Understanding the use of observational and randomized data in cardiovascular medicine.

The availability of large datasets from multiple sources [e.g. registries, biobanks, electronic health records (EHRs), claims or billing databases, implantable devices, wearable sensors, and mobile apps], coupled with advances in computing and analytic technologies, have provided new opportunities for conducting innovative health research. Equally, improved digital access to health information has facilitated the conduct of efficient randomized controlled trials (RCTs) upon which clinical management decisions can be based, for instance, by permitting the identification of eligible patients for recruitment and/or linkage for follow-up via their EHRs. Given these advances in cardiovascular data science and the complexities they behold, it is important that health professionals have clarity on the appropriate use and interpretation of observational, so-called 'real-world', and randomized data in cardiovascular medicine. The Cardiovascular Roundtable of the European Society of Cardiology (ESC) held a workshop to explore the future of RCTs and the current and emerging opportunities for gathering and exploiting complex observational datasets in cardiovascular research. The aim of this article is to provide a perspective on the appropriate use of randomized and observational data and to outline the ESC plans for supporting the collection and availability of clinical data to monitor and improve the quality of care of patients with cardiovascular disease in Europe and provide an infrastructure for undertaking pragmatic RCTs. Moreover, the ESC continues to campaign for greater engagement amongst regulators, industry, patients, and health professionals in the development and application of a more efficient regulatory framework that is able to take maximal advantage of new opportunities for improving the design and efficiency of observational studies and RCT in patients with cardiovascular disease.

A 30-day preclinical safety evaluation study of recombinant human follicle-stimulating hormone in female rhesus monkeys.

The objective of this study was to identify potential target organs for toxicity of recombinant human follicle stimulating hormone (r-hFSH) in female rhesus monkeys and to establish a no observed adverse effect level (NOAEL). In all, 24 female rhesus monkeys (Chinese origin, weighing 3.4-5.2 kg, approximately 5 years of age) received repeated subcutaneous (sc) r-hFSH at doses of 10, 60, and 300 IU/kg per d or vehicle once daily for 30 days followed by a 15-day recovery period. Endometrial hyperplasia and dermal edema in the external genitals were found in some animals at 300 IU/kg per d. Pharmacologic-related multiple cystic follicles were found in all r-hFSH-treated groups. A weak, anti-FSH antibody response was detected at the end of treatment in animals administered 60 and 300 IU/kg per d. These results indicate that the primary effects of r-hFSH in female rhesus monkeys were related to its pharmacological activity on the reproductive system. The NOAEL was considered to be 60 IU/kg per d.

Species and sex differences in the blood clearance and immunogenicity of PEGylated uricase: A comparative 26-week toxicity study in rats and monkeys.

Low response rates and high immunogenicity were observed after repeated injections of pegloticase (Krystexxa) into gout patients during clinical trials. However, related research had not been reported in preclinical animal experiments, which has limited the development of this drug. In this study, the toxicity of mPEG-UHC was studied in rats and monkeys over a 26-week period of repeated intravenous dosing. There were no obvious toxic reactions in the tested animals, with the exception of mPEG-UHC blood clearance and immunogenicity. After repeated injections of mPEG-UHC, rapid loss of uricolytic activity (RLA) was not detected in rats, whereas RLA was observed in 44.4% of drug-treated monkeys. In these monkeys, RLA was observed in 11.1% of males and 77.8% of females, and such incidences increased with higher dosing. High titres of anti-uricase IgG antibodies were associated with RLA but did not result in any toxicity. Remission and recurrence of RLA occurred in one female monkey in the high-dose group because of suppressed and altered immune responses in this animal. The predicted incidence of RLA after repeated injections of mPEG-UHC in gout patients may be lower than that of pegloticase. In this study, the no-observed-adverse-effect levels (NOAELs) of mPEG-UHC in rats and monkeys were 32.0 mg/kg and 20.0 mg/kg, respectively. Therefore, the results showed that rats and monkeys could tolerate long-term and high-dose administrations of mPEG-UHC, and mPEG-UHC blood clearance and immunogenicity showed obvious species and sex differences. These findings will provide valuable information to direct the clinical use of mPEG-UHC.

[Pharmacokinetics of rhGH decorated by polyethylene glycol in rat in vivo].

To study the pharmacokinetics of rhGH decorated by polyethylene glycol (PEG-rhGH) after sc administration in rat, serum PEG-rhGH concentrations were measured by 125I labeled method after sc in rat, the pharmacokinetic model and parameters were fitted and calculated by the 3P97 program. After sc injection at doses of 150, 300, and 600 microg x kg(-1) in rat, the serum PEG-rhGH concentration-time curves were fitted to a one-compartment model. The rhGH decorated by polyethylene glycol could prolong the action duration of rhGH in vivo, and reach the goal of long-action.

Super-resolution architecture of mammalian centriole distal appendages reveals distinct blade and matrix functional components.

Distal appendages (DAPs) are nanoscale, pinwheel-like structures protruding from the distal end of the centriole that mediate membrane docking during ciliogenesis, marking the cilia base around the ciliary gate. Here we determine a super-resolved multiplex of 16 centriole-distal-end components. Surprisingly, rather than pinwheels, intact DAPs exhibit a cone-shaped architecture with components filling the space between each pinwheel blade, a new structural element we term the distal appendage matrix (DAM). Specifically, CEP83, CEP89, SCLT1, and CEP164 form the backbone of pinwheel blades, with CEP83 confined at the root and CEP164 extending to the tip near the membrane-docking site. By contrast, FBF1 marks the distal end of the DAM near the ciliary membrane. Strikingly, unlike CEP164, which is essential for ciliogenesis, FBF1 is required for ciliary gating of transmembrane proteins, revealing DAPs as an essential component of the ciliary gate. Our findings redefine both the structure and function of DAPs.

[Efficacy of once-per-cycle administration pegylated recombinant human granulocyte colony-stimulating factor in chemotherapy-induced neutropenia in a phase I trial].

OBJECTIVE: To explore the efficacy of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in the prophylaxis of chemotherapy-induced neutropenia. METHODS: Patients with previously untreated non-small cell lung cancer or breast cancer and with normal bone marrow function were eligible for the trial. In the phase I trial, patients were to treated with two cycles of paclitaxel/carboplatin chemotherapy every 21 days. In cycle 1, if absolute neutrophil count (ANC) dropped below 1.0 x 10(9)/ L with fever and/or ANC dropped below 0.5 x 10(9)/L, rhG-CSF 150 microg/d was administrated until WBC > or = 10 x 10(9)/L or ANC > or = 5.0 x 10(9)/L. In cycle 2, patients were to receive a single injection of PEG-rhG-CSF (30, 60, 100, or 200 microg/kg) 48 hours after chemotherapy. Pharmacodynamic analyses were performed. RESULTS: All the 16 patients enrolled (4 in each group) were eligible for efficacy evaluation. In cycle 1, 7 patients received rhG-CSF administration because of grade 4 neutropenia, while in cycle 2, there was only 1 episode of grade 4 neutropenia, which were in the 30 microg/kg group. In cycle 1, the mean ANC nadir of 1.37 x 10(9)/L occurred on day 13 in the 9 patients who received no rhG-CSF administration. In cycle 2, the mean ANC nadirs were 0.77 x 10(9)/L, 4.54 x 10(9)/L, 3.00 x 10(9)/L, and 5.56 x 10(9)/L, respectively, in 30, 60, 100, or 200 microg/kg group. The nadirs of the first two groups occurred on day 8 of cycle 2, while those of the other two groups appeared on day 7. After PEG-rhG-CSF administration, two mean ANC peaks were observed. The first one ranging from 20.87 x 10(9)/L to 33.61 x 10(9)/L in the 4 groups appeared on day 3 to day 4. In the 30 microg/ kg group, the mean ANC reached the second peak at 5.03 x 10(9)/L on day 14. The second peaks on day 10 in the other groups were 12.42 x 10(9)/L, 11.59 x 10(9)/L, and 18.92 x 10(9)/L, respectively. Pharmacodynamic analyses showed sustained serum concentrations of PEG-rhG-CSF during the period of neutropenia. CONCLUSIONS: PEG-rhG-CSF administration may decrease the incidence of grade 4 neutopenia and result in earlier and higher nadir ANCs. PEG-rhG-CSF has a potential of once-per-cycle administration. The ANC and serum concentration of PEG-rhG-CSF are consistent with neutrophil receptor-mediated clearance.