Adding Diversity to a Diruthenium Biscyclopentadienyl Scaffold via Alkyne Incorporation: Synthesis and Biological Studies.

We report the synthesis and the assessment of the anticancer potential of two series of diruthenium biscyclopentadienyl carbonyl complexes. Novel dimetallacyclopentenone compounds (2-4) were obtained (45-92% yields) from the thermal reaction (PhCCPh exchange) of [Ru2Cp2(CO)(µ-CO){µ-η1:η3-C(Ph)═C(Ph)C(═O)}], 1, with alkynes HCCR [R = C5H4FeCp (Fc), 3-C6H4(Asp), 2-naphthyl; Cp = η5-C5H5, Asp = OC(O)-2-C6H4C(O)Me]. Protonation of 1-3 by HBF4 afforded the corresponding µ-alkenyl derivatives 5-7, in 40-86% yields. All products were characterized by IR and NMR spectroscopy; moreover, cyclic voltammetry (1, 2, 5, 7) and single-crystal X-ray diffraction (5, 7) analyses were performed on representative compounds. Complexes 5-7 revealed a cytotoxic activity comparable to that of cisplatin in A549 (lung adenocarcinoma), SW480 (colon adenocarcinoma), and ovarian (A2780) cancer cell lines, and 2, 5, 6, and 7 overcame cisplatin resistance in A2780cis cells. Complexes 2, 5, and 7 (but not the aspirin derivative 6) induced an increase in intracellular ROS levels. Otherwise, 6 strongly stabilizes and elongates natural DNA (from calf thymus, CT-DNA), suggesting a possible intercalation binding mode, whereas 5 is less effective in binding CT-DNA, and 7 is ineffective. This trend is reversed concerning RNA, and in particular, 7 is able to bind poly(rA)poly(rU) showing selectivity for this nucleic acid. Complexes 5-7 can interact with the albumin protein with a thermodynamic signature dominated by hydrophobic interactions. Overall, we show that organometallic species based on the Ru2Cp2(CO)x scaffold (x = 2, 3) are active against cancer cells, with different incorporated fragments influencing the interactions with nucleic acids and the production of ROS.

Alkyne-alkenyl coupling at a diruthenium complex.

Dimetallic complexes are suitable platforms for the assembly of small molecular units, and the reactivity of bridging alkenyl ligands has been widely investigated to model C-C bond forming processes. Here, we report the unusual coupling of an alkenyl ligand, bridging coordinated on a diruthenium scaffold, with a series of alkynes, revealing two possible outcomes. The diruthenium complex [Ru2Cp2(Cl)(CO)(µ-CO){µ-η1:η2-C(Ph)CH(Ph)}], 2, was prepared in two steps from [Ru2Cp2(CO)2(µ-CO){µ-η1:η2-C(Ph)CH(Ph)}]BF4, [1]BF4, in 69% yield. Then, the reaction of 2 with C2(CO2Me)2, promoted by AgCF3SO3 in dichloromethane, afforded in 51% yield the complex [Ru2Cp2(CO)2{µ-η3:η2-C(Ph)CH(Ph)C(CO2Me)C(CO2Me)}]CF3SO3, [3]CF3SO3, containing a ruthenacyclopentene-based hydrocarbyl ligand. On the other hand, 2 reacted with other alkynes and AgX salts to give the butadienyl complexes [Ru2Cp2(CO)2{µ-η3:η2-C(R)CH(R')C(Ph)C(Ph)}]X (R = R' = H, [4]BF4; R = R' = Me, [5]CF3SO3; R = R' = Ph, [6]CF3SO3; R = Ph, R' = H, [7]CF3SO3), in 42-56% yields. All products were characterized by IR and NMR spectroscopy, and by single crystal X-ray diffraction in the cases of 2, [3]CF3SO3 and [6]BF4. DFT calculations highlighted the higher stability of [4-7]+-like structures with respect to the corresponding [3]+-like isomers. It is presumable that [3]+-like isomers initially form as kinetic intermediates, then undergo H-migration which is disfavoured in the presence of carboxylato substituents on the alkyne. Such hypothesis was supported by the computational optimization of the transition states for H-migration in the cases of R = R' = H and R = R' = CO2Me.

Course and Lethality of SARS-CoV-2 Epidemic in Nursing Homes after Vaccination in Florence, Italy.

Evidence on the effectiveness of SARS-CoV-2 vaccines in nursing home (NHs) residents is limited. We examined the impact of the BNT162b2 mRNA SARS-CoV-2 vaccine on the course of the epidemic in NHs in the Florence Health District, Italy, before and after vaccination. Moreover, we assessed survival and hospitalization by vaccination status in SARS-CoV-2-positive cases occurring during the post-vaccination period. We calculated the weekly infection rates during the pre-vaccination (1 October-26 December 2020) and post-vaccination period (27 December 2020-31 March 2021). Cox analysis was used to analyze survival by vaccination status. The study involved 3730 residents (mean age 84, 69% female). Weekly infection rates fluctuated during the pre-vaccination period (1.8%-6.5%) and dropped to zero during the post-vaccination period. Nine unvaccinated (UN), 56 partially vaccinated (PV) and 35 fully vaccinated (FV) residents tested SARS-CoV-2+ during the post-vaccination period. FV showed significantly lower hospitalization and mortality rates than PV and UV (hospitalization: FV 3%, PV 14%, UV 33%; mortality: FV 6%, PV 18%, UV 56%). The death risk was 84% and 96% lower in PV (HR 0.157, 95%CI 0.049-0.491) and FV (HR 0.037, 95%CI 0.006-0.223) versus UV. SARS-CoV-2 vaccination was followed by a marked decline in infection rates and was associated with lower morbidity and mortality among infected NH residents.

Caring for nursing home residents with COVID-19: a "hospital-at-nursing home" intermediate care intervention.

BACKGROUND: Nursing home (NH) residents have been dramatically affected by COVID-19, with extremely high rates of hospitalization and mortality. AIMS: To describe the features and impact of an assistance model involving an intermediate care mobile medical specialist team (GIROT, Gruppo Intervento Rapido Ospedale Territorio) aimed at delivering "hospital-at-nursing home" care to NH residents with COVID-19 in Florence, Italy. METHODS: The GIROT activity was set-up during the first wave of the pandemic (W1, March-April 2020) and became a structured healthcare model during the second (W2, October 2020-January 2021). The activity involved (1) infection transmission control among NHs residents and staff, (2) comprehensive geriatric assessment including prognostication and geriatric syndromes management, (3) on-site diagnostic assessment and protocol-based treatment of COVID-19, (4) supply of nursing personnel to understaffed NHs. To estimate the impact of the GIROT intervention, we reported hospitalization and infection lethality rates recorded in SARS-CoV-2-positive NH residents during W1 and W2. RESULTS: The GIROT activity involved 21 NHs (1159 residents) and 43 NHs (2448 residents) during W1 and W2, respectively. The percentage of infected residents was higher in W2 than in W1 (64.5% vs. 38.8%), while both hospitalization and lethality rates significantly decreased in W2 compared to W1 (10.1% vs 58.2% and 23.4% vs 31.1%, respectively). DISCUSSION: Potentiating on-site care in the NHs paralleled a decrease of hospital admissions with no increase of lethality. CONCLUSIONS: An innovative "hospital-at-nursing home" patient-centred care model based on comprehensive geriatric assessment may provide a valuable contribution in fighting COVID-19 in NH residents.

The complex interaction between atrial fibrillation and heart failure in elderly patients.

Heart failure (HF) and atrial fibrillation (AF) often coexist. Subjects with permanent AF show the highest prevalence of HF. Patients with incident AF have HF in a great number of cases and, reciprocally, in patients with incident HF, an AF can be frequently found. The simultaneous presence of the two conditions is associated with mortality rates higher than those observed in individuals with only one or none of them. Interestingly, HF and AF could synergistically promote in elderly patients the development of disability and dementia. Inflammatory mechanisms coupled with changes of renin-angiotensin system, hormonal pathways and neuro-mediators could simultaneously promote left atrium remodeling and sustain both HF and AF. Beta-blockers and digoxin seem to have small therapeutic effect and limited influence on prognosis in these very complex patients. Sinus rhythm restoration could slow down the progression of disability in symptomatic subjects. Recent evidence seem to suggest that upstream therapy coupled with rehabilitation, and that AV node ablation associated with cardiac resynchronization therapy could benefit subjects with HF and AF. In conclusion, elderly patients simultaneously presenting problems of cardiac function and arrhythmia are an important challenge for geriatric medicine, and request important efforts to improve their functional profile and prognosis.

Rate-control vs rhythm-control of atrial fibrillation in elderly patients. From new, age-oriented outcomes to a more complex management strategy.

Atrial fibrillation (AF) is the most frequent arrhythmia in elderly people. Findings derived from clinical trials seem to demonstrate that a rate-control strategy of AF in aged patients improves prognosis if compared to a rhythm-control one. However, epidemiological studies concordantly show that the arrhythmia is associated to increased hospitalization and mortality rates. In last years, the proportion of patients admitted to hospital for AF has progressively increased; this trend is observed in subjects >75 and >85 years, while no change was found in younger cohorts. Importantly, in aged individuals, probably because of the loss of atrial activity, the increase of heart rate and the irregularity of RR intervals, AF begins a vicious cycle, leading from heart failure, through the compromise of functional and neurocognitive status, to overt disability, dementia and increased mortality. Evidence specifically aimed at clarifying the effects of arrhythmia management on outcomes characteristic of aged people is completely lacking. In the elderly, the question regarding the effects of a rate- or a rhythm-control strategy of AF should be considered as an aspect of a more complex strategy, addressed to reduce disability and hospitalizations, and to improve quality of life and survival.

Arterial stiffness and left ventricular performance in elderly patients with persistent atrial fibrillation.

BACKGROUND: The prevalence of atrial fibrillation (AF) and arterial stiffness (AS) increases with age. AIMS: To evaluate if AS is correlated to longitudinal strain (LS), a marker of left ventricular (LV) function, in elderly AF patients with preserved ejection fraction (EF) undergoing external cardioversion. METHODS: AS was measured using the cardio-ankle vascular index (CAVI), LS was calculated from echocardiographic data of three consecutive cardiac cycles. RESULTS: We enrolled 38 patients (age 76 ± 8 years; men 60.5%; EF 65 ± 7%). LS and CAVI were, respectively, - 17.7 ± 3.7% and 9.7 ± 1.3. Multivariate analysis showed that LV performance was inversely related to height (p < 0.001) and to the presence of AF-related symptoms (p = 0.008). LS grew with increasing values of CAVI (p = 0.038). CONCLUSIONS: In elderly AF patients with preserved systolic function, LV performance is directly associated with AS. This link could influence atrium remodeling and the incidence of arrhythmia relapse.

Management and prognosis of atrial fibrillation in diabetic patients: an EORP-AF General Pilot Registry report.

Aims: Diabetes mellitus (DM) is one of the most important cardiovascular risk factors. The aim of this study was to evaluate clinical correlates of DM, including management and outcomes, in the EURObservational Research Programme (EORP)-Atrial Fibrillation (AF) General Pilot (EORP-AF) Registry of the European Society of Cardiology. Methods and results: We studied consecutive patients (N = 3101) enrolled in 70 centres of nine European countries between February 2012 and March 2013, and compared diabetics with non-diabetics during a 1-year follow-up. In the overall cohort, the prevalence of DM was 20.6%. Diabetics were older (71 ± 9 vs. 68 ± 12 years, P < 0.0001) and had more comorbidities, higher CHA2DS2-VASc score (4.6 ± 1.6 vs. 2.9 ± 1.7, P < 0.0001) and higher prevalence of permanent AF (21.5 vs. 16.0%, P = 0.0022). Quality of life amongst DM patients was significantly worse [atrial fibrillation quality of life questionnaire (AF-QoL) score 45.2 ± 19.2 vs. 49.3 ± 20.1, P < 0.0001]. Amongst diabetics, the use of electrical cardioversion (16.2 vs. 24.6%, P < 0.0001) and catheter ablation (3.3 vs. 8.6%, P < 0.0001) was lower, whilst oral anticoagulants were more often prescribed (84.3 vs. 78.9%, P = 0.0027). After one year, diabetic patients had significantly higher all-cause (11.9 vs. 4.9%, P < 0.0001), cardiovascular (6.2 vs. 1.9%, P < 0.0001), and non-cardiovascular mortality (2.3 vs. 1.1%, P = 0.0356). Conclusion: In AF patients, DM is associated with a higher prevalence of comorbidities and a worse quality of life. After one year, all-cause, cardiovascular, and non-cardiovascular mortality were significantly higher in diabetic subjects.

Effects of a new device to guide venous puncture in elderly critically ill patients: results of a pilot randomized study.

BACKGROUND: Novel devices based on the emission of near-infrared electromagnetic radiation (NIR) have been developed to minimize venous puncture failures. These instruments produce an "augmented reality" image, in which subcutaneous veins are depicted on a LCD display. We compared the new technique with standard venipuncture in a population of elderly patients. METHODS: Patients admitted in Intensive Care Unit were randomized to standard or to NIR assisted procedure. RESULTS: In the 103 enrolled patients (age 74 ± 12 years; standard venipuncture-N = 56; NIR-N = 47), no differences were found in procedure length, number of attempts, and referred pain. With NIR there was a lower incidence of hematomas and fewer anxiety and depressive symptoms. CONCLUSIONS: The use of the novel NIR-based device is safer and more psychologically tolerable, and it is not associated to an increase of procedure length or number of attempts.

Atrial fibrillation after electrical cardioversion in elderly patients: a role for arterial stiffness? Results from a preliminary study.

BACKGROUND AND AIMS: Atrial fibrillation (AF) is the most frequent arrhythmia of the elderly, and electrical cardioversion (ECV) is a common procedure, although incidence of recurrences remains high. We evaluated the possible association between arterial stiffness (AS) and the persistence or recurrence of AF in elderly patients after ECV. METHODS: We enrolled all subjects undergoing ECV over a 9-month period. AS was evaluated with the cardio-ankle vascular index (CAVI). Patients were then visited at follow-up (on average at 6 months). RESULTS: Thirty-one patients (age 78 ± 7 years; men 67.7 %; CHA2DS2-VASc 4.1 ± 1.6; AF length >2 months 51.6 %; CAVI 9.9 ± 1.6) underwent ECV. At follow-up, sinus rhythm was recorded in 16 (51.6 %) patients. At multivariate analysis, the presence of AF was directly associated with CHA2DS2-VASc score and CAVI. Amiodarone therapy reduced the risk of relapsed AF. CONCLUSIONS: In elderly AF patients treated with ECV, AS at baseline seems to predict AF at follow-up.

From left bundle branch block to Icelandic whales: the multiple perils of atrial fibrillation management in the elderly.

We present the case of an elderly woman which demonstrates how AF therapy in aged individuals is particularly challenging for the presence of complex conditions. The rhythm- or the rate control strategy must be carefully chosen based on individual risk profile. Oral anticoagulant therapy must be wisely managed to maximize benefits-in terms of stroke and dementia control-and to reduce complications.

Psychological effects of treatment with new oral anticoagulants in elderly patients with atrial fibrillation: a preliminary report.

BACKGROUND AND AIMS: Atrial fibrillation (AF) is the most common arrhythmia in elderly people, yet oral anticoagulation is underused in the aged. We tried to determine whether new oral anticoagulants (NOA) have greater psychological tolerability than warfarin. METHODS: Age-, gender-matched groups of AF patients receiving NOA (N = 15) or warfarin (N = 15) were assessed with the Anti-Clot Treatment Scale (ACTS) and the Perceived Stress Scale (PSS). RESULTS: Patients were old (81 ± 9 years). NOA group showed greater psychological satisfaction, with lower therapy-related burden (ACTS burdens: 16.3 ± 4.5 vs. 32.9 ± 10.2, p < 0.001) and higher awareness of benefits (ACTS benefits: 13.0 ± 1.3 vs. 10.8 ± 1.9, p = 0.001). Even stress was lower (PSS: 13.1 ± 4.0 vs. 17.1 ± 4.2, p = 0.013). The multivariate analysis confirmed these findings, showing that higher levels of anxiety and depression could justify more stress in warfarin patients. CONCLUSIONS: The results of this preliminary study show that NOA have an improved psychological impact compared with warfarin in elderly patients.

Age, left atrial dimension and arterial stiffness after external cardioversion of atrial fibrillation. A vascular component in arrhythmia maintenance? Results from a preliminary study.

BACKGROUND AND AIMS: Atrial fibrillation (AF) is the most frequent arrhythmia in elderly patients. Aims of this study were to evaluate the predictors of arterial stiffness after external cardioversion (ECV) of AF and to establish whether a link exists between vascular properties and left atrial diameter (LAD). METHODS: We studied 33 patients (age 73 ± 12 years). After 5 h from ECV of persistent AF, an echocardiogram was recorded and arterial stiffness was evaluated with cardio-ankle vascular stiffness index (CAVI). RESULTS: In multivariate analysis (R = 0.538, p = 0.006), CAVI (mean 9.60 ± 1.63) increased with age (p = 0.018) and with an AF length ≤3 months (p = 0.022). LAD was significantly related to CAVI (p = 0.007) even after adjustment for interventricular septum thickness (p = 0.018) (R = 0.574, p = 0.002). CONCLUSIONS: In patients with AF, immediately after ECV, arterial stiffness is associated with age and AF length, and could represent an important factor for left atrium remodeling and, therefore, for AF maintenance.