Delirium as late manifestation of infective endocarditis after transcatheter aortic valve implantation.

More than one-third of the cases of infective endocarditis (IE) occur in older patients. The disease is often characterized by atypical symptoms. The incidence of neurological complications is high and represents a strong independent predictor of severe outcomes and mortality. IE is a rare but serious complication of transcatheter aortic valve implantation (TAVI). A persistent delirium as a unique manifestation of post-TAVI IE in an older patient is presented in this clinical case.

Progression of chronic kidney disease in familial LCAT deficiency: a follow-up of the Italian cohort.

Familial LCAT deficiency (FLD) is a rare genetic disorder of HDL metabolism, caused by loss-of-function mutations in the LCAT gene and characterized by a variety of symptoms including corneal opacities and kidney failure. Renal disease represents the leading cause of morbidity and mortality in FLD cases. However, the prognosis is not known and the rate of deterioration of kidney function is variable and unpredictable from patient to patient. In this article, we present data from a follow-up of the large Italian cohort of FLD patients, who have been followed for an average of 12 years. We show that renal failure occurs at the median age of 46 years, with a median time to a second recurrence of 10 years. Additionally, we identify high plasma unesterified cholesterol level as a predicting factor for rapid deterioration of kidney function. In conclusion, this study highlights the severe consequences of FLD, underlines the need of correct early diagnosis and referral of patients to specialized centers, and highlights the urgency for effective treatments to prevent or slow renal disease in patients with LCAT deficiency.

Sarcopenia and swallowing disorders in older people.

Aging is accompanied by several changes which may affect swallowing function. The beginning of these changes, termed presbyphagia, still captures a preserved swallowing function, although burdened by the consequences of the physiological aging process. Several stressors (including diseases and medications) can easily trigger the disruption of this (increasingly weak) equilibrium and lead to overt dysphagia. It is noteworthy that the swallowing dysfunction may be aggravated by the sarcopenic process, characterizing the so-called "sarcopenic dysphagia", potentially responsible for several health-related negative outcomes. The assessment and management of sarcopenic dysphagia largely rely on the evaluation and integrated treatment of both constituting conditions (i.e., sarcopenia and dysphagia). The management of dysphagia requires a multidimensional approach and can be designed as either compensatory (aimed at producing immediate benefit for the patient through postural adjustments, swallowing maneuvers, and diet modifications) or rehabilitative. Interestingly, some evidence suggests that resistance training traditionally applied to tackle the lower extremity in sarcopenia may be simultaneously beneficial for sarcopenic dysphagia. If these preliminary results (discussed in the present review article) will be confirmed, the systemic beneficial effects of physical exercise will be indirectly demonstrated. This will also support the need of promoting healthy lifestyle in all sarcopenic individuals (thus potentially at risk of dysphagia).

Reduced platelet count, but no major platelet function abnormalities, are associated with loss-of-function ATP-binding cassette-1 gene mutations.

Loss-of-function mutations of the the ATP-binding cassette-1 (ABCA1) gene are the cause of Tangier disease (TD) in homozygous subjects and familial HDL deficiency (FHD) in heterozygous subjects. These disorders are characterized by reduced plasma HDL-cholesterol (HDL-C) and altered efflux of cholesterol from cells. Previous studies in TD patients and ABCA1-/- murine models reported defects in platelet count, morphology, and function, but the issue is still controversial. We analyzed three subjects with low to very low HDL-C levels due to the loss-of-function mutations of the ABCA1 gene. Two related patients with FHD were heterozygous carriers of two mutations on the same ABCA1 allele; one, with TD, was homozygous for a different mutation. Mild to moderate thrombocytopenia was observed in all the patients. No morphological platelet abnormalities were detected under optical or EM. History of moderate bleeding tendency was recorded only in one of the FHD patients. Only limited alterations in platelet aggregation and activation of the integrin αIIbß3 were observed in one FHD patient. While α-granule secretion (P-selectin), content, and secretion of platelet δ-granules (serotonin, ATP, and ADP) and thromboxane (TX) A2 synthesis were normal in all the patients, the expression of lysosomal CD63, in response to some agonists, was reduced in TD patients. In conclusion, three patients carrying ABCA1 genetic variants had low platelet count, with the lowest values observed in TD, not associated with major alterations in platelet morphology and response to agonists or bleeding.

Blood pressure and 10-year mortality risk in the Milan Geriatrics 75+ Cohort Study: role of functional and cognitive status.

BACKGROUND: Optimal blood pressure targets in older adults are controversial. OBJECTIVE: to investigate whether the relation of blood pressure with mortality in older adults varies by age, functional and cognitive status. DESIGN: longitudinal geriatric outpatient cohort. SETTING: Milan Geriatrics 75+ Cohort Study. SUBJECTS: One thousand five hundred and eighty-seven outpatients aged 75 years and over. METHODS: The relations of systolic (SBP) and diastolic blood pressure (DBP) with mortality risk were analysed using Cox proportional hazards models. Blood pressure, Mini-Mental State Examination (MMSE) and Basic Activities of Daily Living (ADL) were assessed at baseline. All analyses were adjusted for socio-demographic factors, co-morbidities and medications. RESULTS: One thousand and forty-six patients died during 10-year follow-up. The relationships of SBP and DBP with mortality risk were U-shaped; SBP of 165 mmHg and DBP of 85 mmHg were associated with the lowest mortality. Patients with SBP < 120 mmHg and patients with SBP 120-139 mmHg had 1.64-fold (95% confidence intervals, CI 1.21-2.23) and 1.32-fold (95% CI 1.10-1.60) higher mortality risk than patients with SBP 160-179 mmHg (P values 0.001 and 0.004, respectively). In patients with SBP below 180 mmHg, higher SBP was associated with lower mortality in patients with impaired ADL and MMSE but not in those with preserved ADL and/or MMSE (P for interaction 0.033). Age did not modify the correlation of SBP with mortality. CONCLUSIONS: The correlations of SBP and DBP with mortality were U-shaped. Higher SBP is related to lower mortality in subjects with impaired ADL and MMSE. ADL and MMSE may identify older subjects who benefit from higher blood pressure.

Heart Rate Variability and Cognition: A Narrative Systematic Review of Longitudinal Studies.

BACKGROUND: Heart rate variability (HRV) is a reliable and convenient method to assess autonomic function. Cross-sectional studies have established a link between HRV and cognition. Longitudinal studies are an emerging area of research with important clinical implications in terms of the predictive value of HRV for future cognition and in terms of the potential causal relationship between HRV and cognition. However, they have not yet been the objective of a systematic review. Therefore, the aim of this systematic review was to investigate the association between HRV and cognition in longitudinal studies. METHODS: The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The Embase, PsycINFO and PubMed databases were searched from the earliest available date to 26 June 2023. Studies were included if they involved adult human subjects and evaluated the longitudinal association between HRV and cognition. The risk of bias was assessed with the Newcastle-Ottawa Scale for Cohort Studies. The results were presented narratively. RESULTS: Of 14,359 records screened, 12 studies were included in this systematic review, with a total of 24,390 participants. Two thirds of the studies were published from 2020 onwards. All studies found a longitudinal relationship between HRV and cognition. There was a consistent association between higher parasympathetic nervous system (PNS) activity and better cognition, and some association between higher sympathetic nervous system activity and worse cognition. Also, higher PNS activity persistently predicted better executive functioning, while data on episodic memory and language were more scant and/or controversial. CONCLUSIONS: Our results support the role of HRV as a biomarker of future cognition and, potentially, as a therapeutic target to improve cognition. They will need confirmation by further, more comprehensive studies also including unequivocal non-HRV sympathetic measures and meta-analyses.

Omega-3 polyunsatured fatty acids and physical performance across the lifespan: a narrative review.

Background and Aims: Physical performance is a major contributor of mobility and independence during older life. Despite a progressive decline in musculoskeletal function starts from middle age, several factors acting during the life-course can negatively influence musculoskeletal functional capacities. Lifestyle interventions incorporating nutrition and physical exercise can help maximizing the muscle functional capacities in early life as well as preserving them later in life. Among various dietary compounds, omega-3 polyunsaturated fatty acids (PUFAs) are gaining growing attention for their potential effects on muscle membrane composition and muscle function. Indeed, several pathways are enhanced, such as an attenuation of pro-inflammatory oxidative stress, mitochondrial function, activation of the mammalian target of rapamycin (mTOR) signaling and reduction of insulin resistance. Methods: We performed a narrative review to explore the existing literature on the relationship between omega-3 PUFAs and physical performance across the life-course. Results: Growing evidence from randomized controlled trials (RCTs) suggests beneficial effects of omega-3 PUFAs on muscle function, including physical performance parameters in mid to later life. On the other hand, despite a direct association in early life is not available in literature, some mechanisms by which omega-3 PUFAs may contribute to improved adult physical performance could be hypothesized. Conclusion: Omega-3 PUFAs are gaining growing attention for their positive effect on muscle function parameters. The integration of physical function measures in future studies would be of great interest to explore whether omega-3 PUFAs could contribute to improved muscle function, starting from early life and extending throughout the lifespan. However, larger and high-quality RCTs are needed to fully elucidate the beneficial effects of omega-3 PUFAs supplementation on muscle mass and function.

Diencephalic versus Hippocampal Amnesia in Alzheimer's Disease: The Possible Confabulation-Misidentification Phenotype.

BACKGROUND: Alzheimer's disease (AD) is clinically heterogeneous, including the classical-amnesic (CA-) phenotype and some variants. OBJECTIVE: We aim to describe a further presentation we (re)named confabulation-misidentification (CM-) phenotype. METHODS: We performed a retrospective longitudinal case-series study of 17 AD outpatients with the possible CM-phenotype (CM-ADs). Then, in a cross-sectional study, we compared the CM-ADs to a sample of 30 AD patients with the CA-phenotype (CA-ADs). The primary outcome was the frequency of cognitive and behavioral features. Data were analyzed as differences in percentage by non-parametric Chi Square and mean differences by parametric T-test. RESULTS: Anterograde amnesia (100%) with early confabulation (88.2%), disorientation (88.2%) and non-infrequently retrograde amnesia (64.7%) associated with reduced insight (88.2%), moderate prefrontal executive impairment (94.1%) and attention deficits (82.3%) dominated the CM-phenotype. Neuropsychiatric features with striking misidentification (52.9%), other less-structured delusions (70.6%), and brief hallucinations (64.7%) were present. Marked behavioral disturbances were present early in some patients and very common at later stages. At the baseline, the CM-ADs showed more confabulation (p < 0.001), temporal disorientation (p < 0.02), misidentification (p = 0.013), other delusions (p = 0.002), and logorrhea (p = 0.004) than the CA-ADs. In addition, more social disinhibition (p = 0.018), reduction of insight (p = 0.029), and hallucination (p = 0.03) persisted at 12 months from baseline. Both the CA- and CM-ADs showed anterior and medial temporal atrophy. Compared to HCs, the CM-ADs showed more right fronto-insular atrophy, while the CA-ADs showed more dorsal parietal, precuneus, and right parietal atrophy. CONCLUSION: We described an AD phenotype resembling diencephalic rather than hippocampal amnesia and overlapping the past-century description of presbyophrenia.

Liver Enzymes in a Cohort of Community-Dwelling Older Persons: Focus on Sex Contribution.

Dysfunctions in liver metabolic activities may increase the risk of cognitive impairment and dementia. In a cohort of community-dwelling older persons investigated for a suspected cognitive decline, we studied the association between liver status and dementia, considering sex and frailty contribution. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations, and the AST/ALT ratio were used to assess liver function in 419 older adults (248 persons with dementia and 171 age- and sex-matched subjects without cognitive decline). Although the serum concentrations of the liver enzymes were in the physiologic range, patients with dementia showed lower ALT concentrations (p = 0.005) and higher AST/ALT ratios (p = 0.003) compared to controls. The same differences were found when comparing men with and without dementia (ALT, p = 0.009; AST/ALT ratio, p = 0.003) but disappeared in women. Curiously, comparing women and men with the same diagnosis, the ALT concentrations were lower (p = 0.008), and the AST/ALT ratio was higher (p = 0.001) in control women than men, whereas no significant difference was found between persons with dementia. In conclusion, in our cohort of older people living in the community, the association between serum aminotransferases and dementia was remarked. Moreover, our results support attention to sex difference in liver function, suggesting a role in the pathogenesis of dementia.

Autonomic function predicts cognitive decline in mild cognitive impairment: Evidence from power spectral analysis of heart rate variability in a longitudinal study.

Background: Despite the emerging clinical relevance of heart rate variability (HRV) as a potential biomarker of cognitive decline and as a candidate target for intervention, there is a dearth of research on the prospective relationship between HRV and cognitive change. In particular, no study has addressed this issue in subjects with a diagnosis of cognitive status including cognitive impairment. Objective: To investigate HRV as a predictor of cognitive decline in subjects with normal cognition (NC) or Mild Cognitive Impairment (MCI). Specifically, we tested the literature-based hypothesis that the HRV response to different physical challenges would predict decline in different cognitive domains. Methods: This longitudinal study represents the approximately 3-year follow-up of a previous cross-sectional study enrolling 80 older outpatients (aged ≥ 65). At baseline, power spectral analysis of HRV was performed on five-minute electrocardiographic recordings at rest and during a sympathetic (active standing) and a parasympathetic (paced breathing) challenge. We focused on normalized HRV measures [normalized low frequency power (LFn) and the low frequency to high frequency power ratio (LF/HF)] and on their dynamic response from rest to challenge (Δ HRV). Extensive neuropsychological testing was used to diagnose cognitive status at baseline and to evaluate cognitive change over the follow-up via annualized changes in cognitive Z-scores. The association between Δ HRV and cognitive change was explored by means of linear regression, unadjusted and adjusted for potential confounders. Results: In subjects diagnosed with MCI at baseline a greater response to a sympathetic challenge predicted a greater decline in episodic memory [adjusted model: Δ LFn, standardized regression coefficient (ß) = -0.528, p = 0.019; Δ LF/HF, ß = -0.643, p = 0.001] whereas a greater response to a parasympathetic challenge predicted a lesser decline in executive functioning (adjusted model: Δ LFn, ß = -0.716, p < 0.001; Δ LF/HF, ß = -0.935, p < 0.001). Conclusion: Our findings provide novel insight into the link between HRV and cognition in MCI. They contribute to a better understanding of the heart-brain connection, but will require replication in larger cohorts.

Ischaemic Stroke of the "Hand-Knob" Area Due to Paradoxical Cerebral Air Embolism after Central Venous Catheterization-A Doubly Rare Occurrence: A Case Report and an Overview of Pathophysiology, Diagnosis, and Treatment.

Central venous catheters (CVCs) are increasingly used across specialties for invasive haemodynamic monitoring and for the delivery of fluids, medications, and nutritional support. Cerebral air embolism (CAE) is a rare but potentially fatal complication associated with the insertion, maintenance, and removal of CVCs. It can occur through different mechanisms, including the direct retrograde ascension of air into the cerebral veins and paradoxical embolism due to a right-to-left intracardiac or intrapulmonary shunt. The "hand-knob" area is the cortical region within the primary motor cortex that contains the representation of the hand. It is located in the superior precentral gyrus and is the site of less than 1% of all ischaemic strokes. We report here the case of a patient who experienced an ischaemic stroke of the right "hand-knob" area, due to paradoxical CAE through a previously undiagnosed patent foramen ovale (PFO), after the insertion of a catheter in the right internal jugular vein. We also provide an overview of the pathophysiology, diagnosis, and treatment of CAE. Suspecting CAE in the case of an acute neurological event occurring in close temporal relationship with central venous catheterization is paramount to allow the early recognition and treatment of this uncommon form of iatrogenic stroke.

Comparison between the first and second COVID-19 waves in Internal Medicine wards in Milan, Italy: a retrospective observational study.

COVID-19 spread in two pandemic waves in Italy between 2020 and 2021. The aim of this study is to compare the first with the second COVID-19 wave, analyzing modifiable and non-modifiable factors and how these factors affected mortality in patients hospitalized in Internal Medicine wards. Consecutive patients with SARS-CoV-2 infection and dyspnea requiring O2 supplementation were included. The severity of lung involvement was categorized according to the patients' oxygen need. Six hundred and ten SARS-CoV-2 hospitalized patients satisfied the inclusion criteria. The overall estimated 4-week mortality was similar in the two pandemic waves. Several variables were associated with mortality after univariate analysis, but they lacked the significance after multivariable adjustment. Steroids did not exert any protective effect when analyzed in time-dependent models in the whole sample; however, steroids seemed to exert a protective effect in more severe patients. When analyzing the progression to different states of O2 supplementation during hospital stay, mortality was almost exclusively associated with the use of high-flow O2 or CPAP. The analysis of the transition from one state to the other by Cox-Markov models confirmed that age and the severity of lung involvement at admission, along with fever, were relevant factor for mortality or progression.

Dyslipidemia and prevention of atherosclerotic cardiovascular disease in the elderly.

The atherosclerotic cardiovascular disease (ASCVD) represents the leading cause of death and disability in the elderly. The study of atherosclerosis and the strategies to control ASCVD are evolving. All strategies emphasize the need to lower LDL cholesterol (LDL-C) through an appropriate lifestyle and the use of lipid-lowering drugs, mainly statins. Available evidence coming from clinical trials is useful to inform clinical choices, but the older people are poorly represented in those trials. Thus, evidence supporting the benefit of statin therapy for primary and secondary prevention of fatal and nonfatal ASCVD events in adults aged 75 years and older are limited. The pharmacological therapy of dyslipidemia is recommended by guidelines provided by international expert panels in adults, while in the elderly it is still a matter of debate. Statins are generally well tolerated drugs but their use in the elderly, especially in fragile ones or with multi-pathology that take many other drugs, requires a careful evaluation of the risk-benefit ratio and a shared decision- making process between doctor and patient.

[Dislipidemia and lipid lowering drugs: from guidelines to clinical practice. An updated review of the literature.] / Dislipidemia e terapia ipolipemizzante: dalle linee guida alla pratica clinicaUna rassegna aggiornata della letteratura.

The atherosclerotic cardiovascular disease (ASCVD) represents the leading cause of death and disability not only in countries with a high degree of socio-economic development but also in low- middle-income countries. The study of atherosclerosis and the strategies to control ASCVD are evolving. All strategies emphasize the need to lower LDL cholesterol through an appropriate lifestyle and the use of lipid-lowering drugs. A therapy with statin with or without other lipid lowering drugs is recommended in secondary prevention. In primary prevention, the use of the lipid-lowering drug should instead take into account the cost-benefit ratio. Available evidence coming from clinical trials is useful to inform clinical choices but must be associated with a shared decision-making process between doctor and patient.

LIPA gene mutations affect the composition of lipoproteins: Enrichment in ACAT-derived cholesteryl esters.

BACKGROUND AND AIMS: Cholesteryl ester storage disease (CESD) due to LIPA gene mutations is characterized by hepatic steatosis, hypercholesterolemia and hypoalphalipoproteinemia, exposing affected patients to an increased cardiovascular risk. Further insights into the impact of LIPA gene mutations on lipid/lipoprotein metabolism are limited. Aim of the study was to investigate the effect of carrying one or two mutant LIPA alleles on lipoprotein composition and function. METHODS: Lipoproteins were isolated from 6 adult CESD patients, 5 relatives carrying one mutant LIPA allele (carriers) and 12 sex/age matched controls. Lipid profile, lipoprotein mass composition and the fatty acid distribution of cholesteryl esters (CEs) were assessed. HDL function was evaluated as the ability to promote nitric oxide release by endothelial cells. RESULTS: Despite the lipid-lowering therapy, total cholesterol, LDL-cholesterol and triglycerides were increased in CESD patients compared to controls, while HDL-cholesterol was reduced. Carriers also displayed elevated total and LDL-cholesterol. Very low and intermediate density lipoproteins from CESD patients and carriers were enriched in CEs compared to the control ones, with a concomitant reduction of triglycerides. Fatty acid composition of CEs in serum and lipoproteins showed a depletion of linoleate content in CESD patients, due to the reduced LCAT activity. In CESD HDL, fatty acid distribution of CEs was shifted towards saturated ones, if compared to control HDL. The changes in HDL composition did not affect HDL ability to promote nitric oxide release by endothelial cells. CONCLUSIONS: LIPA gene mutations significantly affected plasma levels and lipid composition of lipoproteins, likely contributing to the increased cardiovascular risk of affected patients.

Thyroid Status and Mortality Risk in Older Adults With Normal Thyrotropin: Sex Differences in the Milan Geriatrics 75+ Cohort Study.

BACKGROUND: Thresholds of optimal thyroid status in old age are controversial. We investigated the longitudinal association between thyroid parameters and 10-year all-cause mortality risk in older outpatients with normal thyrotropin (TSH) and modification by sex and age. METHODS: Baseline TSH, free thyroxine (fT4), and free triiodothyronine (fT3) were assessed in the Milan Geriatrics 75+ Cohort Study. 324 men and 609 women older than 75 years had normal TSH. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for the associations between thyroid parameters and mortality risk using Cox regression. Sex-stratified analyses were adjusted for sociodemographic factors and comorbidities. RESULTS: 233 men and 367 women died during follow-up. After adjustment, each 1-mU/L higher TSH was associated with decreased mortality risk in men (HR 0.83, 95% CI 0.69-0.98), but not in women (HR 1.09, 95% CI 0.95-1.24) (p for sex interaction = .006). Each 1-ng/L higher fT4 was associated with increased mortality risk in men (HR 1.11, 95% CI 1.02-1.22), but not in women (HR 0.98, 95% CI 0.93-1.04) (p for sex interaction = .013). Each 1-pg/mL higher fT3 was associated with decreased mortality risk in women (HR 0.77, 95% CI 0.60-0.98), but not in men (HR 0.80, 95% CI 0.57-1.13). The inverse association between TSH and mortality was most pronounced in men older than 85 years. CONCLUSIONS: Among older outpatients with normal TSH, higher TSH and lower fT4 were associated with decreased mortality risk in men but not in women. When assessing thyroid status, sex and age should be taken into account.