestyle intervention or a control arm, Trial Registration: ISRCTN66987085), K-means clustering and logistic regression analysis were performed based on pre-intervention indices of insulin sensitivity, insulin secretion (AUC-I), and glucose-stimulated insulin response (ratio of incremental areas of insulin and glucose, iAUC I/G). The response to the intervention was evaluated in terms of reduction of OGTT-glucose concentration. Clusters' validation was done in the prospective EGIR-RISC cohort (n = 1538)., Results: Four replicable clusters with different glycemic and metabolomic profiles were identified. Individuals had similar weight loss, but improvement in glycemic profile and β-cell function was different among clusters, highly depending on pre-intervention insulin response to OGTT. Pre-intervention high insulin response was associated with the best improvement in AUC-G, while clusters with low AUC-I and iAUC I/G showed no beneficial effect of weight loss on glucose control, as also confirmed by the logistic regression model., Conclusions: Individuals with preserved β-cell function and high insulin concentrations at baseline have the best improvement in glucose tolerance after weight loss., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Amalia Gastaldelli reports financial support was provided by European Union. John Nolan reports financial support was provided by European Union. Donal O'Gorman reports financial support was provided by European Union. John Petrie reports financial support was provided by European Union. Mark Walker reports financial support was provided by European Union. If there are other authors, they 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Research related to subjective aging, which describes how individuals perceive, interpret and evaluate their own aging, has substantially grown in the past two decades. Evidence from longitudinal studies shows that subjective aging predicts health, quality of life, and functioning in later life. However, the existing literature on successful aging has mostly neglected the role of subjective aging. This paper proposes an extended framework of successful aging linking subjective aging conceptually and empirically to Rowe and Kahn's (1997) three original key criteria of successful aging (i.e., avoiding disease and disability, maintaining high cognitive and physical function, and engagement with life). A particular focus is placed on subjective aging as an antecedent of successful aging. A review of the empirical subjective aging literature shows that subjective aging concepts consistently predict all three of Rowe and Kahn's criteria of successful aging. Mechanisms underlying these relations are discussed at three levels, namely psychological, behavioral, and physiological pathways. The proposed addition also takes into consideration the interconnections between subjective aging and successful aging throughout the lifespan and across historical time. Finally, we discuss the importance of facilitating successful aging through systematic interventions that support more positive views of aging at the individual and societal level., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Aims: To investigate clusters of adipose tissue dysfunction, that is, with adipose tissue insulin resistance (ADIPO-IR) and large waist circumference (WC), identify a worse lipidomic profile characterised by a high proportion of lipids rich in saturated fatty acids (SFA)., Materials and Methods: Hierarchical clustering based on WC and ADIPO-IR (calculated as fasting plasma non-esterified fatty acids times fasting plasma insulin, FFA×INS), was performed in 192 adults with overweight/obesity and type 2 diabetes (T2D) treated with metformin (HbA1c = 7.8%). Free fatty acid composition and lipidomic profile were measured by mass spectrometry (GC-MS and LC-MSQTOF). Indexes of fatty acid desaturation (stearoyl-coA desaturase-1 activity, SCD1 16  = palmitoleic acid/palmitic acid and SCD1 18  = oleic acid/stearic acid) and of insulin resistance (HOMA-IR) were also calculated., Results: Three clusters were identified: CL1 (ADIPO-IR = 4.9 ± 2.4 and WC = 96±7 cm, mean ± SD), CL2 (ADIPO-IR = 6.5 ± 2.5 and WC = 114 ± 7 cm), and CL3 (ADIPO-IR = 15.0 ± 4.7 and WC = 107 ± 8 cm). Insulin concentrations, ADIPO-IR, and HOMA-IR significantly increased from CL1 to CL3 (all p < 0.001), while fasting glucose concentrations, HbA1c, dietary lipids and caloric intake were similar. Moreover, CL3 showed significantly higher concentrations of monounsaturated free fatty acids, oleic and palmitoleic acids, triglycerides (TAG) rich in saturated FA and associated with de novo lipogenesis (i.e., TAG 46-50), higher SCD1 16, SCD1 18 , ceramide (d18:0/18:0), and phosphatidylcholine aa(36:5) compared with CL1/CL2 (all p < 0.005)., Conclusions: High ADIPO-IR and large WC identify a worse lipid profile in T2D characterised by complex lipids rich in SFA, likely due to de novo synthesis given higher plasma monounsaturated FFA and increased desaturase activity indexes., Registration Number Trial: ID NCT00700856 https://clinicaltrials.gov., (© 2024 John Wiley & Sons Ltd.)

The liver is central in regulating glucose homeostasis, being the major contributor to endogenous glucose production and the greatest reserve of glucose as glycogen. It is both a target and regulator of the action of glucoregulatory hormones. Hepatic metabolic functions are altered in and contribute to the highly prevalent steatotic liver disease (SLD), including metabolic dysfunction-associated SLD (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). In this Review, we describe the dysregulation of hepatic glucose metabolism in MASLD and MASH and associated metabolic comorbidities, and how advances in techniques and models for the assessment of hepatic glucose fluxes in vivo have led to the identification of the mechanisms related to the alterations in glucose metabolism in MASLD and comorbidities. These fluxes can ultimately increase hepatic glucose production concomitantly with fat accumulation and alterations in the secretion and action of glucoregulatory hormones. No pharmacological treatment has yet been approved for MASLD or MASH, but some antihyperglycaemic drugs approved for treating type 2 diabetes have shown positive effects on hepatic glucose metabolism and hepatosteatosis. A deep understanding of how MASLD affects glucose metabolic fluxes and glucoregulatory hormones might assist in the early identification of at-risk individuals and the use or development of targeted therapies., (© 2024. Springer Nature Limited.)

Objectives: This daily diary study examined associations between awareness of age-related change (AARC) and satisfaction/frustration of basic psychological needs of autonomy, competence, and relatedness in a sample of midlife and older adults. We expected that greater satisfaction and lower frustration of needs would be associated with higher AARC-gains and lower AARC-losses. We also examined whether within-person associations of need satisfaction/frustration with AARC were moderated by age., Methods: Participants (N = 152; aged 53+) completed measures of AARC and basic psychological need satisfaction and frustration on their smartphones for 10 consecutive days. Data were analyzed using multilevel models, with time-varying basic need satisfaction/frustration variables disaggregated into between-person and within-person components., Results: On days participants reported higher than usual overall satisfaction of needs, and lower than usual frustration of needs, AARC-gains was higher, and AARC-losses was lower. Analysis of individual needs showed that autonomy and competence were more consistently related to higher AARC-gains and lower AARC-losses than relatedness. Within-person autonomy satisfaction was more strongly (negatively) associated with AARC-losses at older ages., Discussion: Findings suggest that daily experiences related to satisfaction and frustration of goals related to autonomy and competence in particular may be proximal antecedents of short-term variation in AARC., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Longitudinal evidence documenting health conditions in spousal caregivers of people with dementia and whether these influence caregivers' outcomes is scarce. This study explores type and number of health conditions over two years in caregivers of people with dementia and subgroups based on age, sex, education, hours of care, informant-rated functional ability, neuropsychiatric symptoms, cognition of the person with dementia, and length of diagnosis in the person with dementia. It also explores whether over time the number of health conditions is associated with caregivers' stress, positive experiences of caregiving, and social networks METHODS: Longitudinal data from the IDEAL (Improving the experience of Dementia and Enhancing Active Life) cohort were used. Participants comprised spousal caregivers (n = 977) of people with dementia. Self-reported health conditions using the Charlson Comorbidity Index, stress, positive experiences of caregiving, and social network were assessed over two years. Mixed effect models were used RESULTS: On average participants had 1.5 health conditions at baseline; increasing to 2.1 conditions over two years. More health conditions were reported by caregivers who were older, had no formal education, provided 10 + hours of care per day, and/or cared for a person with more neuropsychiatric symptoms at baseline. More baseline health conditions were associated with greater stress at baseline but not with stress over time. Over two years, when caregivers' health conditions increased, their stress increased whereas their social network diminished DISCUSSION: Findings highlight that most caregivers have their own health problems which require management to avoid increased stress and shrinking of social networks., (© 2024. The Author(s).)

Background: Equine influenza (EI) is a highly contagious viral disease of equids characterized by pyrexia and respiratory signs. Like other influenza A viruses, antigenic drift or shift could lead to a vaccine-induced immunity breakdown if vaccine strains are not updated. The aim of this study was to genetically characterize EIV strains circulating in Italy, detected in PCR-positive samples collected from suspected cases, especially in the absence of formal active surveillance., Methods: Between February and April 2019, blood samples and nasal swabs collected from each of the 20 symptomatic horses from North and Central Italy were submitted to the National Reference Centre for Equine Diseases in Italy to confirm preliminary analysis performed by other laboratories., Results: None of the sera analysed using haemagglutination inhibition and single radial haemolysis presented a predominant serological reactivity pattern for any antigen employed. All nasal swabs were positive with IAV RRT-PCR. Only one strain, isolated in an embryonated chicken egg from a sample collected from a horse of a stable located in Brescia, Lombardy, was identified as H3N8 Florida lineage clade 1 (FC1). In the constructed phylogenetic trees, this strain is located within the FC1, together with the virus isolated in France in 2018 (MK501761)., Conclusions: This study reports the first detection of H3N8 FC1 in Italy, highlighting the importance of monitoring circulating EIV strains to verify the vaccine composition appropriateness for maximum efficacy.

Objective: Family relationships influence how people appraise their own aging and how their appraisals impact their health. We analyzed felt age (FA) among family caregivers of people with dementia., Methods and Measures: We used a stratified sample of 1,020 spousal and 202 adult-child caregivers from the IDEAL study. We estimated cross-sectional associations and bidirectional influences between caregivers' FA and their health and wellbeing (depression, number of health conditions, stress, positive aspects of caregiving) over 2 years., Results: Among spousal caregivers, 25% had a younger FA and 36% had an older FA. Among adult-child caregivers, 21.8% had a younger FA and 36.1% had an older FA. In spousal and adult-child caregivers an older FA was cross-sectionally associated with higher depression, number of health conditions, and stress, and fewer positive aspects of caregiving. In spousal caregivers, hours of care per day moderated the association between FA and depression, and FA was associated with stress 1 year later., Conclusion: Caregiving may impact FA and its relationship with health. We urge continued research on the connections between caregiving and FA, and how interventions might support caregivers' positive views on their own aging, which will translate views on aging scholarship to meaningfully improve caregivers' lives., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Sabatini, Turner, Morris, Opdebeeck, Thom, Hunt, Allan, Pentecost and Clare.)

Background: Most people with dementia have multiple health conditions. This study explores (1) number and type of health condition(s) in people with dementia overall and in relation to age, sex, dementia type, and cognition; (2) change in number of health conditions over two years; and (3) whether over time the number of health conditions at baseline is related to social isolation, loneliness, quality of life, and/or well-being., Methods: Longitudinal data from the IDEAL (Improving the experience of Dementia and Enhancing Active Life) cohort were used. Participants comprised people with dementia (n = 1490) living in the community (at baseline) in Great Britain. Health conditions using the Charlson Comorbidity Index, cognition, social isolation, loneliness, quality of life, and well-being were assessed over two years. Mixed effects modelling was used., Results: On average participants had 1.8 health conditions at baseline, excluding dementia; increasing to 2.5 conditions over two years. Those with vascular dementia or mixed (Alzheimer's and vascular) dementia had more health conditions than those with Alzheimer's disease. People aged ≥ 80 had more health conditions than those aged < 65 years. At baseline having more health conditions was associated with increased loneliness, poorer quality of life, and poorer well-being, but was either minimally or not associated with cognition, sex, and social isolation. Number of health conditions had either minimal or no influence on these variables over time., Conclusions: People with dementia in IDEAL generally had multiple health conditions and those with more health conditions were lonelier, had poorer quality of life, and poorer well-being., (© 2024. The Author(s).)

We report the analysis of 1 year of data from the first cohort of 15 patients enrolled in an open-label, first-in-human, dose-escalation phase I study (ClinicalTrials.gov: NCT03282760, EudraCT2015-004855-37) to determine the feasibility, safety, and tolerability of the transplantation of allogeneic human neural stem/progenitor cells (hNSCs) for the treatment of secondary progressive multiple sclerosis. Participants were treated with hNSCs delivered via intracerebroventricular injection in combination with an immunosuppressive regimen. No treatment-related deaths nor serious adverse events (AEs) were observed. All participants displayed stability of clinical and laboratory outcomes, as well as lesion load and brain activity (MRI), compared with the study entry. Longitudinal metabolomics and lipidomics of biological fluids identified time- and dose-dependent responses with increased levels of acyl-carnitines and fatty acids in the cerebrospinal fluid (CSF). The absence of AEs and the stability of functional and structural outcomes are reassuring and represent a milestone for the safe translation of stem cells into regenerative medicines., Competing Interests: Declaration of interests S.P. is founder, CSO, and shareholder (>5%) of CITC Ltd. and Chair of the Scientific Advisory Board at ReNeuron plc., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: The bidirectionality between self-perceptions of aging and health-related outcomes may depend on age group. Therefore, we tested such bidirectionality among individuals in late midlife (50-64 years), young-old age (65-74 years), and old-old age (75+ years), taking advantage of the construct of Awareness of Age-Related Change (AARC) and its 2-dimensionality in terms of AARC-gains and AARC-losses. Various conceptualizations of physical, mental, and cognitive functioning were used as outcomes., Methods: Data from 2 measurement occasions (2019 and 2020) from the UK PROTECT study for individuals in late midlife (N = 2,385), young-old age (N = 2,430), and old-old age (N = 539) were used. Data on self-reported functional difficulties, depression, anxiety, and performance on four computerized cognitive tasks (i.e., verbal reasoning, paired associate learning, self-ordered search, and digit span) providing a score for verbal reasoning and a score for working memory were analyzed using cross-lagged panel models., Results: Across all 3 age groups, the bidirectional associations of AARC-gains with indicators of functioning were not significant, whereas higher AARC-losses significantly predicted slightly greater functional difficulties and higher depression and anxiety levels. Higher AARC-losses predicted slightly poorer Verbal Reasoning only in old-old age and poorer Working Memory predicted slightly higher AARC-losses only in young-old age. The remaining associations of AARC-losses with cognitive tasks were not statistically significant., Discussion: In accordance with previous research targeting other indicators of self-perceptions of aging, this study supported a stronger impact of AARC-losses on indicators of physical functioning and mental health than vice versa from midlife to old-old age., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Views of aging predict key developmental outcomes. Less is known, however, about the consequences of constellations of domain-specific perceived gains and losses across the full adult lifespan. First, we explored levels of awareness of age-related gains (AARC-gains) and losses (AARC-losses) in five behavioral domains across adulthood. Second, we identified the number and types of profiles of AARC-gains and AARC-losses in young adulthood, midlife, young-old age, and old-old age. Third, we investigated whether the identified profiles differed in their associations with developmental correlates. Data came from the 2018 German Socio-Economic Panel Innovation Sample (SOEP-IS), comprising 403 young, 721 middle-aged, 260 young-old and 228 old-old individuals. We assessed AARC, physical and mental functioning, information processing speed, social relations, lifestyle, and engagement. At the sample level, AARC-losses were higher in old age, whereas AARC-gains did not differ across adulthood. Latent profile analyses revealed two distinguishable constellations of AARC-gains and AARC-losses that characterize young adulthood and old-old age, whereas four and three gains-to-losses constellations are needed to characterize midlife and young-old age, respectively. In middle, young-old, and old-old age, profiles with more AARC-losses were associated with poorer scores on all developmental correlates. Overall, study results suggest that age-related experiences are most diversified in midlife and young-old age. Asking individuals about their negative age-related experiences may help identify those individuals who are doing less well in important developmental correlates. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Rooted in the premises of lifespan developmental theory, the concept of awareness of age-related change (AARC) posits that growing older comes with both experiences of gains and losses across different behavioral domains. However, little is known about how age-related change is perceived across the entire adult lifespan, provided that respective measures can be validly compared. Further, few studies have adopted an approach that examines gains and losses simultaneously to study a potential shift in the ratio of perceived age-related gains and losses from adolescence to advanced old age. Using cross-sectional data from the German Socio-Economic Panel, this study tested the measurement invariance of the 10-item AARC short form and examined age differences in the awareness of age-related changes across 1,612 participants aged 16-93 years. First, partial measurement invariance of the AARC-Gains and AARC-Losses scales was established, allowing for valid group comparisons across young adulthood, midlife, and old age. Second, results indicated that people experience more AARC-Gains than AARC-Losses throughout the adult lifespan. However, older adults exhibited an increasingly less favorable gains-to-losses ratio, primarily driven by more loss experiences. Gain experiences were mostly stable across age groups. Third, differences in levels of AARC were related to individuals' background characteristics relevant at the respective time of life, such as education (early adulthood), employment (midlife), and social resources (old age). These results highlight the utility of considering a broad age range when examining the nature and correlates of age differences in perceived age-related gains and losses. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background: COVID-19 patients can report 'brain fog' and may exhibit cognitive symptoms for months after recovery (Cognitive COVID). However, evidence on whether and the extent to which SARS-CoV-2 infection impacts cognition irrespective of COVID-19 course and severity is limited to clinical samples and mainly comes from prognostic studies. We aimed to explore the association between serologically confirmed SARS-CoV-2 infection and cognitive functioning in community-based and institutionalized older adults, irrespective of COVID-19 symptoms., Methods: We conducted a case-control study nested into two cohorts in Southern Switzerland. Eligible subjects were Italian speaking older adults, without a previous diagnosis of dementia, who underwent serological testing for anti-SARS-CoV-2 antibodies between November 2020 and July 2021. We manually selected age-, sex- and education-matched cases (i.e., individuals with a serologically confirmed SARS-CoV-2 infection), with seronegative controls, and we conducted in-person neuropsychological assessments using validated, highly sensitive cognitive tests., Results: We completed 38 neuropsychological assessments in a mostly female sample of older adults (Mean age: 83.13 ± 8.95; 86.8% women). 17 were community dwelling individuals while 21 lived in a nursing home. As expected, socio-demographic characteristics of age, gender and educational level were similarly distributed between cases (n = 14) and controls (n = 24). In linear regression models, cases had significantly lower scores in cognitive tasks of memory (β = -0.367, p = 0.023), attention (β = 0.428, p = 0.008) and executive functions (β = 0.326, p = 0.046). We found no significant difference in tests of language and spatial-temporal orientation (all p values > 0.05)., Conclusions: SARS-CoV-2 infection was associated with cognitive impairment in memory, attention, and executive functions in older adults. Our findings are consistent with mechanistic evidence of the neurotropism of the virus and provide empirical support for the "Cognitive COVID" construct also in non-clinical samples. With nearly 800 million COVID-19 cases (in April 2023), and many more infections worldwide, the clinical and public health implications of Cognitive COVID due to SARS-CoV-2 infection may be massive and warrant further epidemiological investigations., Competing Interests: The authors have no declaration of competing interest., (© 2023 The Authors.)

Background: We investigated whether aspects of subjective cognitive aging, including awareness of age-related gains and losses in cognition (AARC-gains, AARC-losses) and subjective cognitive decline (SCD), predict change in objective cognitive function as measured by verbal reasoning (VR) and working memory (WM)., Methods: We used longitudinal data for 3,299 cognitively healthy UK residents aged 65+. We used data on AARC and SCD assessed in 2019, and cognitive tasks assessed in 2019, 2020, and 2021. We used latent growth curve modeling, latent class growth analysis, and growth mixture modeling., Results: For VR, multiple growth trajectories were not evident. Mean VR at baseline was 37.45; this remained stable over time. Higher AARC-gains in cognition (mean intercept = -0.23; 95%CI: -0.31; -0.16), higher AARC-losses in cognition (mean intercept = -0.37; 95%CI: -0.46; -0.28), and lower SCD (mean intercept = 2.92; 95%CI: 2.58; 3.58) were associated with poorer VR at baseline. A three-class growth mixture model-class varying best represented trajectories of WM. In Class 1 ( N  = 182) mean WM at baseline was 31.20; this decreased by 2.48 points each year. In Class 2 ( N  = 119) mean WM at baseline was 23.12; this increased by 3.28 points each year. In Class 3 ( N  = 2,998) mean WM at baseline was 30.11; and it remained stable. Higher AARC-gains (Odds Ratio = 1.08; 95%CI: 1.03; 1.14) and AARC-losses (Odds Ratio = 1.10; 95%CI: 1.04; 1.16) in cognition predicted greater likelihood of being in Class 2 than Class 3., Conclusion: Although both higher AARC-gains and AARC-losses indicate poorer concurrent cognition, higher AARC-gains may be a resource that facilitates future cognitive improvement., Competing Interests: HB was employed by the Ecog Pro Ltd. The remaining 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Sabatini, Cosentino, Chapman, Ballard, Brooker, Corbett and Stephan.)

Background: We explored whether number of languages spoken and language proficiency are associated with cognitive performance among older adults living in the community and in long-term care (LTC) in Switzerland., Methods: Among study participants, 664 lived in the community in the Canton of Zurich (Mean age = 72.97 years; SD = 6.08), 386 lived in the community in Ticino (Mean age = 76.24 years; SD = 6.66), and 176 resided in LTC in Ticino (Mean age = 87.61 years; SD = 6.45). We recorded sociodemographic variables, number of languages spoken, language proficiency, and assessed overall cognitive performance, immediate and delayed memory, and verbal fluency with standardized tests. We used adjusted regression models., Results: A higher number of spoken languages was positively associated with overall cognitive performance, verbal fluency and immediate and delayed memory performance in community-dwelling older adults in the Cantons of Ticino and Zurich, (all p values ≤ 0.012;), but not in in older adults living in LTC homes (all p values ≥ 0.35). Higher language proficiency was associated with better memory performance among individuals living in the community in Ticino (p value = 0.003), and to better performance in verbal fluency and memory tasks in Zurich (p values ≤ 0.002). Among LTC residents, proficiency levels were not associated with cognitive performance., Conclusions: Multilingualism and greater language proficiency were associated with better cognitive functioning in community-dwelling but not in institutionalized older adults. Multilingualism may contribute to cognitive reserve, as well as protect and delay cognitive decline in late life., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objectives: We aimed to co-produce and validate an accessible, evidence-based questionnaire measuring 'living well' with dementia that reflects the experience of people with mild-to-moderate dementia., Methods: Nine people with dementia formed a co-production group. An initial series of workshops generated the format of the questionnaire and a longlist of items. Preliminary testing with 53 IDEAL cohort participants yielded a shortlist of items. These were tested with 136 IDEAL cohort participants during a further round of data collection and assessed for reliability and validity. The co-production group contributed to decisions throughout and agreed the final version., Results: An initial list of 230 items was reduced to 41 for initial testing, 12 for full testing, and 10 for the final version. The 10-item version had good internal consistency and test-retest reliability, and a single factor structure. Analyses showed significant large positive correlations with scores on measures of quality of life, well-being, and satisfaction with life, and expected patterns of association including a significant large negative association with depression scores and no association with cognitive test scores., Conclusions: The co-produced My Life Questionnaire is an accessible and valid measure of 'living well' with dementia suitable for use in a range of contexts.

A fatty liver index (FLI) greater than sixty (FLI ≥ 60) is an established score for metabolic dysfunction-associated steatotic liver disease (MASLD), which carries a high risk for diabetes and cardiovascular disease, while a FLI ≤ 20 rules out the presence of steatosis. Thus, we investigated whether FLI was associated with cardiometabolic risk factors, i.e., visceral (VAT), subcutaneous (SC), epicardial (EPI), extrapericardial (PERI), and total cardiac (CARD-AT) adipose tissue, hepatic fat ((by magnetic resonance imaging, MRI, and spectroscopy, MRS), and insulin resistance (IR, HOMA-IR and OGIS-index), and components of metabolic syndrome. All individuals with FLI ≥ 60 had MASLD, while none with FLI ≤ 20 had steatosis (by MRS). Subjects with FLI ≥ 60 had a higher BMI and visceral and cardiac fat (VAT > 1.7 kg, CARD-AT > 0.2 kg). FLI was positively associated with increased cardiac and visceral fat and components of metabolic syndrome. FLI, VAT, and CARD-AT were all associated with IR, increased blood pressure, cholesterol, and reduced HDL. For FLI ≥ 60, the cut-off values for fat depots and laboratory measures were estimated. In conclusion, FLI ≥ 60 identified not only subjects with steatosis but also those with IR, abdominal and cardiac fat accumulation, increased blood pressure, and hyperlipidemia, i.e., those at higher risk of cardiometabolic diseases. Targeted reduction of FLI components would help reduce cardiometabolic risk., Competing Interests: The authors declare no conflict of interest.

Objective: Lower awareness of age-related gains (AARC-gains) and higher awareness of age-related losses (AARC-losses) may be risk factors for depressive and anxiety symptoms. We explored whether: (1) Baseline AARC-gains and AARC-losses predict depressive and anxiety symptoms at one-year follow-up; (2) age and rumination moderate these associations; (3) levels of AARC-gains and AARC-losses differ among individuals with different combinations of current and past depression and/or with different combinations of current and past anxiety., Methods: In this one-year longitudinal cohort study participants ( N  = 3386; mean age = 66.0; SD = 6.93) completed measures of AARC-gains, AARC-losses, rumination, depression, anxiety, and lifetime diagnosis of depression and anxiety in 2019 and 2020. Regression models with tests of interaction were used., Results: Higher AARC-losses, but not lower AARC-gains, predicted more depressive and anxiety symptoms. Age did not moderate these associations. Associations of lower AARC-gains and higher AARC-losses with more depressive symptoms and of higher AARC-losses with more anxiety symptoms were stronger in those with higher rumination. Individuals with both current and past depression reported highest AARC-losses and lowest AARC-gains. Those with current, but not past anxiety, reported highest AARC-losses., Conclusion: Perceiving many age-related losses may place individuals at risk of depressive and anxiety symptoms, especially those who frequently ruminate.

The superbug Staphylococcus aureus ( S. aureus ) exhibits several resistance mechanisms, including efflux pumps, that strongly contribute to antimicrobial resistance. In particular, the NorA efflux pump activity is associated with S. aureus resistance to fluoroquinolone antibiotics ( e.g ., ciprofloxacin) by promoting their active extrusion from cells. Thus, since efflux pump inhibitors (EPIs) are able to increase antibiotic concentrations in bacteria as well as restore their susceptibility to these agents, they represent a promising strategy to counteract bacterial resistance. Additionally, the very recent release of two NorA efflux pump cryo-electron microscopy (cryo-EM) structures in complex with synthetic antigen-binding fragments (Fabs) represents a real breakthrough in the study of S. aureus antibiotic resistance. In this scenario, supervised molecular dynamics (SuMD) and molecular docking experiments were combined to investigate for the first time the molecular mechanisms driving the interaction between NorA and efflux pump inhibitors (EPIs), with the ultimate goal of elucidating how the NorA efflux pump recognizes its inhibitors. The findings provide insights into the dynamic NorA-EPI intermolecular interactions and lay the groundwork for future drug discovery efforts aimed at the identification of novel molecules to fight antimicrobial resistance.

In plants, developmental plasticity allows for the modulation of organ growth in response to environmental cues. Being in contact with soil, roots are the first organ that responds to various types of soil abiotic stress such as high salt concentration. In the root, developmental plasticity relies on changes in the activity of the apical meristem, the region at the tip of the root where a set of self-renewing undifferentiated stem cells sustain growth. Here, we show that salt stress promotes differentiation of root meristem cells via reducing the dosage of the microRNAs miR165 and 166. By means of genetic, molecular and computational analysis, we show that the levels of miR165 and 166 respond to high salt concentration, and that miR165 and 166-dependent PHABULOSA (PHB) modulation is central to the response of root growth to this stress. Specifically, we show that salt-dependent reduction of miR165 and 166 causes a rapid increase in PHB expression and, hence, production of the root meristem pro-differentiation hormone cytokinin. Our data provide direct evidence for how the miRNA-dependent modulation of transcription factor dosage mediates plastic development in plants., (© 2023. Springer Nature Limited.)

Purpose: To address the paucity of data in patients with historically poor outcomes, we conducted the single-arm phase IIIb CheckMate 401 study to evaluate the safety and efficacy of nivolumab plus ipilimumab followed by nivolumab monotherapy in clinically diverse patient populations with advanced melanoma., Methods: Treatment-naive patients with unresectable stage III-IV melanoma received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg (240 mg following a protocol amendment) once every 2 weeks for ≤24 months. The primary end point was the incidence of grade 3-5 select treatment-related adverse events (TRAEs). Overall survival (OS) was a secondary end point. Outcomes were evaluated in subgroups defined by Eastern Cooperative Oncology Group performance status (ECOG PS), brain metastasis status, and melanoma subtype., Results: In total, 533 patients received at least one dose of study drug. Grade 3-5 select TRAEs affecting the GI (16%), hepatic (15%), endocrine (11%), skin (7%), renal (2%), and pulmonary (1%) systems occurred in the all-treated population; similar incidence rates were observed across all subgroups. At 21.6 months' median follow-up, 24-month OS rates were 63% in the all-treated population, 44% in the ECOG PS 2 subgroup (including patients with cutaneous melanoma only), 71% in the brain metastasis subgroup, 36% in the ocular/uveal melanoma subgroup, and 38% in the mucosal melanoma subgroup., Conclusion: Nivolumab plus ipilimumab followed by nivolumab monotherapy was tolerable in patients with advanced melanoma and poor prognostic characteristics. Efficacy was similar between the all-treated population and patients with brain metastases. Reduced efficacy was observed in patients with ECOG PS 2, ocular/uveal melanoma, and/or mucosal melanoma, highlighting the continued need for novel treatment options for these difficult-to-treat patients.

Objectives: We test whether higher awareness of age-related gains (AARC-gains), lower awareness of age-related losses (AARC-losses), and more positive attitudes toward own aging (ATOA) are cross-sectionally related to more frequent social media use. We also investigate the strength and direction of the associations of AARC-gains, AARC-losses, and ATOA with social media use over 1 year, from before to after the onset of the coronavirus 2019 pandemic., Methods: We used cross-sectional data from 8,320 individuals (mean age = 65.95 years; standard deviation = 7.01) and longitudinal data from a subsample of 4,454 individuals participating in the UK PROTECT study in 2019 and 2020. We used ordered regression models, linear regression models, and tests of interaction. Models were adjusted for age, sex, education, and employment., Results: Higher AARC-gains and more positive ATOA, but not AARC-losses, were cross-sectionally associated with more frequent social media use. Social media use became more frequent at follow-up. In the longitudinal models controlling for baseline levels of the outcome variable, more frequent baseline social media use predicted increases in AARC-gains, whereas baseline AARC-gains did not significantly predict the frequency of social media use at follow-up. Baseline frequency of social media use did not significantly predict AARC-losses, nor ATOA at follow-up, whereas lower levels of AARC-losses and more positive ATOA predicted more frequent social media use at follow-up., Discussion: Although effect sizes were small, decreasing negative views on aging may help increase the engagement of middle-aged and older people with social media. At the same time, fostering social media use could promote positive self-perceptions of aging., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: The concept of Awareness of Age-Related Changes captures people's perceptions of the positive (AARC-gains) and negative (AARC-losses) age-related changes they experience in several life domains, including their health. We investigated the cross-sectional associations of number and type of physical and mental health conditions with AARC-gains and AARC-losses., Methods: The sample comprised 3,786 middle-aged and older adults (mean age = 67.04 years; SD = 6.88) participating to the UK PROTECT study. We used hierarchical regression models to analyze whether after having included sociodemographic variables (model 1), number of physical (model 2) and of mental (model 3) health conditions explained a significant additional amount of variance in AARC-gains and AARC-losses, and whether the association between number of conditions and AARC depended on participants' age. We used multiple regression models to analyze the associations of types of physical and mental health conditions with AARC-gains and AARC-losses., Results: A higher number of physical health conditions was associated with higher AARC-gains and higher AARC-losses, but the association did not depend on participant age. After controlling for the number of physical health conditions, a higher number of mental health conditions was associated with higher AARC-losses but not with AARC-gains, and the association was stronger among older participants. Small effects were found between greater AARC-gains and current cancer and between greater AARC-losses and diagnoses of mild cognitive impairment, Parkinson's disease, arthritic condition, cancer in full remission, osteoporosis, depression, anxiety disorders, and personality disorder. The remaining health conditions were either negligibly or non-statistically related to AARC-losses., Conclusion: Middle-aged and older adults having more physical health conditions and more mental health conditions may be at higher risk of negative views on their own aging. However, specific physical health conditions, such as arthritis, and certain mental health conditions, such as depression, may make adults particularly vulnerable to negative age-related perceptions., Competing Interests: HB is the funder/head of Ecog Pro Ltd. The remaining 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 © 2023 Sabatini, Turner, Brooker, Ballard, Corbett and Hampshire.)

Objective: We explored (1) social, cultural, and economic capital in spousal carers of people with dementia; (2) profiles of carers with different levels of capital; (3) whether the identified profiles differ in levels of stress and positive experiences of caring, and likelihood of depression over time., Methods: Baseline (2014-2016), 12-month, and 24-month follow-up data were analyzed for 984 coresident spousal carers of people with dementia. We assessed social, cultural, and economic capital, stress, positive experiences of caring, depression., Results: On average, carers reported infrequent social and cultural participation. Most carers were not socially isolated, trusted their neighbours, had education at least to age 16, and had an income aligned with the 2014 UK average. We identified four groups of carers with different levels of capital. Although on average stress was low, depression was infrequent, and positive experiences of caring were moderately frequent, the group of carers with lowest capital was the least stressed and reported the most positive experiences of caring over time. Compared to the two groups with better capital, those with poorer capital were more likely to be depressed over time., Conclusion: Social, cultural, and economic resources may decrease likelihood of depression, but not stress, in carers of people with dementia.

There is an urgent need to identify efficient antiviral compounds to combat existing and emerging RNA virus infections, particularly those related to seasonal and pandemic influenza outbreaks. While inhibitors of the influenza viral integral membrane proton channel protein (M2), neuraminidase (NA), and cap-dependent endonuclease are available, circulating influenza viruses acquire resistance over time. Thus, the need for the development of additional anti-influenza drugs with novel mechanisms of action exists. In the present study, a cell-based screening assay and a small molecule library were used to screen for activities that antagonized influenza A non-structural protein 1 (NS1), a highly conserved, multifunctional accessory protein that inhibits the type I interferon response against influenza. Two potential anti-influenza agents, compounds 157 and 164 , were identified with anti-NS1 activity, resulting in the reduction of A/PR/8/34(H1N1) influenza A virus replication and the restoration of IFN-β expression in human lung epithelial A549 cells. A 3D pharmacophore modeling study of the active compounds provided a glimpse of the structural motifs that may contribute to anti-influenza virus activity. This screening approach is amenable to a broader analysis of small molecule compounds to inhibit other viral targets.

Background: The effectiveness of different types of electric toothbrushes in terms of removing bacterial plaque is still a debated issue. The aim of the study was to compare the plaque removal after a single use of two types of electric toothbrushes, sonic and roto-oscillating, in patients with fixed orthodontics., Methods: Twenty-five subjects with fixed multibrackets appliances were randomly selected. Plaque scores were detected using a fluorescein-based detector. After using the sonic toothbrush with a surfactant-free toothpaste, the plaque scores were detected again. After 3 months, the procedure is performed again following the same methods, using the roto-oscillating toothbrush. For the statistical analysis a Student's t-test using Microsoft Excel 2021 (Microsoft Corp., Redmond, WA, USA) was performed. The differences were considered statistically significant for probability values P<0.05., Results: It can be seen that the brushing carried out with a sonic technology is more effective than the roto-oscillating technology. However, the FMPS, MOPI and OPI indexes do not show differences between the use of the two toothbrushes. The OHI-S index shows a statistically significant difference using the sonic toothbrush with a significance level of 0.05%., Conclusions: It can be said that both electric toothbrushes are effective for maintaining a good home oral hygiene in patients with fixed orthodontics.

Objectives: We compared socio-demographic characteristics, health-related variables, vaccination-related beliefs and attitudes, vaccination acceptance, and personality traits of individuals who vaccinated against COVID-19 and who did not vaccinate by December 2021. Methods: This cross-sectional study used data of 10,642 adult participants from the Corona Immunitas eCohort, an age-stratified random sample of the population of several cantons in Switzerland. We used multivariable logistic regression models to explore associations of vaccination status with socio-demographic, health, and behavioral factors. Results: Non-vaccinated individuals represented 12.4% of the sample. Compared to vaccinated individuals, non-vaccinated individuals were more likely to be younger, healthier, employed, have lower income, not worried about their health, have previously tested positive for SARS-CoV-2 infection, express lower vaccination acceptance, and/or report higher conscientiousness. Among non-vaccinated individuals, 19.9% and 21.3% had low confidence in the safety and effectiveness of SARS-CoV-2 vaccine, respectively. However, 29.1% and 26.7% of individuals with concerns about vaccine effectiveness and side effects at baseline, respectively vaccinated during the study period. Conclusion: In addition to known socio-demographic and health-related factors, non-vaccination was associated with concerns regarding vaccine safety and effectiveness., Competing Interests: The authors declare that they do not have any conflicts of interest., (Copyright © 2023 Sabatini, Kaufmann, Fadda, Tancredi, Noor, Van Der Linden, Cullati, Frank, Michel, Harju, Luedi, Frei, Ballouz, Menges, Fehr, Kohler, Kahlert, Scheu, Ortega, Chocano-Bedoya, Rodondi, Stringhini, Baysson, Lorthe, Zufferey, Suggs, Albanese, Vincentini, Bochud, D’Acremont, Nusslé, Imboden, Keidel, Witzig, Probst-Hensch and von Wyl.)

One promising approach in treating antibiotic-resistant bacteria is to "break" resistances connected with antibacterial efflux by co-administering efflux pump inhibitors (EPIs) with antibiotics. Here, ten compounds, previously optimized to restore the susceptibility to ciprofloxacin (CIP) of norA -overexpressing Staphylococcus aureus , were evaluated for their ability to inhibit norA -mediated efflux in Staphylococcus pseudintermedius and synergize with CIP, ethidium bromide (EtBr), gentamycin (GEN), and chlorhexidine digluconate (CHX). We focused efforts on S. pseudintermedius as a pathogenic bacterium of concern within veterinary and human medicine. By combining data from checkerboard assays and EtBr efflux inhibition experiments, the hits 2-arylquinoline 1 , dihydropyridine 6, and 2-phenyl-4-carboxy-quinoline 8 were considered the best EPIs for S. pseudintermedius . Overall, most of the compounds, except for 2-arylquinoline compound 2 , were able to fully restore the susceptibility of S. pseudintermedius to CIP and synergize with GEN as well, while the synergistic effect with CHX was less significant and often did not show a dose-dependent effect. These are valuable data for medicinal chemistry optimization of EPIs for S. pseudintermedius and lay the foundation for further studies on successful EPIs to treat staphylococcal infections., Competing Interests: The authors declare no conflict of interest.

Dengue virus (DENV), a mosquito-borne flavivirus, continues to be a major public health threat in many countries and no approved antiviral therapeutics are available yet. In this work, we designed and synthesized a series of sulfonyl anthranilic acid (SAA) derivatives using a ligand-based scaffold morphing approach of the 2,1-benzothiazine 2,2-dioxide core, previously used by us to develop DENV polymerase inhibitors resulting devoid of any cell-based antiviral activity. Several derivatives based on the new SAA chemotype exhibited potent inhibition against DENV infection in the cell-based assay but did not inhibit DENV NS5 polymerase activity in the in vitro de novo initiation and elongation assays. Notably, best compounds 26 and 39 showed EC 50 values in the range of 0.54-1.36 μM against cells infected with the four dengue serotypes (DENV-1-4). Time-of-drug-addition assay revealed that analogue 26 is a post-entry replication inhibitor that appears to be specific for cells of primate origin, implicating a host target with a high barrier to resistance. In conclusion, SAA derivatives offer a valuable starting point for developing effective Dengue antiviral therapeutics., 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 © 2023 Elsevier Masson SAS. All rights reserved.)

During organogenesis, a key step toward the development of a functional organ is the separation of cells into specific domains with different activities. Mutual inhibition of gene expression has been shown to be sufficient to establish and maintain these domains during organogenesis in several multicellular organisms. Here, we show that the mutual inhibition between the PLETHORA transcription factors (PLTs) and the ARABIDOPSIS RESPONSE REGULATORs (ARRs) transcription factors is sufficient to separate cell division and cell differentiation during root organogenesis. In particular, we show that ARR1 suppresses PLT activities and that PLTs suppress ARR1 and ARR12 by targeting their proteins for degradation via the KISS ME DEADLY 2 F-box protein. These findings reveal new important aspects of the complex process of root zonation and development., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: We explored which factors are associated with subjective age (SA), i.e. feeling younger, the same as, or older than one's chronological age, and whether these factors differ between men and women and between two age sub-groups., Design: Cross-sectional study using qualitative and quantitative data for 1457 individuals (mean age= 67.2 years)., Main Outcome Measures: Participants reported how old they feel they are and provided comments in relation to their SA judgments., Results: By using content analysis participants' comments were assigned to 13 categories, grouped into three higher-order categories ( antecedents of age-related thoughts, mental processes, and issues when measuring subjective age ). SA may result from the interaction between factors that increase or decrease age-related thoughts and mental processes that individuals use to interpret age-related changes. Chi-squared tests show that individuals reporting an older SA are more likely to experience significant negative changes and to engage in negative age-related thoughts than individuals reporting an age-congruent SA or a younger SA. Women experience a more negative SA and more age-salient events than men., Conclusion: Individuals reporting an older SA may benefit from interventions promoting adaptation to negative age-related changes. There is the need to eradicate negative societal views of older women.