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Objectives: Consistency among population-based studies investigating the relationship between diet and cognition in older inhabitants in the Mediterranean area is poor. The present study investigated whether diet changes over 12 years were associated with cognitive function in older people in Southern-Italy., Methods: From the 'Salus in Apulia Study', that includes the MICOL and GreatAGE Studies, 584 participants were selected, firstly enrolled in MICOL3 (M3) and later in the GreatAGE Study (MICOL4, M4). Foods and micronutrients intake were recorded in both studies, and global cognitive function in M4, assessed with the Mini Mental State Examination., Results: Plant-based foods, particularly coffee and vegetables, as well as vitamin A sources, were inversely associated to age-related cognitive impairment. Alcohol consumption showed a detrimental role on cognition, while red meat appeared to be beneficial in the present study, although its role is traditionally considered harmful for cognitive function., Discussion: Our study confirmed that a traditional Mediterranean dietary pattern based on agricultural products and low alcohol consumption may help to prevent/delay age-related cognitive impairment.

The liver contribution to the biological network underlying physical frailty in aging is underestimated. How best to measure this contribution magnitude and impact on health risk trajectories in frail individuals is not yet entirely clear. We analyzed the association of a novel liver frailty phenotype with the risk of death in older participants of the Salus in Apulia Study cohort. Clinical and physical examination, routine biomarkers, medical history, and anthropometry were analyzed in 1929 older adults (65 +). Physical frailty was classified by Cardiovascular Health Study criteria, and liver fibrosis risk by fibrosis-4 (FIB-4). The liver frailty phenotype was defined as physical frailty plus high-risk liver fibrosis (score > 2.67). Physical frailty, high-risk liver fibrosis, and liver frailty subjects were compared to subjects without these conditions (non-frail). Proportional Cox regression tested the adjusted association between liver frailty and all-cause mortality for each category. The liver frailty prevalence was relatively low (3.8%), but higher in men (58.1%). Compared to non-frail older subjects, liver frailty subjects were significantly older (effect size (ES) - 1.11, 95% confidence interval (CI) - 1.35 to - 0.87), with a lower education (ES 0.48, 95%CI 0.24 to 0.71) and higher multimorbidity (ES 15.81, 95%CI 4.20 to 27.41). Cox multivariate analyses showed a two-fold increased risk of overall mortality (hazard ratio 2.09, 95%CI 1.16-3.74) even after the adjustment for age, sex, education, and alcohol consumption. The liver frailty phenotype runs twice the risk of overall mortality compared with the non-frail population. This clinical tool, validated in a Southern Italian population, is based on simple sets of measures that can conveniently be assessed also in the primary care setting., (© 2021. American Aging Association.)

Human apolipoprotein E (ApoE) is a 299-amino acid secreted glycoprotein that binds cholesterol and phospholipids. ApoE exists as three common isoforms (ApoE2, ApoE3, and ApoE4) and heterozygous carriers of the ε4 allele of the gene encoding ApoE ( APOE ) have a fourfold greater risk of developing Alzheimer's disease (AD). The enzymes thrombin, cathepsin D, α-chymotrypsin-like serine protease, and high-temperature requirement serine protease A1 are responsible for ApoE proteolytic processing resulting in bioactive C-terminal-truncated fragments that vary depending on ApoE isoforms, brain region, aging, and neural injury. The objectives of the present narrative review were to describe ApoE processing, discussing current hypotheses about the potential role of various ApoE fragments in AD pathophysiology, and reviewing the current development status of different anti-ApoE drugs. The exact mechanism by which APOE gene variants increase/decrease AD risk and the role of ApoE fragments in the deposition are not fully understood, but APOE is known to directly affect tau-mediated neurodegeneration. ApoE fragments co-localize with neurofibrillary tangles and amyloid β (Aβ) plaques, and may cause neurodegeneration. Among anti-ApoE approaches, a fascinating strategy may be to therapeutically overexpress ApoE2 in APOE ε4/ε4 carriers through vector administration or liposomal delivery systems. Another approach involves reducing ApoE4 expression by intracerebroventricular antisense oligonucleotides that significantly decreased Aβ pathology in transgenic mice. Differences in the proteolytic processing of distinct ApoE isoforms and the use of ApoE fragments as mimetic peptides in AD treatment are also under investigation. Treatment with peptides that mimic the structural and biological properties of native ApoE may reduce Aβ deposition, tau hyperphosphorylation, and glial activation in mouse models of Aβ pathology. Alternative strategies involve the use of ApoE4 structure correctors, passive immunization to target a certain form of ApoE, conversion of the ApoE4 aminoacid sequence into that of ApoE3 or ApoE2, and inhibition of the ApoE-Aβ interaction., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Dietary behaviour is a core element in diabetes self-management. There are no remarkable differences between nutritional guidelines for people with type 2 diabetes and healthy eating recommendations for the general public. This study aimed to evaluate dietary differences between subjects with and without diabetes and to describe any emerging dietary patterns characterizing diabetic subjects. In this cross-sectional study conducted on older adults from Southern Italy, eating habits in the "Diabetic" and "Not Diabetic" groups were assessed with FFQ, and dietary patterns were derived using an unsupervised learning algorithm: principal component analysis. Diabetic subjects ( n = 187) were more likely to be male, slightly older, and with a slightly lower level of education than subjects without diabetes. The diet of diabetic subjects reflected a high-frequency intake of dairy products, eggs, vegetables and greens, fresh fruit and nuts, and olive oil. On the other hand, the consumption of sweets and sugary foods was reduced compared to non-diabetics (23.74 ± 35.81 vs. 16.52 ± 22.87; 11.08 ± 21.85 vs. 7.22 ± 15.96). The subjects without diabetes had a higher consumption of red meat, processed meat, ready-to-eat dishes, alcoholic drinks, and lower vegetable consumption. The present study demonstrated that, in areas around the Mediterranean Sea, older subjects with diabetes had a healthier diet than their non-diabetic counterparts.

Unbalanced diets and altered micronutrient intake are prevalent in the aging adult population. We conducted a systematic review to appraise the evidence regarding the association between single (α-carotene, β-carotene, lutein, lycopene, β-cryptoxanthin) or total carotenoids and frailty syndrome in the adult population. The literature was screened from study inception to December 2021, using six different electronic databases. After establishing inclusion criteria, two independent researchers assessed the eligibility of 180 retrieved articles. Only 11 fit the eligibility requirements, reporting five carotenoid entries. No exclusion criteria were applied to outcomes, assessment tools, i.e., frailty constructs or surrogates, recruitment setting, general health status, country, and study type (cohort or cross-sectional). Carotenoid exposure was taken as either dietary intake or serum concentrations. Cross-sectional design was more common than longitudinal design ( n = 8). Higher dietary and plasma levels of carotenoids, taken individually or cumulatively, were found to reduce the odds of physical frailty markedly, and the evidence showed consistency in the direction of association across all selected studies. Overall, the methodological quality was rated from moderate (27%) to high (73%). Prevention of micronutrient deficiencies has some potential to counteract physical decline. Considering carotenoids as biological markers, when monitoring micronutrient status, stressing increased fruit and vegetable intake may be part of potential multilevel interventions to prevent or better manage disability.

Background: Diet and social determinants influence the state of human health. In older adults, the presence of social, physical and psychological barriers increases the probability of deprivation. This study investigated the relationship between social deprivation and eating habits in non-institutionalized older adults from Southern Italy, and identified foods and dietary habits associated with social deprivation., Methods: We recruited 1,002 subjects, mean age 74 years, from the large population based Salus in Apulia Study. In this cross-sectional study, eating habits and the level of deprivation were assessed with FFQ and DiPCare-Q, respectively., Results: Deprived subjects ( n = 441) included slightly more females, who were slightly older and with a lower level of education. They consumed less fish (23 vs. 26 g), fruiting vegetables (87 vs. 102 g), nuts (6 vs. 9 g) and less "ready to eat" dishes (29 vs. 33 g). A Random Forest (RF) model was used to identify a dietary pattern associated with social deprivation. This pattern included an increased consumption of low-fat dairy products and white meat, and a decreased consumption of wine, leafy vegetables, seafood/shellfish, processed meat, red meat, dairy products, and eggs., Conclusion: The present study showed that social factors also define diet and eating habits. Subjects with higher levels of deprivation consume cheaper and more readily available food., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tatoli, Lampignano, Donghia, Castellana, Zupo, Bortone, De Nucci, Campanile, Lofù, Vimercati, Lozupone, De Pergola, Panza, Giannelli, Di Noia, Boeing and Sardone.)

Background: Retinal microvasculature assessment at capillary level may potentially aid the evaluation of early microvascular changes due to hypertension. We aimed to investigate associations between the measures obtained using optical coherence tomography (OCT) and OCT-angiography (OCT-A) and hypertension, in a southern Italian older population., Methods: We performed a cross-sectional analysis from a population-based study on 731 participants aged 65 years+ subdivided into two groups according to the presence or absence of blood hypertension without hypertensive retinopathy. The average thickness of the ganglion cell complex (GCC) and the retinal nerve fiber layer (RNFL) were measured. The foveal avascular zone area, vascular density (VD) at the macular site and of the optic nerve head (ONH) and radial peripapillary capillary (RPC) plexi were evaluated. Logistic regression was applied to assess the association of ocular measurements with hypertension., Results: GCC thickness was inversely associated with hypertension (odds ratio (OR): 0.98, 95% confidence interval (CI): 0.97-1). A rarefaction of VD of the ONH plexus at the inferior temporal sector (OR: 0.95, 95% CI: 0.91-0.99) and, conversely, a higher VD of the ONH and RPC plexi inside optic disc (OR: 1.07, 95% CI: 1.04-1.10; OR: 1.04, 95% CI: 1.02-1.06, respectively) were significantly associated with hypertension., Conclusion: A neuroretinal thinning involving GCC and a change in capillary density at the peripapillary network were related to the hypertension in older patients without hypertensive retinopathy. Assessing peripapillary retinal microvasculature using OCT-A may be a useful non-invasive approach to detect early microvascular changes due to hypertension.

The widespread interest in free radicals in biology extends far beyond the effects of ionizing radiation, with recent attention largely focusing on reactions of free radicals derived from peroxynitrite (i.e., hydroxyl, nitrogen dioxide, and carbonate radicals). These radicals can easily be generated individually by reactions of radiolytically-produced radicals in aqueous solutions and their reactions can be monitored either in real time or by analysis of products. This review first describes the general principles of selective radical generation by radiolysis, the yields of individual species, the advantages and limitations of either pulsed or continuous radiolysis, and the quantitation of oxidizing power of radicals by electrode potentials. Some key reactions of peroxynitrite-derived radicals with potential biological targets are then discussed, including the characterization of reactions of tyrosine with a model alkoxyl radical, reactions of tyrosyl radicals with nitric oxide, and routes to nitrotyrosine formation. This is followed by a brief outline of studies involving the reactions of peroxynitrite-derived radicals with lipoic acid/dihydrolipoic acid, hydrogen sulphide, and the metal chelator desferrioxamine. For biological diagnostic probes such as 'spin traps' to be used with confidence, their reactivities with radical species have to be characterized, and the application of radiolysis methods in this context is also illustrated.

Background: the possible relationship between dietary habits and the incidence of late-onset depression (LOD), defined as first depression onset at later age, is unclear., Objective: to investigate the relationship between consumption of different food groups and incident LOD., Design: longitudinal population-based study with a 12-year follow-up., Setting: Castellana Grotte, Bari, Italy., Subjects: five hundred and forty-six older subjects from the Salus in Apulia Study., Methods: baseline data were recorded in 2003-06, and diagnostic data were recorded in 2013-18 at follow-up. Dietary intake was assessed with a food frequency questionnaire. Depressive disorders were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders. Subjects who already suffered from depression or other psychiatric disorders at baseline were excluded from the analysis. The association between LOD and single dietary determinants was examined by Cox regression analysis and then applying the hazard ratio (HR)., Results: subjects with incident LOD (n = 34) had lower global cognition and total cholesterol levels and a higher body mass index (BMI) at baseline. Only processed meat significantly increased the risk of incident LOD of about 10% by 5 g/day intake (HR adjusted for age, sex, education, multimorbidity and BMI: 1.13, 95% confidence intervals: 1.04-1.22). A similar relationship was found for single foods in the processed meat food group such as sausages, salami and mortadella and baked ham, but not for raw ham., Conclusions: in midlife, a higher intake of processed meat was not only associated with an increased risk of cardiovascular- and metabolic-related chronic diseases in older age but also with an increased risk of developing LOD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: We declare no competing interests. We thank Mary Victoria Pragnell for her help as a native English language supervisor. All authors accessed all the data reported in this Comment.

The prevalence of late-life depression (LLD) depends on the study sample, measurements, and diagnostic approaches. We estimated the 30 item-Geriatric Depression Scale (GDS-30) accuracy against the gold standard LLD diagnosis made with the Semi-structured Clinical Diagnostic Interview for DSM-IV-TR Axis I Disorders, focusing on the prevalence of a late-life major depressive disorder (MDD), in a population-based sample of 843 subjects aged>65 years, subdivided into three groups: normal cognition, subjective memory complaints, and mild cognitive impairment. At the optimal cut-off score (≥4), the GDS-30 showed 65.1% sensitivity and 68.4% specificity for LLD (63% and 66% for late-life MDD, respectively). Using the standard cut-off score (≥10), the GDS-30 specificity reached 91.2%, while sensitivity dropped to 37.7%, indicating a lower screening accuracy [area under the curve(AUC):0.728, 95% confidence interval(CI):0.67-0-78]. The GDS-30 performance was associated with educational level, but not with age, gender, cognition, apathy, and somatic/psychiatric multimorbidity. For subjective memory complaints subjects, at the optimal cut-off score (≥7), the GDS-30 showed better discrimination performances (AUC=0.792,95%CI:0.60-0.98), but again the educational level affected the diagnostic performance. In subjective memory complaints subjects, symptom-based scales like the GDS-30 may feature a better performance for diagnosing depression in older age, but the GDS-30 seems to require adjustment to the patient's educational level., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Phototherapeutic keratectomy (PTK) plays an important role in the management of Reis-Bucklers' corneal dystrophy. The usage of PTK for the treatment of anterior corneal dystrophies is limited by the depth of ablation. This case shows the usage of high ablation depth PTK as one of the management strategies to visually rehabilitate a patient of advanced Reis-Bucklers' corneal dystrophy., Observations: We present a case of 32-year-old lady who was diagnosed with Reis-Bucklers' dystrophy in both eyes. The patient had advanced form of the disease and history of recurrent corneal erosions. For visual rehabilitation and symptomatic relief, phototherapeutic keratectomy was planned in both eyes. In view of the advanced nature of the disease, the ablation depth had to be high to get an acceptably clear central cornea., Conclusions and Importance: PTK with high ablation depth is possible in advanced Reis-Bucklers' corneal dystrophy unlike other types of anterior corneal dystrophies., Competing Interests: None., (© 2022 Published by Elsevier Inc.)

Hepatic steatosis, often known as fatty liver, is the most common hepatic disease in Western countries. The latest guidelines for the treatment of nonalcoholic fatty liver disease emphasize lifestyle measures, such as changing unhealthy eating patterns. Using a propensity score-matching approach, this study investigated the effect of adhering to a Mediterranean diet (MedDiet) on fatty liver risk in an older population (≥65 years) from Southern Italy. We recruited 1.403 subjects (53.6% men, ≥65 years) who completed a food frequency questionnaire (FFQ) and underwent clinical assessment between 2015 and 2018. For the assessment of the liver fat content, we applied the Fatty Liver Index (FLI). To evaluate the treatment effect of the MedDiet, propensity score matching was performed on patients with and without FLI > 60. After propensity score-matching with the MedDiet pattern as treatment, we found a higher consumption of red meat ( p = 0.04) and wine ( p = 0.04) in subjects with FLI > 60. Based on the FLI, the inverse association shown between adherence to the MedDiet and the risk of hepatic steatosis shows that the MedDiet can help to prevent hepatic steatosis. Consuming less red and processed meat, as well as alcoholic beverages, may be part of these healthy lifestyle recommendations.

Tweetable abstract There is growing evidence of a role of environmental exposures in the pathogenesis and epigenetics of suicidal behavior in older age.

Background: In 2010, the European Working Group on Sarcopenia in Older People (EWGSOP1) issued its first operational definition to diagnose sarcopenia. This was updated in 2019 with a revised sequence of muscle mass and muscle strength (EWGSOP2). The aim of the study was to investigate the impact of these different operational definitions on sarcopenia prevalence in a representative population-based sample., Methods: For each algorithm, the prevalence of sarcopenia-related categories was calculated and related to sociodemographic and lifestyle variables, anthropometric parameters, and laboratory biomarkers. The present analysis used data from the Salus in Apulia Study (Italy, 740 subjects, mean age 75.5 ± 5.9 years, 54% women)., Results: The application of the EWGSOP1 adapted algorithm resulted in 85% [95% confidence intervals (CI): 82-88%] non-sarcopenic subjects, 10% (95% CI: 8-12%) pre-sarcopenic subjects, and 5% (95% CI: 3-7%) sarcopenic/severe sarcopenic subjects. The sarcopenia-related categories were inversely related to weight and body mass index (BMI), particularly in overweight/obese subjects, and these categories showed favorable metabolic biomarkers. The EWGSOP2 algorithm yielded 73% (95% CI: 69-76%) non-sarcopenic subjects, 24% (95% CI: 21-27%) probably sarcopenic subjects, and 4% (95% CI: 2-5%) sarcopenic subjects., Conclusions: The present study identified BMI as a potential confounder of the prevalence estimates of sarcopenia-related categories in population-based settings with different EWGSOP operational definitions.

Objectives: Non-alcoholic fatty liver disease (NAFLD) currently affects a quarter of the global population. Systemic inflammation, metabolic syndrome, and coronary artery disease, all conditions associated with NAFLD, have also been related to cognitive dysfunction in older age. The present study aimed to investigate the relationship between NAFLD risk and a dementia diagnosis in a large population-based sample aged > 65 years. Methods: We selected 1,542 participants (723 men) from the Salus in Apulia Study. To assess the risk of fat distribution in the liver, we used the Fatty Liver Index (FLI). Dementia was diagnosed according to the American Psychiatric Association criteria (DSM-5). Results: The overall prevalence of dementia was 8.5% [95% confidence interval (CI): 7-10%]. Subjects with dementia were older [effect size (ES): -0.89, 95% CI: -1.07 to -0.70], had a lower level of education (ES:0.88, 95% CI:0.69-1.06), higher levels of gamma-glutamyl transferase (ES: -0.21, 95% CI: -0.39 to -0.03), lower levels of total cholesterol (ES: -0.24, 95% CI: -0.42 to -0.06) and low-density lipoprotein cholesterol (ES: -0.20, 95% CI: -0.38 to 0.02), and a higher FLI (ES: -0.22, 95% CI: -0.39 to -0.04). In the logistic regression model adjusted for age, sex, education, hypertension, diabetes mellitus, alcohol consumption, smoking habits, stroke, cholesterol, and Apo-E, a dementia diagnosis was positively associated with FLI > 60 [odds ratio (OR):1.81; standard error (SE): 0.53; 95% CI: 1.02-3.21]. Conclusion: Our findings suggested that an increased NAFLD risk may be associated to dementia and cognitive decline in older age. Considering the high NAFLD prevalence, the possible adverse disease effects on cognitive performance pose a health problem with significant social and economic implications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lampignano, Donghia, Griseta, Lagravinese, Sciarra, Zupo, Castellana, Bortone, Guerra, Tirelli, De Nucci, Tatoli, Lozupone, Sborgia, Leo, De Pergola, Giannelli, Panza and Sardone.)

Objectives: There are no comparative studies between patients belonging to the first and second waves of the SARS-CoV-2 pandemic, the virus triggering coronavirus disease 2019 (COVID-19). In this retrospective observational study, we analyzed the clinical characteristics and the short-term outcomes of two groups of laboratory-confirmed COVID-19 patients with moderate-to-severe acute respiratory distress syndrome (ARDS) belonging to two different waves of the pandemic.  Methods: We analyzed 97 consecutive patients from 11 March 2020 to 31 May 2020 and 52 consecutive patients from 28 August 2020 to 15 October 2020.  Results: Patients belonging to the second wave were younger, had a lower number of concomitant chronic conditions (multimorbidity), and had a milder clinical phenotype. Medical treatments and respiratory support use have changed during the COVID-19 pandemic, based on different laboratory results and disease clinical features. Patients in the second wave had better short-term clinical outcomes, with lower death rates and more step-down transfers to a general ward.  Conclusion: The present findings show a clear phenotypic difference in patients hospitalized at different stages of the COVID-19 pandemic in Italy. These results can help to stratify clinical risk and to better tailor medical treatments and respiratory support for patients with ARDS and COVID-19 pneumonia.

Background: Age-related hearing loss (ARHL) and retinal vessel changes have both been associated to neurodegeneration/dementia, suggesting a possible link between these 2 conditions in older age. We aimed to determine whether superficial and deep vascular density (SVD and DVD) of the capillary plexi of macular vasculature can be associated with peripheral ARHL and age-related central auditory central processing (CAPD)., Method: We analyzed data on 886 older participants (65 years+, age range: 65-92 years) in the cross-sectional population-based Salus in Apulia Study. Optical coherence tomography angiography was used to measure SVD and DVD of the capillary plexi of the macula at the 3-mm circle area centered on the fovea (whole retina), the parafoveal quadrant, and foveal quadrant. Disabling peripheral ARHL was defined as >40 dB hearing level of pure tone average on the frequencies from 0.5, 1, 2, and 4 KHz in the better ear, and age-related CAPD as <50% at the Synthetic Sentence Identification with Ipsilateral Competitive Message test in at least one ear., Results: DVD at the whole retina and at the parafoveal quadrant were inversely associated only with age-related CAPD (odds ratio [OR]: 0.93, 95% confidence interval [CI]: 0.88-0.96 and OR: 0.94, 95 CI: 0.90-0.99, respectively). No further associations with peripheral ARHL were evident., Conclusions: Retinal vasculature is associated with central auditory processing pathology, possibly playing an important role in early detection and intervention. The association of retinal vascular density with age-related CAPD may bring us a further step forward in understanding the biological mechanisms underlying the links between neurodegeneration/dementia and ARHL., (© The Author(s) 2020. 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.)

Age is a major contributor to the liver fibrosis rate and its adverse health-related outcomes, including mortality, but older populations are still under-explored. We investigated multimorbidity and inflammatory biomarkers in relation to the increasing liver fibrosis risk to delineate 8-year all-cause mortality trajectories in 1929 older adults from the population-based Salus in Apulia Study. Liver fibrosis risk was assumed using the fibrosis-4 (FIB-4) score, assigned to three liver fibrosis risk groups (low, intermediate, high). In the secondary analyses, the APRI score was also calculated to allow for comparisons. Male subjects (prevalence difference: -13.49, 95% confidence interval (CI): -18.96 to -8.03), a higher multimorbidity burden (effect size, ES: -0.14, 95% CI: -0.26 to -0.02), a higher prevalence of physical frailty (ES: 6.77, 95% CI: 0.07 to 13.47), and a more pronounced inflammatory pattern as indicated by tumor growth factor-α circulating levels (ES: -0.12, 95% CI: -0.23 to -0.01) were significantly more common in the highest-risk FIB-4 score group. Liver function characterized by lipid profile and platelet levels worsened with increasing FIB-4 risk score. The 8-year risk of death was nearly double in subjects in the highest-risk FIB-4 score group, even after controlling for possible confounders. Furthermore, a steeper mortality curve was clearly observed for FIB-4 scores as compared with the APRI scoring system with respect to liver fibrosis risk. In conclusion, using a scoring tool based on simple routine biomarkers to detect liver fibrosis risk may enhance biological knowledge of age-related outcomes of chronic liver disease and be helpful in the clinical setting to identify subjects at risk for adverse health-related outcomes, including mortality.

Frailty is a critical intermediate status of the aging process with a multidimensional and multisystem nature and at higher risk for adverse health-related outcomes, including falls, disability, hospitalizations, institutionalization, mortality, dementia, and Alzheimer's disease. Among different frailty phenotypes, oral frailty has been recently suggested as a novel construct defined as a decrease in oral function with a coexisting decline in cognitive and physical functions. We briefly reviewed existing evidence on operational definitions of oral frailty, assessment and screening tools, and possible relationships among oral frailty, oral microbiota, and Alzheimer's disease neurodegeneration. Several underlying mechanism may explain the oral health-frailty links including undernutrition, sarcopenia linked to both poor nutrition and frailty, psychosocial factors, and the chronic inflammation typical of oral disease. Oral microbiota may influence Alzheimer's disease risk through circulatory or neural access to the brain and the interplay with periodontal disease, often causing tooth loss also linked to an increased Alzheimer's disease risk. On this bases, COR388, a bacterial protease inhibitor targeting Porphyromonas gingivalis implicated in periodontal disease, is now being tested in a double-blind, placebo-controlled Phase II/III study in mild-to-moderate Alzheimer's disease. Therefore, oral status may be an important contributor to general health, including Alzheimer's disease and late-life cognitive disorders, suggesting the central role of preventive strategies targeting the novel oral frailty phenotype and including maintenance and improvement of oral function and nutritional status to reduce the burden of both oral dysfunction and frailty., Competing Interests: None

Introduction: Preventive nutritional management of frailty, a multidimensional intermediate status in the ageing process, may reduce the risk of adverse health-related outcomes. We investigated the ability of a measure combining physical frailty with nutritional imbalance, defined as nutritional frailty, to predict all-cause mortality over a period of up to 8 years., Methods: We analysed data on 1,943 older adults from the population-based 'Salus in Apulia Study'. Physical frailty was operationalized using Cardiovascular Health Study criteria and cognitive frailty by combining physical frailty with cognitive impairment. A novel five-item construct was built to assess the extent of nutritional imbalance identified with a machine learning algorithm. Cox models and Kaplan-Meier survival probability analyses of physical frailty, nutritional imbalance (two or more of the following: low body mass index, low skeletal muscle index, ≥2.3 g/day sodium intake, <3.35 g/day potassium intake and <9.9 g/day iron intake), cognitive frailty and the novel nutritional frailty phenotype (physical frailty plus nutritional imbalance) were applied to assess all-cause mortality risk, adjusted for age, sex, education and multimorbidity., Results: The overall prevalence of nutritional frailty was 4.52% (95% confidence interval, CI:3.55-5.44), being more frequent in males. Subjects with nutritional frailty were at higher risk for all-cause mortality [hazard ratio (HR):2.31; 95%CI:1.41-3.79] than those with physical frailty (HR:1.45,95% CI:1.0-2.02), nutritional imbalance (HR:1.39; 95%CI:1.05-1.83) and cognitive frailty (HR:1.06; 95%CI:0.56-2.01)., Conclusions: Efforts to identify, manage and prevent frailty should include the nutritional domain. The nutritional frailty phenotype may highlight major nutritional determinants that could drive survival and health trajectories in older adults., (© 2021 The Association for the Publication of the Journal of Internal Medicine.)

Little study has yet been made of the effect of different beverages on oral health outcomes in the aging population. The purpose of this systematic review is to evaluate the association between different beverages, including alcohol intake, coffee, milk, tea, and sugary drinks, and a cluster of oral health outcomes, including periodontal disease, oral dysbiosis, and tooth loss in older adults. The literature was screened from the inception up to May 2021 using six different electronic databases. Two independent researchers assessed the eligibility of 1308 retrieved articles regarding inclusion criteria; only 12 fitted the eligibility requirements, representing 16 beverage entries. A minimum age of 60 was the inclusion criterion. No exclusion criteria were applied to outcomes assessment tools, recruiting facilities (hospital or community), general health status, country, and study type (longitudinal or cross-sectional). The consumption of alcoholic beverages was expressed as alcohol intake in all eligible studies, thereby replacing alcoholic beverages in the analysis. The quality of evidence was judged as moderate for alcohol and low or very low for beverages. In regard to oral health in the elderly, the review identified information on alcohol (56.25%), followed by coffee (18.75%), milk (12.50%), tea (6.25%), and sugary drinks (6.25%). Alcohol, sugary drinks, and coffee were found to be related to tooth loss. Periodontal disease was inversely related to coffee and milk, but fostered by alcohol consumption. In one article, tea but not coffee seemed to improve oral microbiota. In summary, alcohol seems to be a driver for tooth loss and periodontal disease in the aging population. However, more research is needed to gain a more solid knowledge in this research area. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, PROSPERO, Identifier: CRD42021256386., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zupo, Castellana, De Nucci, Dibello, Lozupone, Giannelli, De Pergola, Panza, Sardone and Boeing.)

Introduction: Women with gestational diabetes (GDM) are at greatly increased risk of type 2 diabetes (T2DM). The UK guidance recommends screening for T2DM at around 6-week postpartum and annually thereafter. We evaluated conformity to this guidance in two separate time periods., Methods: The proportion of tests performed within guidance was assessed using longitudinal plasma glucose and glycated haemoglobin data in two cohorts (1999-2007, n = 251; 2015-2016, n = 260) from hospital records on women previously diagnosed with GDM., Results: In the 1999-2007 and 2015-2016 cohorts, 59.8% and 35.0% of women had the recommended postpartum testing, respectively (P < .001); just 13.5% and 14.2%, respectively, underwent the first annual test on time. During long-term follow-up of the 1999-2007 cohort (median follow-up: 12.3 years), the proportion of women tested in any given year averaged 34.2% over a 17-year period; there was a progressive decline in the proportion of women receiving a yearly test with time since delivery (P = .002). Over the follow-up period, 85 women from the 1999-2007 cohort developed blood test results in the diabetic range with a median time to presumed DM diagnosis of 5.2 years (range 0.11-15.95 years). Kaplan-Meier analysis showed that 18.8% of women had blood test results in the diabetes range by 5-year postpartum and 37.8% by 10-year postpartum., Conclusions: Despite high profile guidelines and a clear clinical rationale to screen women with a past diagnosis of GDM, many women did not receive adequate screening for T2DM both in the short term and long term. This suggests that alternative approaches are needed to ensure effective follow-up of this high-risk group. To have an impact, interventions need to be tailored to a young, generally healthy group in which traditional approaches to follow-up may not be best suited., (© 2021 John Wiley & Sons Ltd.)

In older age, several observational studies investigated risk factors for suicide attempts/completed suicides; however, contrasting evidence came from population-based setting. In the present systematic review, we described through a narrative synthesis the significant associations existing among risk factors and suicide attempts/completed suicides in subjects aged >65 years. From the 39 population-based studies selected in six different databases until February 15, 2021, we analyzed the most frequent 28 risk factors for suicidal behaviour. The risk factors more associated to suicide attempts than other variables frequently related to suicidal behavior in older age were: depressive disorders, methods employed to self-harm (particularly poisoning), and psychotropic drug utilization followed by psychological factors and disability. Moreover, male sex, violent methods to self-harm, any psychiatric disorder (depression, anxiety and bipolar disorders), a poor medical condition, stressors/bereavement, and living alone appeared to be more significant for predicting completed suicides in late life. In older age, efforts for suicide prevention should be based on strategies to assess and treat psychiatric disorders along with psychological interventions, particularly in males., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Undoubtedly, a better understanding and the further development of approaches for damage tolerant component design of AM parts are among the most significant challenges currently facing the use of these new technologies. This article presents a thorough overview of the workshop discussions. It aims to provide a review of the parameters affecting the damage tolerance of parts produced by additive manufacturing (shortly, AM parts) with special emphasis on the process parameters intrinsic to the AM technologies, the resulting defects and the residual stresses. Based on these aspects, basic concepts are reviewed and critically discussed specifically for AM materials: Criteria for damage tolerant component design;Criteria for the determination of fatigue and fracture properties;Strategies for the determination of the fatigue life in dependence of different manufacturing conditions;Methods for the quantitative characterization of microstructure and defects;Methods for the determination of residual stresses;Effect of the defects and the residual stresses on the fatigue life and behaviour. We see that many of the classic concepts need to be expanded in order to fit with the particular microstructure (grain size and shape, crystal texture) and defect distribution (spatial arrangement, size, shape, amount) present in AM (in particular laser powder bed fusion). For instance, 3D characterization of defects becomes essential, since the defect shapes in AM are diverse and impact the fatigue life in a different way than in the case of conventionally produced components. Such new concepts have immediate consequence on the way one should tackle the determination of the fatigue life of AM parts; for instance, since a classification of defects and a quantification of the tolerable shapes and sizes is still missing, a new strategy must be defined, whereby theoretical calculations (e.g. FEM) allow determining the maximum tolerable defect size, and non-destructive testing (NDT) techniques are required to detect whether such defects are indeed present in the component. Such examples show how component design, damage and failure criteria, and characterization (and/or NDT) become for AM parts fully interlinked. We conclude that the homogenization of these fields represents the current challenge for the engineer and the materials scientist., Competing Interests: Declaration of 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.

Background and Purpose: In older age, physical and cognitive declines have been shown to occur simultaneously or consequent to one another, and several operational definitions have been proposed to consider the co-presence of the two declines; for example, "Motoric cognitive risk syndrome" (MCR) has been proposed as a definition for the coexistence of slow gait plus subjective cognitive complaints. Given the increasing interest in MCR and its potential role as both biomarker and therapeutic target, we aimed to estimate its prevalence in a large cohort of non-demented older subjects, and to examine the associations between physical status, global cognitive dysfunction, and impairment in various cognitive domains in MCR., Methods: A population-based sample of 1041 older people in Southern Italy (mean age 75.15 years) was enrolled. We defined MCR using slowness and a single question for subjective cognitive complaints. We also administered a comprehensive neuropsychological test battery, together with tests assessing physical function., Results: The prevalence of MCR was 9.9% (95% confidence interval 8.2-11.9). MCR was associated with decreased processing speed and executive function after adjusting for all relevant confounders. However, we found no significant association of MCR with decreased global cognition and immediate/delayed free recall of verbal memory. MCR was also associated with increased exhaustion, low muscle strength, and low physical activity, and increased levels of C-reactive protein and interleukin-6., Conclusions: The present findings on MCR prevalence and associated cognitive and physical domains and inflammatory biomarkers may help to uncover altered pathways and therapeutic targets for intervention during the long preclinical phase of neurodegenerative dementia., (© 2021 European Academy of Neurology.)

Poor oral health is common among older adults and can impair essential activities of daily living and contribute to frailty. We did a systematic review of studies on the relationship between oral health factors and frailty among older adults (>60 years), consulting six different electronic databases for studies published from database inception to March 20, 2021. In total, 39 articles met the eligibility requirements, including 12 different indicators of poor oral health related to frailty, which we grouped in four different categories: oral health status deterioration; deterioration of oral motor skills; chewing, swallowing, and saliva disorders; and oral pain. Factors of oral health status deterioration (52%), in particular few remaining teeth (29%), were most frequently associated with frailty. Reduced oral motor skills (27%), especially masticatory function (9%), oral diadochokinesis (5%), occlusal force (7%), and chewing, swallowing, and saliva disorders (20%), especially chewing difficulties [11%]), were less frequent but were similarly considered to be associated with frailty. Our findings could help to assess the contribution of each oral health item to a possible operational definition of this novel frailty phenotype, defined as an age-related gradual loss of oral function together with a decline in cognitive and physical functions., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Importance: The association between age-related hearing loss (ARHL) and physical or cognitive frailty has been poorly explored. These associations could define new perspectives for delaying frailty-related processes in older age., Objective: To examine whether peripheral ARHL and age-related central auditory processing disorder (CAPD) are independently associated with physical or cognitive frailty., Design, Setting, and Participants: This cross-sectional study analyzed registry data from December 31, 2014, on 1929 older (≥65 years) participants of the Salus in Apulia Study (Southern Italy) who underwent audiologic, physical, and neuropsychological assessment. Data analysis was performed from December 12, 2019, to January 4, 2020., Main Outcomes and Measures: Prevalence of peripheral ARHL in older individuals with physical and/or cognitive frailty and those without frailty assessed using the Fried criteria (physical) and the Mini-Mental State Examination (cognitive). Multivariable logistic regression models were used to assess associations of audiologic variables with frailty phenotype., Results: Data from 1929 participants (mean [SD] age, 73.6 [6.3] years; 974 male [50.5%]) were eligible for the analyses. The prevalence of peripheral ARHL was higher in the physical frailty group (96 [26.6%]) than in the nonfrail group (329 [21.0%]) (difference, 5.61 percentage points; 95% CI, 0.63-10.59 percentage points) and in the cognitive frailty group (40 [38.8%]) than in the nonfrail group (385 [21.1%]) (difference, 17.75 percentage points; 95% CI, 8.2-27.3 percentage points). Age-related CAPD was more prevalent in the physical frailty group (62 [17.2%]) than in the nonfrail group (219 [14.0%]) (difference, 3.21 percentage points; 95% CI, -1.04 to 7.46 percentage points) and in the cognitive frailty group (28 [27.2%]) than in the nonfrail group (253 [13.9%]) (difference, 13.33 percentage points; 95% CI, 4.10-22.21 percentage points). In the multivariable models, age-related CAPD was associated with cognitive frailty in the fully adjusted model (odds ratio [OR], 1.889; 95% CI, 1.094-3.311). There was also an inverse association between the unitary increase in Synthetic Sentence Identification With the Ipsilateral Competitive Message scores, indicating a lower likelihood of this disorder, and cognitive frailty (OR, 0.989; 95% CI, 0.988-0.999). Peripheral ARHL was associated with cognitive frailty only in the partially adjusted model (OR, 1.725; 95% CI, 1.008-2.937)., Conclusions and Relevance: In this cross-sectional study of 1929 participants, age-related CAPD was independently associated with cognitive frailty. Whether the management of ARHL may help prevent the development of different frailty phenotypes or improve their clinical consequences should be addressed in longitudinal studies and, eventually, well-designed randomized clinical trials.

Objectives: Central auditory processing disorder (CAPD) commonly occurs in older age. However, few studies of a possible link between age-related CAPD and diet in an older population have been conducted. The objective of the present study was to investigate the relationship between eating habits and age-related CAPD in a population >65 years, using cross-sectional and retrospective data obtained in the same population-based study about 12 years ago., Methods: We selected 734 participants (403 men) from a large population-based study. For age-related CAPD assessment, we used the Synthetic Sentence Identification with Ipsilateral Competitive Message test. Dietary habits were assessed by a Food Frequency Questionnaire. Associations between age-related CAPD and food groups/macro-and micronutrients were explored using adjusted logistic regression models., Results: Age-related CAPD subjects consumed more dairy (111 vs. 98 g/d), olives and vegetable oil (63 vs. 52 g/d) and spirits (2 vs.1 g/d), and less fruits (536 vs. 651 g/d) in the cross-sectional analysis. Age-related CAPD subjects had a lower intake of potassium, vitamin C, and a higher fat intake. Further analyses identified dietary fiber as being inversely related to age-related CAPD., Discussion: The present study provided evidence that the dietary hypotheses proposed for explaining the development of cognitive disorders in older age might also hold for age-related CAPD. Further data from other large and prospective population-based studies are needed for confirming these findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lampignano, Quaranta, Bortone, Tirelli, Zupo, Castellana, Donghia, Guerra, Griseta, Pesole, Chieppa, Logroscino, Lozupone, Cisternino, De Pergola, Panza, Giannelli, Boeing and Sardone.)

In mammals, milk is essential for the growth, development, and health. Milk quantity and quality are dependent on mammary development, strongly influenced by nutrition. This review provides an overview of the data on nutritional regulations of mammary development and gene expression involved in milk component synthesis. Mammary development is described related to rodents, rabbits, and pigs, common models in mammary biology. Molecular mechanisms of the nutritional regulation of milk synthesis are reported in ruminants regarding the importance of ruminant milk in human health. The effects of dietary quantitative and qualitative alterations are described considering the dietary composition and in regard to the periods of nutritional susceptibly. During lactation, the effects of lipid supplementation and feed restriction or deprivation are discussed regarding gene expression involved in milk biosynthesis, in ruminants. Moreover, nutrigenomic studies underline the role of the mammary structure and the potential influence of microRNAs. Knowledge from three lactating and three dairy livestock species contribute to understanding the variety of phenotypes reported in this review and highlight (1) the importance of critical physiological stages, such as puberty gestation and early lactation and (2) the relative importance of the various nutrients besides the total energetic value and their interaction.

The association between late-life depression (LLD) and age-related hearing loss (ARHL) was suggested by preliminary studies, but reliance on LLD subtypes may introduce significant bias. We examined the association between ARHL and LLD according to the age of onset (early-onset depression (EOD) and late-onset depression (LOD)). We investigated the association between ARHL and LLD diagnosed according to the Semi-structured Clinical Diagnostic Interview for DSM-IV-TR in 1749 Italian community-dwelling older subjects from the population-based GreatAGE Study, Southern Italy. Peripheral ARHL was assessed as a pure tone average (PTA) threshold > 40 dB hearing level in the better ear- and age-related CAPD as a score of < 50% to the Synthetic Sentences Identification with Ipsilateral Competitive Message (SSI-ICM) test. LLD amounted at 10.29% of the sample, subdivided in LOD (6.21%) and EOD (4.08%). Age-related CAPD tended to be higher in LOD (28.91%) than in EOD (19.05%). After accounting for covariates, LOD was tendentially associated to age-related CAPD, but not to peripheral ARHL. This trend was confirmed by the linear models in which LOD was significantly associated to worsen SSI-ICM percentages (odds ratio 2.38, 95% confidence interval 1.32-4.30, p = 0.004), but not to PTA values. In a fully adjusted model of LOD, the effect of the association between CAPD and LOD was explained by social dysfunction. LLD was not associated to peripheral ARHL. Age-related CAPD was associated to LOD, a form of depression with cognitive dysfunction hallmark. The ARHL assessment may be an important opportunity to prevent depressive disorders in later life, particularly for LOD.

Aging is often associated with a decline in physical function that eventually leads to loss of autonomy in activities of daily living (ADL). Walking is a very common ADL, important for main determinants of quality of life in older age, and it requires the integration of many physiological systems. Gait speed has been described as the 'sixth vital sign' because it is a core indicator of health and function in aging and disease. We reviewed original studies up to June 2020 that assessed frailty in both longitudinal and cross-sectional observational studies, paying particular attention to how gait is measured in older population and how the gait parameter adopted may influence the estimated frailty models and the health-related outcomes of the various studies (i.e. clinical, cognitive, physical, and nutritional outcomes). Eighty-five studies met the search strategy and were included in the present systematic review. According to the frailty tools, more than 60% of the studies used the physical phenotype model proposed by Fried and colleagues, while one-third referred to multi-domain indexes or models and only 5% referred to other single-domain frailty models (social or cognitive). The great heterogeneity observed in gait measurements and protocols limited the possibility to directly compare the results of the studies and it could represent an important issue causing variability in the different outcome measures in both clinical-and population-based settings. Gait appeared to be an indicator of health and function also in frail older adults, and different gait parameters appeared to predict adverse health-related outcomes in clinical, cognitive, and physical domains and, to a lesser extent, in nutritional domain. Gait has the potential to elucidate the common basic mechanisms of cognitive and motor decline. Advances in technology may extend the validity of gait in different clinical settings also in frail older adults, and technology-based assessment should be encouraged. Combining various gait parameters may enhance frailty prediction and classification of different frailty phenotypes., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Brazil nut (Bertholletia excelsa) fruits are capable of resisting high mechanical forces when released from trees as tall as 50 m, as well as during animal dispersal by sharp-teethed rodents. Thick mesocarp plays a crucial part in seed protection. We investigated the role of microstructure and how sclereids, fibers, and voids affect nutshell performance using compression, tensile and fracture toughness tests. Fractured specimens were analyzed through scanning electron microscopy (SEM) and microtomography (microCT). Mesocarp showed high deformability (strain at max. stress of ~30%) under compression loading, a critical tensile strength of ~24.9 MPa, a Weibull modulus of ~3, and an elastic modulus of ~2 GPa in the tensile test. The fracture toughness, estimated through the work of fracture of SENB tests, reached ~2 kJ/m 2 . The thick and strong walls of mesocarp cells, with a weaker boundary between them (compound middle lamella), promote a tortuous intercellular crack path. Several toughening mechanisms, such as crack deflection, breaking of fiber bundles, fiber pullout and bridging as well as crack branching, occur depending on how fiber bundles and voids are oriented., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Although the pathophysiological bases of Alzheimer's disease (AD) remain incompletely understood and disease-modifying therapies are not available, intervention on modifiable risk factors is warranted. Research on nutrition and dietary components is challenging and controversies still persist about the role of micro- and macronutrients and health outcomes in dementia. Importantly, results of preclinical investigations have shown that vitamin D triggers different neural pathways that may be protective against these neurodegenerative mechanisms, including the deposition of amyloid plaques, inflammatory processes, neurofibrillary degeneration, glutamatergic excitotoxicity, excessive intraneuronal calcium influx, and oxidative stress, although its relationship with AD still needs to be fully understood., Areas Covered: The authors analyzed the recent evidence about the effects of vitamin D insufficiency on AD and the role of supplementation., Expert Opinion: Both insufficient (25-49.9 ng/ml) and deficient levels (<25 ng/ml) of vitamin D may contribute to an increased susceptibility to AD. However, further well-designed prospective studies are needed for a better understanding of the involvement of low vitamin D concentrations in the AD natural history. Randomized clinical trials will also be necessary to address the issue of causality and determine whether vitamin D supplementation may be effective for the prevention or treatment of AD.

Objectives: We first estimated the prevalence of physical frailty in older subjects from the population-based Salus in Apulia Study (Apulia, Southern Italy), and its impact on all-cause mortality. Second, we explored the relationship between multimorbidity and physical frailty., Design: Cross-sectional and longitudinal analyses from a population-based study., Setting and Participants: We analyzed data from the Salus in Apulia study, a population-based sample of 1929 subjects aged 65 years and older., Methods: These older participants underwent clinical, physical, and laboratory assessments. Physical frailty was operationalized using slightly modified Fried criteria. Multimorbidity status was defined as the co-presence of 2 or more chronic conditions., Results: The overall prevalence of physical frailty in this older population from Southern Italy was 14.8% [95% confidence interval (CI): 13.26-16.49]. Physical frailty subjects were significantly older (P < .01), had a lower educational level (P < .01), increased executive dysfunction (P < .01), higher serum levels interleukin-6 (P < .01), and white blood cells (P = .01). Multimorbidity status (P < .01), diabetes mellitus (P = .05), peripheral age-related hearing loss (P < .01), cognitive impairment (P < .01), chronic obstructive pulmonary disease (P = .02), and metabolic syndrome (P = .02) were also directly related to physical frailty. Apathy increased according to the severity of physical frailty status (P = .02). There was a significant increased risk of all-cause mortality for physical frailty subjects (hazard ratio: 1.48; 95% CI: 1.03-2.12, adjusted for age and sex) during the observation from the date of enrollment to the date of death (mean ± SD: 55.70 ± 22.19 months, median: 54 months)., Conclusions and Implications: Frailty is the consequence of the contributory action of the aging process and some chronic diseases that hasten some of the changes concurrent with aging., (Copyright © 2020. Published by Elsevier Inc.)

Tyrosine is a critical component of many proteins and can be the subject of oxidative posttranslational modifications. Furthermore, the oxidation of tyrosine residues to phenoxyl radicals, sometimes quite stable, is essential for some enzymatic functions. The lifetime and fate of tyrosine phenoxyl radicals in biological systems are largely driven by the availability and proximity of oxidants and reductants. Tyrosine phenoxyl radicals have extremely low reactivity with molecular oxygen whereas reactions with nitric oxide are diffusion controlled. This is in contrast to equivalent reactions with tryptophanyl and cysteinyl radicals where reactions with oxygen are much faster. Despite, the quite disparate apparent reactivity of tyrosine phenoxyl radicals with oxygen and nitric oxide being known, the products of the reactions are not well established. Changes in the levels from expected basal concentrations of stable products resulting from tyrosine phenoxyl radicals, for example naturally occurring 3,3'-dityrosine, 3-nitrotyrosine, and 3-hydroxytyrosine, can be indicative of oxidative and/or nitrosative stress. Using the radiolytic generation of specific oxidizing radicals to form tyrosine phenoxyl radicals in an aqueous solution at a known rate, we have compared the products in the absence and presence of nitric oxide or oxygen. Possible reactions of the phenoxyl radicals with oxygen remain unclear although we show evidence for a small decrease in the yield of dityrosine and loss of tyrosine in the presence of 20% oxygen. Low concentrations of nitric oxide in anoxic conditions react with tyrosine phenoxyl radicals, by what is most probably through the formation of an unstable intermediate, regenerating tyrosine and forming nitrite.

Introduction: Dementia with Lewy bodies (DLB) has no approved symptomatic or disease-modifying treatments in the US and Europe, despite being the second most common cause of neurodegenerative dementia., Areas Covered: Herein, the authors briefly review the DLB drug development pipeline, providing a summary of the current pharmacological intervention studies. They then focus on the anticonvulsant zonisamide, a benzisoxazole derivative with a sulfonamide group and look at its value for treating parkinsonism in DLB., Expert Opinion: Several new compounds are being tested in DLB, the most innovative being those aimed at decreasing brain accumulation of α-synuclein. Unfortunately, new drug testing is challenging in terms of consistent diagnostic criteria and lack of reliable biomarkers. Few randomized controlled trials (RCTs) are well-designed, with enough power to detect significant drug effects. Levodopa monotherapy can treat the parkinsonism in DLB, but it can cause agitation or visual hallucination worsening. Two Phase II/III RCTs of DLB patients recently reported a statistically significant improvement in motor function in those receiving zonisamide as an adjunctive treatment to levodopa. New biomarker strategies and validated outcome measures for DLB or prodromal DLB may enhance clinical trial design for the development of specific disease-modifying treatments.

Different methods have been proposed for the assessment of the nutritional status in frailty phenotypes. In the present narrative review article, we have summarized the number and specifications of nutritional items in existing frailty tools, in order to develop a possible means of assessment and operational definition of the nutritional frailty phenotype. In six different databases until December 2019, we searched for original articles regarding frailty tools (i.e., scales, indexes, scores, questionnaires, instruments, evaluations, screening, indicators), analyzing each tool regarding nutritional items. We identified 160 articles describing 71 frailty tools. Among the selected frailty tools, 54 were community-based (70 %), 17 hospital-based (22 %), 4 validated in long-term care institutions for older adults (LTCIOA) (5.1 %) and 2 validated in both community- and hospital-based settings, including LTCIOA (2.5 %). Fifty-two of these tools (73 %) included at least one nutritional item. Twenty-two (42 %) reported two or more nutritional items. The items were grouped in the following categories: A) anthropometric measurements, B) laboratory measurements, and C) other nutritional-related measurements. Anthropometric measurements stood out compared to all other items. Nutritional items are included in the majority of frailty tools, strengthening the concept that they may have a direct implication on an increased risk of adverse health-related outcomes in frail subjects. This supports the development of the concept of nutritional frailty as an independent frailty phenotype. Subsequent steps will be to assess the contribution of each nutritional item to a possible operational definition of nutritional frailty and define the items that may best identify this new frailty phenotype., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Persulfides (RSSH/RSS - ) participate in sulfur trafficking and metabolic processes, and are proposed to mediate the signaling effects of hydrogen sulfide (H 2 S). Despite their growing relevance, their chemical properties are poorly understood. Herein, we studied experimentally and computationally the formation, acidity, and nucleophilicity of glutathione persulfide (GSSH/GSS - ), the derivative of the abundant cellular thiol glutathione (GSH). We characterized the kinetics and equilibrium of GSSH formation from glutathione disulfide and H 2 S. A p K a of 5.45 for GSSH was determined, which is 3.49 units below that of GSH. The reactions of GSSH with the physiologically relevant electrophiles peroxynitrite and hydrogen peroxide, and with the probe monobromobimane, were studied and compared with those of thiols. These reactions occurred through S N 2 mechanisms. At neutral pH, GSSH reacted faster than GSH because of increased availability of the anion and, depending on the electrophile, increased reactivity. In addition, GSS - presented higher nucleophilicity with respect to a thiolate with similar basicity. This can be interpreted in terms of the so-called α effect, i.e. the increased reactivity of a nucleophile when the atom adjacent to the nucleophilic atom has high electron density. The magnitude of the α effect correlated with the Brønsted nucleophilic factor, β nuc , for the reactions with thiolates and with the ability of the leaving group. Our study constitutes the first determination of the p K a of a biological persulfide and the first examination of the α effect in sulfur nucleophiles, and sheds light on the chemical basis of the biological properties of persulfides., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Benchoam et al.)

Special attention and efforts to protect from or reduce health-related outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus triggering coronavirus disease 2019 (COVID-19), should be applied in susceptible populations, including frail older people. In particular, the early death cases occurred primarily in older people with a frailty status, possibly due to a weaker immune system fostering faster progression of the viral infection. Frailty is an age-related multidimensional clinical condition defined as a non-specific state of vulnerability, identifying older people at increased risk of falls, institutionalization, hospitalization, disability, dementia, and death. Among frailty phenotypes, social frailty has been least studied. It considers the role of socioeconomic context as a vulnerability status later in life. COVID-19 does not affect all populations equally, and social inequalities contribute to drive the spread of infections. It was known that the perception of social isolation, e.g., loneliness, affects mental and physical health, but the implicated molecular mechanisms, also related to the immune system, and its associated cognitive and health-related sequelae, are poorly understood. The increasing psychological distress derived by prolonged exposure to stress due to the lockdown scenario, and the reduced sources of support, contributed to making heavy demands on personal resources, i.e., self-efficacy and interpersonal variables. So, perceived loneliness may be a factor associated with psychological distress and an outcome in itself. In the COVID-19 pandemic era, a correct assessment of social frailty may be essential in terms of the prevention of late-life neuropsychiatric disorders., (Copyright © 2020 Lozupone, La Montagna, Di Gioia, Sardone, Resta, Daniele, Giannelli, Bellomo and Panza.)

Objectives: Cause-of-death information, reported by frontline clinicians after a patient's death, is an irreplaceable source of public health data. However, systematic bias in cause-of-death reporting can lead to over- or underestimation of deaths attributable to different causes. New York City consistently reports higher rates of deaths attributable to pneumonia and influenza than many other US cities and the country. We investigated systematic erroneous reporting as a possible explanation for this phenomenon., Methods: We reviewed all deaths from 2 New York City hospitals during 2013-2014 in which pneumonia or influenza was reported as the underlying cause of death (n = 188), and we examined the association between erroneous reporting and multiple extrinsic factors that may influence cause-of-death reporting (patient demographic characteristics and medical comorbidities, time and hospital location of death, type of medical provider reporting the death, and availability of certain diagnostic information)., Results: Pneumonia was erroneously reported as the underlying cause of death in 163 (86.7%) reports. We identified heart disease and dementia as the more likely underlying cause of death in 21% and 17% of erroneously reported deaths attributable to pneumonia, respectively. We found no significant association between erroneous reporting and the multiple extrinsic factors examined., Conclusions: Our results underscore how erroneous reporting of 1 condition can lead to underreporting of other causes of death. Misapplication or misunderstanding of procedures by medical providers, rather than extrinsic factors influencing the reporting process, are key drivers of erroneous cause-of-death reporting.

Introduction: Currently available Alzheimer's disease (AD) therapeutics are only symptomatic, targeting cholinergic and glutamatergic neurotransmissions. Several putative disease-modifying drugs in late-stage clinical development target amyloid-β (Aβ) peptide and tau protein, the principal neurophatological hallmarks of the disease., Areas Covered: Phase III randomized clinical trials of anti-Aβ drugs for AD treatment were searched in US and EU clinical trial registries and principal biomedical databases until May 2020., Expert Opinion: At present, compounds in Phase III clinical development for AD include four  anti-Ab monoclonal antibodies (solanezumab, gantenerumab, aducanumab, BAN2401), the combination of cromolyn sodium and ibuprofen (ALZT-OP1), and two small molecules (levetiracetam, GV-971). These drugs are mainly being tested in subjects during early AD phases or at preclinical stage of familial AD or even in asymptomatic subjects at high risk of developing AD. The actual results support the hypothesis that elevated Aβ represents an early stage in the AD continuum and demonstrate the feasibility of enrolling these high-risk participants in secondary prevention trials to slow cognitive decline during the AD preclinical stages. However, a series of clinical failures may question further development of Aβ-targeting drugs and the findings from current ongoing Phase III trials will hopefully give light to this critical issue.

Introduction: Alzheimer's disease (AD) is the main cause of dementia and represents a huge burden for patients, carers, and healthcare systems. Extensive efforts for over 20 years have failed to find effective disease-modifying drugs. Although amyloid-β (Aβ) accumulation in the brain predicts cognitive decline, effective reduction of plaque load by numerous drug candidates has not yielded significant clinical benefits. A similar pattern is now emerging for drugs which target hyperphosphorylated tau, and trials with anti-inflammatory drugs have been negative despite neuroinflammation appearing to have a crucial role in AD pathogenesis., Areas Covered: This article reviews key drugs that have been discontinued while in development for AD and delineates the future landscape for present and alternative approaches., Expert Opinion: Anti-Aβ drugs have failed to validate the Aβ cascade hypothesis of AD. Early findings suggest that the same is happening with therapeutics targeting tau and focussing future research solely on anti-tau drugs is inappropriate. Alternative targets should be pursued, including apolipoprotein E, immunomodulation, plasma exchange, protein autophagy and clearance, mitochondrial dysfunction, abnormal glucose metabolism, neurovascular unit support, epigenetic dysregulation, synaptic loss and dysfunction, microbiota dysbiosis, and combination therapies. Meanwhile, repurposing of drugs approved for other indications is justified where scientific rationale and robust preclinical evidence exist.