Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Dioxygen Reactivity of Copper(I) Complexes with Tetradentate Tripodal Ligands Having Aliphatic Nitrogen Donors: Synthesis, Structures, and Properties of Peroxo and Superoxo Complexes

Oxygenation of copper(I) with tetradentate tripodal ligands (L) comprised of a tris(aminoethyl)amine (tren) skeleton having sterically bulky substituent(s) on the terminal nitrogens has been investigated, where L = tris(N-benzylaminoethyl)amine (LH,Bn), tris(N-benzyl-N-methylaminoethyl)amine (LMe,Bn), or tris(N,N-dimethylaminoethyl)amine (LMe,Me). All the copper(I) complexes reacted with dioxygen at low temperatures to produce superoxocopper(II) and/or trans-(μ-1,2-peroxo)-dicopper(II) complexes depending on the steric bulkiness of the terminal nitrogens and the reaction conditions. The reaction of a copper(I) complex [Cu(LH,Bn)]+ at −90 °C in acetone resulted in the formation of a superoxo complex [Cu(LH,Bn)(O2)]+ as a less stable species and a peroxo complex [{Cu(LH,Bn)}2(O2)]2+ as a stable species. The structures of [Cu(LH,Bn)]ClO4 and [{Cu(LH,Bn)}2(O2)](BPh4)2·8(CH3)2CO were determined by X-ray crystallography. [{Cu(LH,Bn)}2(O2)]2+ has a trans-(μ-1,2-peroxo)-dicopper(II) core with a trigonal bipyramidal structure. The O–O bond distance is 1.450(5) Å with an intermetallic Cu···Cu separation of 4.476(2) Å. The resonance Raman spectrum of [{Cu(LH,Bn)}2(O2)]2+ measured at −90 °C in acetone-d6 showed a broad ν(O–O) band at 837–834 cm−1 (788 cm−1 for an 18O labeled sample) and two ν(Cu–O) bands at 556 and 539 cm−1, suggesting the presence of two peroxo species in solution. [Cu(LMe,Bn)]+ also produced both superoxo and trans-μ-1,2-peroxo species, [Cu(LMe,Bn)(O2)]+ and [{Cu(LMe,Bn)}2(O2)]2+. At a lower concentration of [Cu(LMe,Bn)]+ (∼0.24 mM) and higher dioxygen concentration (P(O2) = ∼1 atm), the superoxo species is predominantly formed, whereas at a higher concentration of [Cu(LMe,Bn)]+ (∼1 mM) and lower dioxygen concentration (P(O2) = ∼0.02 atm) the formation of the peroxo species is observed. The resonance Raman spectrum of [Cu(LMe,Bn)(O2)]+ (∼1 mM) in acetone-d6 at ∼−95 °C exhibited a ν(O–O) band at 1120 cm−1 (1059 cm−1 for an 18O labeled sample) and that of [{Cu(LMe,Bn)}2(O2)]2+ (∼3 mM) in acetone-d6 at ∼−90 °C showed two ν(O–O) bands at 812 and 797 cm−1 (767 and 753 cm−1 for an 18O labeled sample), respectively. A similar observation was also made for [{Cu(LMe,Me)}2(O2)]2+. Relationships between the energies of the LMCT and d–d transitions and those of the ν(O–O) and ν(Cu–O) stretching vibrations and the steric constraints in the Cu(II)–(O22−)–Cu(II) core are discussed

Effect of Progranulin on Proliferation and Differentiation of Neural Stem/Progenitor Cells after Oxygen/Glucose Deprivation

We previously demonstrated that sivelestat, a selective neutrophil elastase inhibitor, attenuates the cleavage of progranulin (PGRN) and ischemia-induced cell injury in the brain. To obtain further insight into the role of PGRN, in the present study we evaluated the direct effects of sivelestat and recombinant PGRN (rPGRN) on the proliferation and differentiation of neural stem cells in cultures of neural stem/progenitor cells (NS/PC) under the ischemic condition in vitro. We demonstrated that oxygen/glucose deprivation (OGD)-induced cell proliferation of NS/PC was increased by rPGRN treatment. In addition, this increase was accompanied by increased phosphorylation of Akt and GSK-3&beta; (Ser9) after OGD. But none of these responses occurred by treatment with sivelestat. Therefore, activation of the Akt/GSK-3&beta; pathway could well be involved in this proliferative effect of rPGRN. Although OGD and reoxygenation-induced changes in the differentiation of NS/PC into neurons or astrocytes was not affected by treatment with rPGRN or sivelestat, it is noteworthy that rPGRN enhanced neurite outgrowth of &beta;3-tubulin-positive neurons that had differentiated from the NS/PC. These findings suggest that enhancement of proliferation of endogenous NS/PC and neurite outgrowth of differentiated neurons from NS/PC by PGRN could be useful for a new therapeutic approach for cerebral ischemia

PGC-1α and FOXO1 mRNA levels and fiber characteristics of the soleus and plantaris muscles in rats after hindlimb unloading

Fifteen-week-old rats were subjected to unloading induced by hindlimb suspension for 3 weeks. The peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and forkhead box-containing protein O1 (FOXO1) mRNA levels and fiber profiles of the soleus and plantaris muscles in rats subjected to unloading (unloaded group) were determined and compared with those of age-matched control rats (control group). The body weight and both the soleus and plantaris muscle weights were lower in the unloaded group than in the control group. The PGC-1α mRNA was downregulated in the soleus, but not in the plantaris muscle of the unloaded group. The FOXO1 mRNA was upregulated in both the soleus and plantaris muscles of the unloaded group. The oxidative enzyme activity was reduced in the soleus, but not in the plantaris muscle of the unloaded group. The percentage of type I fibers was decreased and the percentages of type IIA and IIC fibers were increased in the soleus muscle of the unloaded group, whereas there was no change in fiber type distribution in the plantaris muscle of the unloaded group. Atrophy of all types of fibers was observed in both the soleus and plantaris muscles of the unloaded group. We conclude that decreased oxidative capacity and fiber atrophy in unloaded skeletal muscles are associated with decreased PGC-1α and increased FOXO1 mRNA levels