Clinical impact of high platelet reactivity in patients with atrial fibrillation and concomitant percutaneous coronary intervention on dual or triple antithrombotic therapy.

High platelet reactivity (HPR) on clopidogrel is an established thrombotic risk factor after percutaneous coronary intervention (PCI). The introduction of more potent antiplatelet drugs has partially surpassed this issue. However, in the setting of concomitant atrial fibrillation (AF) and PCI clopidogrel is still the most adopted P2Y12 inhibitor. In the present study all consecutive patients with history of AF discharged from our cardiology ward with dual (DAT) or triple (TAT) antithrombotic therapy after a PCI from April 2018 to March 2021 were enrolled in an observational registry. For all subjects, blood serum samples were collected and tested for platelet reactivity by arachidonic acid and ADP (VerifyNow system) and genotyping of the CYP2C19*2 loss-of-function polymorphism. We recorded at 3 and 12-months follow-up: (1) major adverse cardiac and cerebrovascular events (MACCE), (2) major hemorrhagic or clinically relevant non-major bleeding and (3) all-cause mortality. A total of 147 patients were included (91, 62% on TAT). In 93.4% of patients, clopidogrel was chosen as P2Y12 inhibitor. P2Y12 dependent HPR resulted an independent predictor of MACCE both at 3 and 12 months (HR 2.93, 95% C.I. 1.03 to 7.56, p = 0.027 and HR 1.67, 95% C.I. 1.20 to 2.34, p = 0.003, respectively). At 3-months follow-up the presence of CYP2C19*2 polymorphism was independently associated with MACCE (HR 5.21, 95% C.I. 1.03 to 26.28, p = 0.045). In conclusion, in a real-world unselected population on TAT or DAT, the entity of platelet inhibition on P2Y12 inhibitor is a potent predictor of thrombotic risk, suggesting the clinical utility of this laboratory evaluation for a tailored antithrombotic therapy in this high-risk clinical scenario. The present analysis was performed in patients with AF undergoing PCI on dual or triple antithrombotic therapy. At 1 year follow-up MACCE incidence was consistent, and it was not different in different antithrombotic pattern groups. P2Y12 dependent HPR was a potent independent predictor of MACCE both at 3- and 12-months follow-up. In the first 3 months after stenting the carriage of CYP2C19*2 allele was similarly associated with MACCE. Abbreviation: DAT, dual antithrombotic therapy; HPR, high platelet reactivity; MACCE, major adverse cardiac and cerebrovascular events; PRU, P2Y12 reactive unit; TAT, triple antithrombotic therapy. Created with BioRender.com.

Magnetization Process of Atacamite: A Case of Weakly Coupled S=1/2 Sawtooth Chains.

We present a combined experimental and theoretical study of the mineral atacamite Cu_{2}Cl(OH)_{3}. Density-functional theory yields a Hamiltonian describing anisotropic sawtooth chains with weak 3D connections. Experimentally, we fully characterize the antiferromagnetically ordered state. Magnetic order shows a complex evolution with the magnetic field, while, starting at 31.5 T, we observe a plateaulike magnetization at about M_{sat}/2. Based on complementary theoretical approaches, we show that the latter is unrelated to the known magnetization plateau of a sawtooth chain. Instead, we provide evidence that the magnetization process in atacamite is a field-driven canting of a 3D network of weakly coupled sawtooth chains that form giant moments.

Thermodynamic Perspective on Field-Induced Behavior of α-RuCl_{3}.

Measurements of the magnetic Grüneisen parameter (Γ_{B}) and specific heat on the Kitaev material candidate α-RuCl_{3} are used to access in-plane field and temperature dependence of the entropy up to 12 T and down to 1 K. No signatures corresponding to phase transitions are detected beyond the boundary of the magnetically ordered region, but only a shoulderlike anomaly in Γ_{B}, involving an entropy increment as small as 10^{-5}Rlog2. These observations put into question the presence of a phase transition between the purported quantum spin liquid and the field-polarized state of α-RuCl_{3}. We show theoretically that at low temperatures Γ_{B} is sensitive to crossings in the lowest excitations within gapped phases, and identify the measured shoulderlike anomaly as being of such origin. Exact diagonalization calculations demonstrate that the shoulderlike anomaly can be reproduced in extended Kitaev models that gain proximity to an additional phase at finite field without entering it. We discuss manifestations of this proximity in other measurements.

Pregnancy in CADASIL.

OBJECTIVES: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral small vessel disease caused by NOTCH3 gene mutations. CADASIL women are frequently considered at high risk of systemic vascular events during pregnancy and often prescribed with antithrombotic drugs. This decision is not evidence-based considering the lack of data about pregnancy outcome in CADASIL. We describe our experience on pregnancy in CADASIL patients. MATERIALS AND METHODS: We reviewed records of 50 CADASIL females followed in our center, and we collected prospective information in six patients for a total of 93 pregnancies. RESULTS: No woman had the disease onset or suffered from cerebral vascular ischemic events during pregnancy. Sixteen miscarriages (17.2%) were recorded. There were 72 vaginal births, and five cesarean sections. Considering the six patients followed prospectively (for a total of eight pregnancies), data on fetal growth and newborns weight were in line with those from the general population. Considering gestational complications, we recorded mild proteinuria without hypertension in one patient and hyperinsulinemia and pre-eclampsia in another affected by a known nephropathy. Antithrombotic drugs were used in three patients, in one for an unrelated coexisting prothrombotic condition. CONCLUSIONS: CADASIL does not seem to be associated with an unfavorable outcome of pregnancy either for women and fetuses. Patients and treating physicians should be reassured that pregnancy can be safely initiated in CADASIL, as there is no evidence to support a specific preventive antithrombotic treatment during pregnancy in CADASIL. Larger studies are needed to definitively confirm these conclusions.

Microscopic origin of the charge transfer in single crystals based on thiophene derivatives: A combined NEXAFS and density functional theory approach.

We have investigated the charge transfer mechanism in single crystals of DTBDT-TCNQ and DTBDT-F4TCNQ (where DTBDT is dithieno[2,3-d;2',3'-d'] benzo[1,2-b;4,5-b']dithiophene) using a combination of near-edge X-ray absorption spectroscopy (NEXAFS) and density functional theory calculations (DFT) including final state effects beyond the sudden state approximation. In particular, we find that a description that considers the partial screening of the electron-hole Coulomb correlation on a static level as well as the rearrangement of electronic density shows excellent agreement with experiment and allows to uncover the details of the charge transfer mechanism in DTBDT-TCNQ and DTBDT-F4 TCNQ, as well as a reinterpretation of previous NEXAFS data on pure TCNQ. Finally, we further show that almost the same quality of agreement between theoretical results and experiment is obtained by the much faster Z+1/2 approximation, where the core hole effects are simulated by replacing N or F with atomic number Z with the neighboring atom with atomic number Z+1/2.

Artificial atoms based on correlated materials.

Low-dimensional electron systems fabricated from quantum matter have in recent years become available and are being explored with great intensity. This article gives an overview of the fundamental properties of such systems and summarizes the state of the field. We furthermore present and consider the concept of artificial atoms fabricated from quantum materials, anticipating remarkable scientific advances and possibly important applications of this new field of research. The surprising properties of these artificial atoms and of molecules or even of solids assembled from them are presented and discussed.

Clinical, familial, and neuroimaging features of CADASIL-like patients.

OBJECTIVES: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused by NOTCH3 mutations. There are no clinical and neuroimaging findings pathognomonic of the disease. The aim of this paper was to provide a description of a group of NOTCH3-negative patients with a phenotype closely resembling that of CADASIL. MATERIALS AND METHODS: We performed NOTCH3 analysis (exons 2-23) in 117 probands because of a clinician's suspicion of CADASIL. The CADASIL scale, a recently developed tool that allows to better select patients for NOTCH3 analysis, was retrospectively applied to NOTCH3-negative patients; the patient subgroup that scored higher than the screening cutoff for CADASIL was defined as CADASIL-like. RESULTS: Thirty-four CADASIL-like patients (mean age at onset 57.8 years [52.1-63.4], 50% males) were identified. Compared with 25 patients with CADASIL for clinical, familial, and neuroimaging features, only the following variables were significantly (α level <0.05) different in frequency between patients with CADASIL and CADASIL-like patients: a positive family history for stroke at age ≤ 60 years, more frequent in patients with CADASIL, and hypertension, more frequent in CADASIL-like patients. CONCLUSIONS: Our experience highlights the growing number of patients presenting with a high suspicion of a cerebral small vessel disease with an autosomal dominant pattern of inheritance and a phenotype closely similar to that of CADASIL but without NOTCH3 mutations. This group remains to be characterized from the genetic point of view. The role of other genes or NOTCH3 alterations on exons other than 2-23 or introns has to be further assessed.

Mild cognitive impairment etiologic subtyping using pragmatic and conventional criteria: preliminary experience in the Florence VAS-COG clinic.

BACKGROUND: Mild cognitive impairment (MCI) is an abnormal condition defined by the presence of cognitive decline not severe enough to fit dementia criteria. According to Winblad et al.'s criteria, the clinical distinction of MCI subtypes (amnestic/non-amnestic, single/multiple domain) is based on the cognitive profiling (conventional diagnosis) and infers possible different MCI etiologies. MCI prodromic of vascular dementia (Vasc-MCI) is thought to be characterized by a multiple domain profile. In our outpatient clinic (the "Florence VAS-COG clinic"), the diagnosis of MCI and of its different subtypes (vascular, degenerative, mixed) is based on a comprehensive evaluation of clinical and neuroimaging features (pragmatic diagnosis). AIMS: To compare the pragmatic and conventional diagnoses in terms of etiologic subtyping of MCI. METHODS: We retrospectively assessed the agreement between the two diagnoses in 30 MCI patients. Agreement was considered present when degenerative MCI was of the amnestic type (single or multiple domain) and Vasc-MCI was of the multiple domain type (amnestic or non-amnestic MCI). RESULTS: In 15/30 (50 %) patients, the diagnoses were in disagreement: 5/9 (56 %) patients diagnosed with a degenerative MCI type presented a non-amnestic cognitive profile (4 single domain and 1 multiple domain); 10/21 (48 %) Vasc-MCI were classified as non-amnestic single domain. CONCLUSIONS: The application of MCI etiologic subtyping using pragmatic or conventional diagnoses leads to different results. In our setting, not all the Vasc-MCI patients have a multiple domain profile. Our preliminary study suggests that the cognitive profile of Vasc-MCI is more heterogeneous than previously suggested.

Evidence of a field-induced Berezinskii-Kosterlitz-Thouless scenario in a two-dimensional spin-dimer system.

Two-dimensional (2D) systems with continuous symmetry lack conventional long-range order because of thermal fluctuations. Instead, as pointed out by Berezinskii, Kosterlitz and Thouless (BKT), 2D systems may exhibit so-called topological order driven by the binding of vortex-antivortex pairs. Signatures of the BKT mechanism have been observed in thin films, specially designed heterostructures, layered magnets and trapped atomic gases. Here we report on an alternative approach for studying BKT physics by using a chemically constructed multilayer magnet. The novelty of this approach is to use molecular-based pairs of spin S=½ ions, which, by the application of a magnetic field, provide a gas of magnetic excitations. On the basis of measurements of the magnetic susceptibility and specific heat on a so-designed material, combined with density functional theory and quantum Monte Carlo calculations, we conclude that these excitations have a distinct 2D character, consistent with a BKT scenario, implying the emergence of vortices and antivortices.

tst1-positive ST22-MRSA-IVa in healthy Italian preschool children.

A survey was performed in May 2013 to assess methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization in healthy children attending 26 municipal daycare centres in Palermo, Italy. Of the 500 children, ten (2 %) tested positive. Eight MRSA isolates were tst1-positive ST22-MRSA-IVa, spa t223; the other two isolates were identified as ST1-IVa and ST398-V, respectively. tst1-positive ST22-MRSA, spa t223 has been previously identified only in the Middle Eastern area.

Influence of vascular risk factors and neuropsychological profile on functional performances in CADASIL: results from the MIcrovascular LEukoencephalopathy Study (MILES).

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral small vessel disease that may lead to disability and whose phenotype modulators are still unknown. METHODS: In the MIcrovascular LEukoencephalopathy Study (MILES), we assessed the influence of vascular risk factors and the effect of different cognitive domains (memory, psychomotor speed and executive functions) performances on functional abilities in CADASIL in comparison with age-related leukoencephalopathy (ARL). RESULTS: We evaluated 51 CADASIL patients (mean age 50.3 ± 13.8 years, 47.1% males) and 68 ARL patients (70.6 ± 7.4 years, 58.8% males). Considering vascular risk factors, after adjustment for age, CADASIL patients had higher mean BMI values than ARL patients. Stroke history frequency was similar in the two groups. After adjustment for age, more CADASIL patients were disabled (impaired on ≥ 2 items of the Instrumental Activities of Daily Living scale) in comparison with ARL patients, and CADASIL patients had worse functional performances evaluated with the Disability Assessment for Dementia (DAD) scale. In CADASIL patients, hypertension was related to both DAD score and disability. The cognitive profile of CADASIL and ARL patients was similar, but on a stepwise linear regression analysis functional performances were mainly associated with the memory index (ß = -0.418, P < 0.003) in CADASIL patients and the executive function index (ß = -0.321, P = 0.028) in ARL. CONCLUSIONS: This study suggests that hypertension may contribute to functional impairment in CADASIL and that memory impairment has a large influence on functional decline in contrast with that observed in a sample of subjects with ARL.

Major depression and bipolar disorders in CADASIL: a study using the DSM-IV semi-structured interview.

OBJECTIVE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral microangiopathy characterized by migraine, cerebrovascular events, and cognitive impairment. Although recognized as a cardinal feature of the disease, psychiatric disturbances have rarely been the object of focused studies. We performed a structured evaluation of mood disorders in CADASIL. MATERIALS AND METHODS: Twenty-three patients with CADASIL (five men and 18 women) were assessed by psychiatrists using the Structured Clinical Interview for the DSM-IV, clinician version. For the quantitative assessment of current mood disorder symptoms, the Hamilton Rating Scale for Depression (HRSD) and the Young Mania Rating Scale (YMRS) were used. RESULTS: A lifetime depressive episode was recorded in 17/23 (73.9%) patients with CADASIL. Six (26.1%) patients with CADASIL reported a current depressive episode. A diagnosis of manic lifetime episode was made in 6 (26.1%) patients with CADASIL. The HRSD mean score in patients with current depression was 9.1 ± SD 8.1. The YMRS mean score was 14.2 ± SD 4.1 for manic CADASIL. CONCLUSION: This study confirms that mood disorders are frequent in CADASIL. The use of a structured psychiatric interview outlines a frequency of depression higher than that previously reported but also reveals a considerable frequency of bipolar disorders. If confirmed in larger series, these data suggest that a greater attention should be paid to the psychiatric aspects in CADASIL.

Delayed-type hypersensitivity in classic Kaposi sarcoma patients and controls.

BACKGROUND: Immune perturbation likely affects the development of Kaposi sarcoma (KS) among people infected with the KS-associated herpesvirus (KSHV). We tested whether KSHV-seropositive individuals or cases of classic KS (cKS), which typically originates in the leg, had differing delayed-type hypersensitivity (DTH) in the forearm or leg. METHODS: Mantoux DTH with three antigens (Candida, tetanus, PPD) was performed on the forearm and leg of 15 cKS cases, 14 KSHV-positives without KS, and 15 KSHV-negative controls. The diameters of induration responses were compared by group and body site. RESULTS: Leg DTH was greater than forearm DTH among controls (mean difference 5.6 mm, P=0.0004), whereas this was not observed in cKS cases (-2.2 mm, P=0.32) or KSHV-positives (0.5 mm, P=0.56). Leg-minus-forearm DTH difference was greater in controls compared with cKS cases (P=0.004) and KSHV-positives (P=0.002). Leg-plus-forearm DTH was similar in controls (mean 28.2 mm) and cKS cases (24.5 mm, P=0.60), but it was reduced in KSHV-positives (11.8 mm, P=0.02), particularly in the leg (P=0.004) and marginally in the forearm (P=0.07). CONCLUSION: KS cases had weaker DTH only in the leg, whereas both body sites appeared weaker in KSHV-positives without KS. Both systemic and regional immune alterations may influence the development of this malignancy.

The speed of sound correlates with implant insertion torque in rabbit bone: an in vitro experiment.

OBJECTIVES: This study investigated the correlation of quantitative ultrasound with bone quality as evaluable from implant final insertion torque. MATERIAL AND METHODS: Implants were planned at diaphyses (group 1) and epiphyses (group 2) of 16 rabbit femurs where amplitude-dependent speed of sound (Ad-SOS) was measured. The insertion torque from 7-mm-long implants placed at planned sites was recorded. The correlation between cutting torque and Ad-SOS was evaluated using Spearman's coefficient. RESULTS: Statistics were based on data from 15 diaphyses and 13 epiphyses. The mean insertion torque was 8.8 N cm while the mean Ad-SOS was 1710.9 m/s. A negative correlation resulted between insertion torque and Ad-SOS. CONCLUSIONS: In the rabbit bone model investigated, quantitative ultrasound correlates inversely with implant insertion torque. Although this correlation remains to be verified in humans because rabbit femur does not convincingly represents different human bone qualities, it seems that ultrasound could convey potentially useful, pre-surgical, site-specific, non-invasive information on bone mechanical characteristics therefore deserving further research efforts.

Upward oriented sellar spine. MRI findings. A case report.

The sellar spine is a rare congenital malformation due to the persistence of a notochord rest within the fetal sella turcica. We describe a unique case of a sellar spine vertically oriented displacing the pituitary stalk upwards and forwards. The MRI findings are briefly discussed.

Time course of serum collagen types I and III metabolism products after reperfused acute myocardial infarction in patients with and without systemic hypertension.

We examined 55 consecutive patients successfully treated with primary percutaneous coronary intervention (PCI) for a first acute myocardial infarction with left ventricular (LV) systolic dysfunction. In all patients we performed echocardiographic examination, dosage of plasma brain natriuretic peptide, serum carboxy-terminal propeptide and telopeptide of procollagen type I and amino-terminal propeptide of procollagen type III at days 1 and 3, and at 1 and 6 months after index infarction. The hypertensive patients (group 1; n=30) differed for higher baseline blood pressure (133+/-4 mm Hg vs 118+/-4 mm Hg; P=0.03), greater LV mass index (108+/-5 vs 94+/-4 g m(-2), P=0.03) and lower mitral E/A wave peak (0.8+/-0.06 vs 1.1+/-0.12, P=0.02) with respect to non-hypertensive patients (group 2; n=25). From day 1 to month 6 carboxy-terminal propeptide of procollagen type I and amino-terminal propeptide of procollagen type III increased (P<0.005 and P<0.05, respectively) in both groups, whereas carboxy-terminal telopeptide of procollagen type I increased from day 1 to day 3 (P<0.01 in both groups, respectively) and then decreased from day 3 to month 6 (P<0.01 and P<0.05 in both groups, respectively). From day 1, brain natriuretic peptide decreased in both groups (P<0.005). There was no significant difference between the two groups in values of procollagens and natriuretic peptide. Finally, LV diastolic volume and function at 6 months were similar in the two groups. Thus, in patients with reperfused acute myocardial infarction and LV dysfunction, antecedent hypertension was not associated with a different pattern of serum procollagen release and ventricular remodelling at 6 months of follow-up.

Psychiatric disturbances in CADASIL: a brief review.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease, clinically characterized by a variable combination of migraine, recurrent transient ischemic attack (TIA) or lacunar strokes, cognitive decline, and mood disturbances. However, the assessment of psychiatric disturbances in this disease has never been carried out systematically. METHODS: This paper presents a brief review of the literature regarding the occurrence of psychiatric disorders in CADASIL patients. RESULTS: The prevalence of psychiatric disorders in CADASIL patients is reported to range from 20% to 41%. The psychiatric disturbances reported with the highest frequency are mood disturbances (9-41%). Pooling together the studies and considering a total of 454 CADASIL patients reported in the literature, 106 of these were affected by mood disturbances (24%). The majority of studies however did not use any defined criteria to assess the presence of psychiatric disorders and diagnoses were mainly based on history or review of clinical records. CONCLUSIONS: The review of CADASIL literature suggests the need for a more structured approach to the investigation of these disturbances that are highly prevalent and may greatly impact quality of life in these patients.

Tumour-released exosomes and their implications in cancer immunity.

Tumour cells release vesicular structures, defined as microvesicles or exosomes, carrying a large array of proteins from their originating cell. The expression of antigenic molecules recognized by T cells has originally suggested a role for these organelles as a cell-free antigen source for anticancer vaccines. However, recent evidence shows that tumour exosomes may also exert a broad array of detrimental effects on the immune system, ranging from apoptosis in activated antitumour T cells to impairment of monocyte differentiation into dendritic cells and induction of myeloid suppressive cells. Immunosuppressive exosomes of tumour origin can be found in neoplastic lesions and sera from cancer patients, implying a potential role of this pathway in in vivo tumour progression. Through the expression of molecules involved in angiogenesis promotion, stromal remodelling, delivery of signalling pathways through growth factor/receptor transfer, chemoresistance and genetic intercellular exchange, tumour exosomes could represent a versatile tool for moulding host environment. Hence, their secretion by neoplastic cells may in the future become a novel pathway to target for therapeutic intervention in cancer patients.

Effects of two energy scales in weakly dimerized antiferromagnetic quantum spin chains.

By means of thermal expansion and specific heat measurements on the high-pressure phase of (VO)(2)P(2)O(7), the effects of two energy scales of the weakly dimerized antiferromagnetic S=1/2 Heisenberg chain are explored. The low-energy scale, given by the spin gap Delta, is found to manifest itself in a pronounced thermal expansion anomaly. A quantitative analysis, employing the density-matrix renormalization-group approach for transfer matrices calculations, shows that this feature originates from changes in the magnetic entropy with respect to Delta, partial differentialS(m)/partial differentialDelta. This term, inaccessible by specific heat, is visible only in the weak-dimerization limit, where it reflects peculiarities of the excitation spectrum and its sensitivity to variations in Delta.