Beyond Immunity: Challenges in Kidney Retransplantation Among Persons Living With HIV.

INTRODUCTION: While superb outcomes have been observed in the HIV-positive (HIV+) population, graft failure and subsequent need for kidney retransplantation (re-KT) remain a concern. This study aims to investigate the difference in success rates of re-KT allograft survival in the HIV+ versus HIV-negative (HIV-) population in the current era of transplantation (2014-2022). METHODS: Data was collected from the Organ Procurement and Transplantation Network on all kidney transplant donors and recipients who had their first re-KT between 2014 and 2022. Allograft survival was assessed using Kaplan-Meier analysis with a log-rank test, while risk factors for graft loss were assessed using Cox proportional hazards with statistical significance set to P = 0.05. RESULTS: HIV+ recipients were significantly more likely to be Black (P < 0.001), have an HLA mismatch >3 (P = 0.018), delayed graft function (P = 0.023), and graft loss from primary nonfunction (P < 0.001). Their HIV- counterparts were more likely to be White (P < 0.001) and Hispanic (<0.001), lose their graft from acute rejection (P = 0.044), and have a living donor (P = 0.001). Being HIV+ was associated with a 1.68-fold increased risk of graft loss, an HLA mismatch >3 held a 1.18-fold increase, experiencing delayed graft function held a 1.89-fold increase, and having diabetes was associated with a 1.16-fold increased risk. Living donor kidneys were associated with a 15.8% decrease in risk for graft failure. Kaplan-Meier curves showed a significantly lower duration of kidney allograft survival in the HIV+ community (P = 0.02). CONCLUSIONS: Disproportional graft failure and inadequate HLA mismatching persist within the HIV+ Re-KT community. Stronger organ matching and new approaches for desensitizing retransplant candidates are vital.

Benefit of Kidney Transplantation for Post Lung Transplantation Renal Failure.

INTRODUCTION: Nephrotoxicity is a significant side effect of thoracic transplantation. Many lung transplant patients will require subsequent renal transplantation (KAL). Recently, simultaneous lung/kidney transplants (SLuK) have become an attractive option for patients with end-stage renal disease at the time of lung transplantation. This article explores SLuK outcomes compared to conventional KAL, as well as outcomes among KAL patients against those were KAL listed but never transplanted. MATERIALS AND METHODS: The United Network for Organ Sharing/the Organ Procurement and Transportation Network database was used to identify SLuK patients (n = 74), KAL transplants (n = 456), and patients who were listed for KAL but were never transplanted (n = 626). Significance was determined by chi2, Wilcoxon rank sum test, or independent t-tests. Death-censored graft survival for subgroups was estimated using Kaplan-Meier with log-rank for significance. Analyses were completed using SPSS Statistics 28. RESULTS: The SLuK cohort was older (P = 0.04), more likely diabetic (P < 0.001), and had shorter life expectancies (P < 0.001) than KAL patients. Of those SLuK transplants within 5 y, 84% of patients were alive 1 y post transplant and 82% were alive 3 y post-transplant (compared to 74.6% and 60.3% of overall SLuK). Patients who did undergo KAL were younger and had a lower body mass index (both P < 0.001) compared to those who did not. Those who received a kidney had increased survival times compared to WL patients (P < 0.001). CONCLUSIONS: Conventional KAL transplants are still favorable for average lung recipients. However, recent improvements have made SLuK an option for patients with renal dysfunction. Those patients who were able to receive KAL transplants were better surgical candidates than those who remained on the waitlist.

Frailty Prevalence, Incidence, and Association with Incident Disability in the Italian Longitudinal Study on Aging.

INTRODUCTION: Data on frailty frequency are heterogeneous and mostly based on cross-sectional studies. Little is known about frailty development and progression over time. Our aim was to conduct a systematic analysis of frailty prevalence and incidence in a large cohort of older adults and to evaluate the association with incident disability, in order to tackle the current paucity and fragmentation of longitudinal data on frailty. METHODS: As secondary analysis of the Italian Longitudinal Study on Aging (ILSA) population-based cohort (n = 5,632, 65-84), frailty status was operationalized according to Fried criteria (n = 2,457). Weighted prevalence and incidence rates were calculated at each ILSA wave (T0 1992-1993, T1 1995-1996, T2 2000-2001). The association with incident disability in Activities of Daily Living (ADL) or Instrumental Activities of Daily Living (IADL) was investigated through Cox proportional hazard models, controlling for possible confounders. RESULTS: Prevalence of frailty and pre-frailty at baseline (mean age 71.6 years; women 58.9%) were 4.0% (95% confidence interval [CI]: 3.4-4.6) and 44.6% (95% CI: 43.1-46.1), respectively. Incidence rates per 1,000 person-years for the T0-T1 interval were 7.3 (95% CI: 5.2-9.3) for frailty and 83.7 (95% CI: 73.6-93.8) for pre-frailty. Prevalence and incidence of frailty, and to a lesser degree of pre-frailty, were overall higher for women and increased with age, yet no increasing trend with advancing age was detected for pre-frailty incidence. Frailty incidence rates were significantly higher among pre-frail than non-frail individuals at follow-up entry. After full adjustment, being frail markedly increased the risk of incident disability in ADL (hazard ratio [HR] 3.58, 95% CI: 1.97-6.52) and IADL (HR 2.56, 95% CI: 1.58-4.16) over a 4-year period. DISCUSSION/CONCLUSION: According to our findings, frailty is common among older people and is a strong and independent predictor of disability. Further research on factors and characteristics related to frailty progression, and especially remission, over time is crucial to calibrate effective public health preventive measures.

Influence of atrial fibrillation subtypes on anticoagulant therapy in a high-risk older population: the FAI project.

BACKGROUND AND AIM: Benefits of oral anticoagulants (OAC) in atrial fibrillation (AF) patients with moderate-to-high risk of stroke are independent of AF pattern. We evaluated whether AF clinical subtype influenced OAC use in a representative sample of the Italian older population. METHODS: A cross-sectional examination of all subjects aged 65 + years from three general practices in northern, central, and southern Italy started in 2016. A double-screening procedure was followed by clinical and ECG confirmation. Patients were categorized as having paroxysmal, persistent, or permanent AF. OAC use was evaluated in confirmed AF patients. RESULTS: The sample included 6016 subjects. Excluding 235 non-eligible, participation was 78.3%, which left 4528 participants (mean age 74.5 ± 6.8 years, 47.2% men). Overall, 319 AF cases were identified: 43.0% had paroxysmal, 21.3% persistent, and 35.7% permanent AF. Frequency of OAC therapy was 91.2% in permanent, 85.3% in persistent, and only 43.0% in paroxysmal AF (P < 0.001). In multivariate analysis, controlled for baseline variables and risk scales, persistent and permanent AF were associated with a significant increase in the likelihood of receiving OAC compared with paroxysmal AF (P < 0.001). This was confirmed for permanent AF also in multivariate analyses considering separately vitamin K antagonists or direct-acting oral anticoagulants (OR, 4.37, 95% CI, 2.43-7.85; and 1.92, 95% CI, 1.07-3.42, respectively) and for persistent AF and direct-acting oral anticoagulants (OR, 4.33, 95% CI, 2.30-8.15). CONCLUSIONS: In a population-based survey, AF pattern was an independent predictor of OAC treatment. Paroxysmal AF is still perceived as carrying a lower risk of vascular events.

Myocardial GRK2 Reduces Fatty Acid Metabolism and ß-Adrenergic Receptor-Mediated Mitochondrial Responses.

G-protein coupled receptor (GPCR) kinase 2 (GRK2) is upregulated in heart failure (HF) patients and mouse models of cardiac disease. GRK2 is a regulator of ß-adrenergic receptors (ßARs), a GPCR involved in ionotropic and chronotropic responses. We and others have recently reported GRK2 to be localized in the mitochondria, although its function in the mitochondria and/or metabolism remain not clearly defined. We hypothesized that upregulation of GRK2 reduced mitochondrial respiratory function and responses to ßAR activation. Utilizing isolated mouse primary adult cardiomyocytes (ACMs), we investigated the role of glucose, palmitate, ketone bodies, and BCAAs in mediating cell survival. Our results showed that myocyte upregulation of GRK2 promotes palmitate-induced cell death. Isotopologue labeling and mass spectrometry showed that the upregulation of GRK2 reduces ß-hydroxybutyryl CoA generation. Next, using isoproterenol (ISO), a non-selective ßAR-agonist, we determined mitochondrial function in mouse and human primary ACMs. Upregulation of GRK2 impaired ISO-mediated mitochondrial functional responses, which we propose is important for metabolic adaptations in pathological conditions. Increased cardiac levels of GRK2 reduced fatty acid-specific catabolic pathways and impaired ISO-stimulated mitochondrial function. Our data support the notion that GRK2 participates in bioenergetic remodeling and may be an important avenue for the development of novel pharmacological strategies in HF.

Prevalence of atrial fibrillation in the Italian elderly population and projections from 2020 to 2060 for Italy and the European Union: the FAI Project.

AIMS: To estimate prevalence of atrial fibrillation (AF) in a representative sample of the Italian elderly population, projecting figures for Italy and the European Union. METHODS AND RESULTS: A cross-sectional examination of all subjects aged 65+ years from three general practices in Northern, Central, and Southern Italy started in 2016. Participants were administered a systematic and an opportunistic screening, followed by clinical and electrocardiogram confirmation. The study sample included 6016 subjects. Excluding 235 non-eligible, among the remaining 5781 participation was 78.3%, which left 4528 participants (mean age 74.5 ± 6.8 years, 47.2% men). Prevalence of AF was 7.3% [95% confidence intervals (CI) 6.6-8.1], higher in men and with advancing age (6.6% from systematic plus 0.7% from opportunistic screening). Using prevalence figures, Italian elderly having AF in 2016 were estimated at ∼1 081 000 (95% CI 786 000-1 482 000). Considering stable prevalence, this number will increase by 75% to ∼1 892 000 in 2060 (95% CI 1 378 000-2 579 000). European Union elderly having AF in 2016 were estimated at ∼7 617 000 (95% CI 5 530 000-10 460 000), increasing by 89% to ∼14 401 000 in 2060 (95% CI 10 489 000-19 647 000). In 2016, subjects aged 80+ years represented 53.5% of cases in Italy and 51.2% in the European Union; in 2060, 69.6% and 65.2%, respectively. CONCLUSIONS: Our findings indicate a high burden of AF in coming decades, especially among the oldest-old, who carry the higher AF-related risk of stroke and medical complications.

Biopsychosocial frailty and the risk of incident dementia: The Italian longitudinal study on aging.

INTRODUCTION: Frailty is a critical intermediate status of the aging process including physical, cognitive, and psychosocial domains/phenotypes. We operationalized a new biopsychosocial frailty (BF) construct, estimating its impact on the risk of incident dementia and its subtypes. METHODS: In 2171 older individuals from the population-based Italian Longitudinal Study on Aging (ILSA), we identified by latent class procedures the BF construct as the physical frail status plus at least one of the two items of the 30-item Geriatric Depression Scale impaired (items 3/10). RESULTS: Over a 3.5-year follow-up, participants with BF showed an increased risk of overall dementia (hazard ratio [HR]: 2.16, 95% confidence interval [CI]:1.07-4.37), particularly vascular dementia (VaD) (HR: 3.21, 95% CI: 1.05-9.75). Similarly, over a 7-year follow-up, an increased risk of overall dementia (HR: 1.84, 95% CI: 1.06-3.20), particularly VaD (HR: 2.53, 95% CI: 1.08-5.91), was also observed. DISCUSSION: In a large cohort of Italian older individuals without cognitive impairment at baseline, a BF model was a short- and long-term predictor of overall dementia, particularly VaD.

Additive Role of a Potentially Reversible Cognitive Frailty Model and Inflammatory State on the Risk of Disability: The Italian Longitudinal Study on Aging.

OBJECTIVE: Cognitive frailty is a condition recently defined by operationalized criteria describing the simultaneous presence of physical frailty and mild cognitive impairment (MCI). Two subtypes for this clinical construct have been proposed: "potentially reversible" cognitive frailty (physical frailty plus MCI) and "reversible" cognitive frailty (physical frailty plus pre-MCI subjective cognitive decline). Here the prevalence of a potentially reversible cognitive frailty model was estimated. It was also evaluated if introducing a diagnosis of MCI in older subjects with physical frailty could have an additive role on the risk of dementia, disability, and all-cause mortality in comparison with frailty state or MCI condition alone, with analyses separately performed for inflammatory state. METHODS: In 2,373 individuals from the population-based Italian Longitudinal Study on Aging with a 3.5-year-follow-up, we operationally categorized older individuals without dementia into four groups: non-frail/non-MCI, non-frail/MCI, frail/non-MCI, and frail/MCI. RESULTS: The prevalence of potentially reversible cognitive frailty was 1%, increasing with age and more represented in women than in men, and all groups were associated with significant increased incident rate ratios of dementia, disability, and mortality. A significant difference in rates of disability has been found between the MCI and non-MCI groups (contrasts of adjusted predictions: 0.461; 95% confidence interval: 0.187-0.735) in frail individuals with high inflammatory states (fibrinogen >339 mg/dL). CONCLUSION: In older individuals without dementia and with elevated inflammation, a potentially reversible cognitive frailty model could have a significant additional predictive effect on the risk of disability than the single conditions of frailty or MCI.

The Italian stroke-app: ICTUS3R.

Any strategy to reduce stroke burden involves crucial inputs from individuals (risk reduction, rapid recognition and response to symptoms onset) which imply a certain level of stroke knowledge. Health-related applications (apps) have been identified as a novel platform for dissemination of health information to the public. Only few apps about stroke are currently available with scientifically valid information, none of them are available in Italian. We developed the first and only Italian stroke app, ICTUS3R. We also pilot tested ICTUS3R in terms of its usage during the first 12 months following release (October 30, 2014). ICTUS3R was developed in collaboration with communication experts, stroke leaders and web producers. ICTUS3R was pilot tested in terms of number and distribution of downloads. Data about 1 year usage were anonymously collected from ICTUS 3R release on October 30, 2014. ICTUS3R includes a stroke screening tool, information how to react in case of suspected stroke, and information about risk factors including personal stroke risk calculator. ICTUS 3R web site was visited 36,242 times. Mean session duration was over 2 min. The 48 % of downloads were by individuals aged 25-44 years, 12 % by individuals ≥55 years. ICTUS3R downloads were distributed across all the Italian provinces, in varying proportions. The 4.3 % of downloads were done outside Italy. ICTUS3R can be an important contribution to stroke management and prevention, it proved to be well received for dissemination of stroke information among Italians. Its use could contribute to reduce stroke burden in Italy.

Methods of Implementation of Evidence-Based Stroke Care in Europe: European Implementation Score Collaboration.

BACKGROUND AND PURPOSE: Differences in stroke care and outcomes reported in Europe may reflect different degrees of implementation of evidence-based interventions. We evaluated strategies for implementing research evidence into stroke care in 10 European countries. METHODS: A questionnaire was developed and administered through face-to-face interviews with key informants. Implementation strategies were investigated considering 3 levels (macro, meso, and micro, eg, policy, organization, patients/professionals) identified by the framing analysis, and different settings (primary, hospital, and specialist) of stroke care. Similarities and differences among countries were evaluated using the categorical principal components analysis. RESULTS: Implementation methods reported by ≥7 countries included nonmandatory policies, public financial incentives, continuing professional education, distribution of educational material, educational meetings and campaigns, guidelines, opinion leaders', and stroke patients associations' activities. Audits were present in 6 countries at national level; national and regional regulations in 4 countries. Private financial incentives, reminders, and educational outreach visits were reported only in 2 countries. At national level, the first principal component of categorical principal components analysis separated England, France, Scotland, and Sweden, all with positive object scores, from the other countries. Belgium and Lithuania obtained the lowest scores. At regional level, England, France, Germany, Italy, and Sweden had positive scores in the first principal component, whereas Belgium, Lithuania, Poland, and Scotland showed negative scores. Spain was in an intermediate position. CONCLUSIONS: We developed a novel method to assess different domains of implementation in stroke care. Clear variations were observed among European countries. The new tool may be used elsewhere for future contributions.