Introduction
Combination antihypertensive therapy is required by most patients to achieve guideline-recommended blood pressure (BP) goals. This study assessed the effectiveness and tolerability of ...bisoprolol/perindopril (Bis/Per) single-pill combination (SPC) in Russian patients with hypertension and coronary artery disease (CAD) treated in routine clinical practice.
Methods
STYLE (NCT03730116) was an open-label, uncontrolled, prospective observational study conducted in patients who were already receiving Bis/Per SPC, switched to SPC from Bis or Per monotherapy, or switched from a free combination of Bis and Per. Primary endpoint criteria were assessed at 1 and 3 months and included change in mean office systolic/diastolic blood pressure (SBP/DBP), proportion achieving target BP (< 140/90 mmHg), and measures of antianginal effectiveness.
Results
The full analysis set comprised 1892 subjects. Mean age was 61.9 ± 8.8 years, 53.2% were women, and mean durations of hypertension and CAD were 12.5 ± 7.9 and 7.2 ± 6.4 years, respectively. Mean SBP/DBP decreased by 22.3/11.0 mmHg and 31.5/15.9 mmHg at 1 and 3 months, respectively (
P
< 0.0001 vs baseline). Target BP was achieved by 49.2% and 86.7% of patients at 1 and 3 months, respectively. Reductions in mean number of angina attacks and nitrate consumption and improvements in heart rate were statistically significant. Treatment was well tolerated.
Conclusion
Treatment of patients with hypertension and CAD with Bis/Per SPC for 3 months was associated with significant decreases in SBP/DBP and a high proportion of patients achieving BP treatment goals. This was accompanied by an improvement in angina symptoms. Treatment was well tolerated in a broad patient population representative of those seen in everyday clinical practice.
Infographic
Purpose
To identify demographic, (bio)physical, behavioral, and psychological determinants of successful lifestyle change and program completion by performing a secondary analysis of the intervention ...arm of a randomized-controlled trial, investigating a preconception lifestyle intervention.
Methods
The 6-month lifestyle intervention consisted of dietary counseling, physical activity, and behavioral modification, and was aimed at 5–10% weight loss. We operationalized successful lifestyle change as successful weight loss (≥ 5% weight/BMI ≤ 29 kg/m
2
), weight loss in kilograms, a reduction in energy intake, and an increase in physical activity during the intervention program. We performed logistic and mixed-effect regression analyses to identify baseline factors that were associated with successful change or program completion.
Results
Women with higher external eating behavior scores had higher odds of successful weight loss (OR 1.10, 95% CI 1.05–1.16). Women with the previous dietetic support lost 0.94 kg less during the intervention period (95% CI 0.01–1.87 kg). Women with higher self-efficacy reduced energy intake more than women with lower self-efficacy (
p
< 0.01). Women with an older partner had an increased energy intake (6 kcal/year older, 95% CI 3–13). A high stage of change towards physical activity was associated with a higher number of daily steps (
p
= 0.03). A high stage of change towards weight loss was associated with completion of the intervention (
p
= 0.04).
Conclusions
Determinants of lifestyle change and program completion were: higher external eating behavior, not having received previous dietetic support, high stage of change. This knowledge can be used to identify women likely to benefit from lifestyle interventions and develop new interventions for women requiring alternative support.
Trial registration
The LIFEstyle study was registered at the Dutch trial registry (NTR 1530;
http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1530
).
Do age, ovulatory status, severity of obesity and body fat distribution affect the effectiveness of lifestyle intervention in obese infertile women?
We did not identify a subgroup in which lifestyle ...intervention increased the healthy live birth rate however it did increase the natural conception rate in anovulatory obese infertile women.
Obese women are at increased risk of infertility and are less likely to conceive after infertility treatment. We previously demonstrated that a 6-month lifestyle intervention preceding infertility treatment did not increase the rate of healthy live births (vaginal live birth of a healthy singleton at term) within 24 months of follow-up as compared to prompt infertility treatment in obese infertile women. Natural conceptions occurred more frequently in women who received a 6-month lifestyle intervention preceding infertility treatment.
This is a secondary analysis of a multicentre RCT (randomized controlled trial), the LIFEstyle study. Between 2009 and 2012, 577 obese infertile women were randomly assigned to a 6-month lifestyle intervention followed by infertility treatment (intervention group) or to prompt infertility treatment (control group). Subgroups were predefined in the study protocol, based on frequently used cut-off values in the literature: age (≥36 or <36 years), ovulatory status (anovulatory or ovulatory), BMI (≥35 or <35 kg/m
) and waist-hip (WH) ratio (≥0.8 or <0.8).
Data of 564 (98%) randomized women who completed follow-up were analyzed. We studied the effect of the intervention program in various subgroups on healthy live birth rate within 24 months, as well as the rate of overall live births (live births independent of gestational age, mode of delivery and health) and natural conceptions within 24 months. Live birth rates included pregnancies resulting from both treatment dependent and natural conceptions. Logistic regression models with randomization group, subgroup and the interaction between randomization group and subgroup were used. Significant interaction was defined as a P-value <0.1.
Neither maternal age, ovulatory status nor BMI had an impact on the healthy live birth rate within 24 months, nor did they influence the overall live birth rate within 24 months after randomization. WH ratio showed a significant interaction with the effect of lifestyle intervention on healthy live birth rate (P = 0.05), resulting in a lower healthy live birth rate in women with a WH ratio <0.8. WH ratio had no interaction regarding overall live birth rate (P = 0.27) or natural conception rate (P = 0.38). In anovulatory women, the effect of lifestyle intervention resulted in more natural conceptions compared to ovulatory women (P-value for interaction = 0.02). There was no interaction between other subgroups and the effect of the intervention on the rate of natural conception.
Since this was a subgroup analysis of a RCT and sample size determination of the trial was based on the primary outcome of the study, the study was not powered for analyses of all subgroups.
Our finding that lifestyle intervention leads to increased natural conception in anovulatory obese women could be used in the counselling of these women, but requires further research using an appropriately powered study in order to confirm this result.
The study was supported by a grant from ZonMw, the Dutch Organisation for Health Research and Development (50-50110-96-518). The Department of Obstetrics and Gynaecology of the UMCG received an unrestricted educational grant from Ferring pharmaceuticals BV, The Netherlands. Ben Mol is a consultant for ObsEva, Geneva. Annemieke Hoek received a speaker's fee for a postgraduate education from MSD pharmaceutical company, outside the submitted work.
The LIFEstyle study was registered at the Dutch trial registry (NTR 1530).
This paper reports the critical role of microstructural length scale in dealloying for the fabrication of bimodal or monolithic functional nanoporous metal structures and the underlying mechanisms ...and kinetics. Two dual-phased (Al2CuAlCu) precursor alloys Al65Cu35 and Al55Cu45 (at.%) were selected to demonstrate the concept. Microstructural observations revealed that the two constituent phases Al2Cu and AlCu in each alloy can undergo either sequential dealloying, which leads to bimodal nanoporous Cu, or simultaneous dealloying, which results in monolithic nanoporous Cu. In-situ and ex-situ synchrotron X-ray diffraction (XRD), focused ion beam scanning electron microscopy (FIB-SEM), and potentiodynamic polarization scans were used to identify the detailed phase evolution processes and kinetics. It is concluded that microstructural length scale plays a decisive role in regulating the dealloying pathways. Sequential dealloying of Al2Cu and AlCu occurs when both phases are micrometer-scaled, while simultaneous dealloying takes over when both phases are nanoscaled. The nanosize effect of Al2Cu and AlCu can override their intrinsic difference in electrochemical potential at the micro- or macro-scale, and the advantage of tetragonal Al2Cu over monoclinic AlCu in crystallographic transition to face-centered-cubic (FCC) Cu by dealloying. The high-resolution in-situ synchrotron XRD data revealed a two-stage kinetic process for dealloying of Al2Cu to Cu. The Avrami-Erofe′ev kinetic model provides an excellent description of each stage. The underlying rationales and implications are discussed.
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Bim is one of the proapoptotic BH3-only homologs of the Bcl-2 family proteins, which interacts with other Bcl-2 family proteins to activate the intrinsic apoptotic pathway. The expression and protein ...level of Bim are highly regulated in cells at both transcriptional and post-translational levels, and inadequate control of Bim level may largely determine its proapoptic activity. In the present study, we reported that carbachol, a muscarinic cholinergic receptor agonist, regulated Bim in human SH-SY5Y neuroblastoma cells. Carbachol rapidly induced an upward gel mobility shift of Bim, which was abolished by protein phosphatase treatment, indicating an increased Bim phosphorylation by carbachol. The effect of carbachol was mimicked by the protein kinase C activator 12-myristate 13-acetate (PMA) and was blocked by the protein kinase C inhibitor rottlerin, suggesting that activation of protein kinase C was required for carbachol-induced phosphorylation of Bim. Prolonged treatment with carbachol and PMA significantly decreased Bim protein levels in total cell lysates and mitrochondria. Carbachol and PMA had no effect in the transcriptional regulation of Bim, whereas the reduction of Bim by both carbachol and PMA was reversed by the proteosome inhibitors, suggesting that carbachol and PMA facilitated the proteosome-dependent Bim degradation. Thus, this study identified the muscarinic receptor-protein kinase C signaling pathway as a regulator of Bim in neuroblastoma cells, and activation of muscarinic receptor and protein kinase C functions to induce Bim phosphorylation, followed by down-regulation of the proapoptotic protein.
FOXO3a is a ubiquitously expressed mammalian forkhead transcription factor with a high expression level in adult brain. The activity of FOXO3a is inhibited by growth factors through activation of ...phosphatidylinositol 3-kinase (PI3K)/Akt signaling, which phosphorylates FOXO3a and decreases the level of FOXO3a in the nucleus. In the present study, we examined the regulation of FOXO3a by brain-derived neurotrophic factor (BDNF) in retinoic acid (RA)-differentiated human SH-SY5Y neuroblastoma cells. BDNF caused a rapid and time-dependent decrease of nuclear FOXO3a with a corresponding increase of cytosolic FOXO3a. The rate of the BDNF-induced nuclear/cytosolic redistribution was consistent with the time course of BDNF-induced threonine
32-phosphorylation of FOXO3a, and was mediated by the PI3K/Akt signaling pathway. Active FOXO3a rapidly increased the level of Bcl-2-interacting mediator (bim) in differentiated SH-SY5Y cells, and BDNF decreased the FOXO3a-induced increase of bim through activation of both PI3K/Akt and Erk signaling pathways. Thapsigargin, an endoplasmic reticulum (ER) stress-inducing agent, significantly decreased threonine
32-phosphorylation of FOXO3a, and increased nuclear and decreased cytosolic FOXO3a, suggesting that thapsigargin activates FOXO3a. Treatment with BDNF completely reversed and blocked the thapsigargin-induced dephosphorylation and nuclear accumulation of FOXO3a. In addition, protein phosphatase 1/2A inhibitors increased threonine
32-phosphorylation of FOXO3a, decreased nuclear FOXO3a, and blocked thapsigargin-induced activity of FOXO3a. The regulatory effect of BDNF on FOXO3a and its target genes may play a significant role in the BDNF-mediated neuronal survival, differentiation, and plasticity.
Zeitschrift für Kristallographie. Supplement Volume 30 presents the complete Proceedings of all contributions to the XI European Powder Diffraction Conference in Warsaw 2008: Method Development and ...Application,Instrumental, Software Development, Materials. Supplement Series of Zeitschrift für Kristallographie publishes Proceedings and Abstracts of international conferences on the interdisciplinary field of crystallography.
Objective To compare the effect on the course of advanced prostate cancer of hormone treatment commenced on diagnosis with that deferred until clinically significant progression occurs.
Patients and ...methods Nine hundred and thirty‐eight patients with locally advanced or asymptomatic metastatic prostate cancer were randomized either to immediate treatment (orchidectomy or luteinizing hormone‐releasing hormone analogue) or to the same treatment deferred until an indication occurred. Follow‐up and management were otherwise according to the participating clinician's normal practice. Information was collected annually on survival, local and distant progression, and major complications (pathological fracture, spinal cord compression, ureteric obstruction and extra‐skeletal metastases).
Results Follow‐up data were returned on 934 patients; 51 deferred patients died from causes other than prostate cancer before treatment was started (but only five of these presented at age <70 years) and 29 died from prostate cancer before treatment could be started. Treatment was commenced for local progression almost as frequently as for metastatic disease. Progression from M0 to M1 disease (P<0.001, two‐tailed) and development of metastatic pain occurred more rapidly in deferred patients; 141 deferred patients needed transurethral resection for local progression compared with 65 treated immediately (P<0.001, two‐tailed). Pathological fracture, spinal cord compression, ureteric obstruction and development of extra‐skeletal metastases were twice as common in deferred patients. Of the patients who died, 67% did so from prostate cancer; 361 patients died in the deferred arm compared with 328 in the immediate arm (P=0.02, two‐tailed), where 257 and 203 were deaths from prostate cancer, respectively (P=0.001 two‐tailed). This difference was seen largely in M0 patients, with 119 and 81 deaths from prostate cancer, respectively (P<0.001 two‐tailed).
Conclusions The results consistently favour immediate treatment, although some of the data, especially on M0 patients, are immature. The implications for management of advanced prostate cancer are discussed.
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