Aims/hypothesis Improved glucose control in type 2 diabetes is known to reduce the risk of microvascular events. There is, however, continuing uncertainty about its impact on macrovascular disease. ...The aim of these analyses was to generate more precise estimates of the effects of more-intensive, compared with less-intensive, glucose control on the risk of major cardiovascular events amongst patients with type 2 diabetes. Methods A prospectively planned group-level meta-analysis in which characteristics of trials to be included, outcomes of interest, analyses and subgroup definitions were all pre-specified. Results A total of 27,049 participants and 2,370 major vascular events contributed to the meta-analyses. Allocation to more-intensive, compared with less-intensive, glucose control reduced the risk of major cardiovascular events by 9% (HR 0.91, 95% CI 0.84-0.99), primarily because of a 15% reduced risk of myocardial infarction (HR 0.85, 95% CI 0.76-0.94). Mortality was not decreased, with non-significant HRs of 1.04 for all-cause mortality (95% CI 0.90-1.20) and 1.10 for cardiovascular death (95% CI 0.84-1.42). Intensively treated participants had significantly more major hypoglycaemic events (HR 2.48, 95% CI 1.91-3.21). Exploratory subgroup analyses suggested the possibility of a differential effect for major cardiovascular events in participants with and without macrovascular disease (HR 1.00, 95% CI 0.89-1.13, vs HR 0.84, 95% CI 0.74-0.94, respectively; interaction p = 0.04). Conclusions/interpretation Targeting more-intensive glucose lowering modestly reduced major macrovascular events and increased major hypoglycaemia over 4.4 years in persons with type 2 diabetes. The analyses suggest that glucose-lowering regimens should be tailored to the individual.
Summary
VRC‐HIVMAB060‐00‐AB (VRC01) is a broadly neutralizing HIV‐1 monoclonal antibody (mAb) isolated from the B cells of an HIV‐infected patient. It is directed against the HIV‐1 CD4 binding site ...and is capable of potently neutralizing the majority of diverse HIV‐1 strains. This Phase I dose‐escalation study in healthy adults was conducted at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Primary objectives were the safety, tolerability and pharmacokinetics (PK) of VRC01 intravenous (i.v.) infusion at 5, 20 or 40 mg/kg, given either once (20 mg/kg) or twice 28 days apart (all doses), and of subcutaneous (s.c.) delivery at 5 mg/kg compared to s.c. placebo given twice, 28 days apart. Cumulatively, 28 subjects received 43 VRC01 and nine received placebo administrations. There were no serious adverse events or dose‐limiting toxicities. Mean 28‐day serum trough concentrations after the first infusion were 35 and 57 μg/ml for groups infused with 20 mg/kg (n = 8) and 40 mg/kg (n = 5) doses, respectively. Mean 28‐day trough concentrations after the second infusion were 56 and 89 μg/ml for the same two doses. Over the 5–40 mg/kg i.v. dose range (n = 18), the clearance was 0·016 l/h and terminal half‐life was 15 days. After infusion VRC01 retained expected neutralizing activity in serum, and anti‐VRC01 antibody responses were not detected. The human monoclonal antibody (mAb) VRC01 was well tolerated when delivered i.v. or s.c. The mAb demonstrated expected half‐life and pharmacokinetics for a human immunoglobulin G. The safety and PK results support and inform VRC01 dosing schedules for planning HIV‐1 prevention efficacy studies.
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This study presents a framework for process and product development on a continuous direct compression manufacturing platform. A challenging sustained release formulation with high ...content of a poorly flowing low density drug was selected. Two HPMC grades were evaluated as matrix former: standard Methocel CR and directly compressible Methocel DC2. The feeding behavior of each formulation component was investigated by deriving feed factor profiles. The maximum feed factor was used to estimate the drive command and depended strongly upon the density of the material. Furthermore, the shape of the feed factor profile allowed definition of a customized refill regime for each material. Inline NIRs was used to estimate the residence time distribution (RTD) in the mixer and monitor blend uniformity. Tablet content and weight variability were determined as additional measures of mixing performance. For Methocel CR, the best axial mixing (i.e. feeder fluctuation dampening) was achieved when an impeller with high number of radial mixing blades operated at low speed. However, the variability in tablet weight and content uniformity deteriorated under this condition. One can therefore conclude that balancing axial mixing with tablet quality is critical for Methocel CR. However, reformulating with the direct compressible Methocel DC2 as matrix former improved tablet quality vastly. Furthermore, both process and product were significantly more robust to changes in process and design variables. This observation underpins the importance of flowability during continuous blending and die-filling. At the compaction stage, blends with Methocel CR showed better tabletability driven by a higher compressibility as the smaller CR particles have a higher bonding area. However, tablets of similar strength were achieved using Methocel DC2 by targeting equal porosity. Compaction pressure impacted tablet properties and dissolution. Hence controlling thickness during continuous manufacturing of sustained release tablets was crucial to ensure reproducible dissolution.
Breast cancer is the most common malignancy in women worldwide. Tea has anticarcinogenic effects against breast cancer in experimental studies. However, epidemiologic evidence that tea protects ...against breast cancer has been inconsistent. A case–control study was conducted in Southeast China between 2004 and 2005. The incidence cases were 1009 female patients aged 20–87 years with histologically confirmed breast cancer. The 1009 age-matched controls were healthy women randomly recruited from breast disease clinics. Information on duration, frequency, quantity, preparation, type of tea consumption, diet and lifestyle were collected by face-to-face interview using a validated and reliable questionnaire. Conditional logistic regression analyses were used to estimate odds ratios (ORs) and associated 95% confidence intervals. Compared with non-tea drinkers, green tea drinkers tended to reside in urban, have better education and have higher consumption of coffee, alcohol, soy, vegetables and fruits. After adjusting established and potential confounders, green tea consumption was associated with a reduced risk of breast cancer. The ORs were 0.87 (0.73–1.04) in women consuming 1–249 g of dried green tea leaves per annum, 0.68 (0.54–0.86) for 250–499 g per annum, 0.59 (0.45–0.77) for 500–749 g per annum and 0.61 (0.48–0.78) for ≥750 g per annum, with a statistically significant test for trend (P < 0.001). Similar dose–response relationships were observed for duration of drinking green tea, number of cups consumed and new batches prepared per day. We conclude that regular consumption of green tea can protect against breast cancer. More research to closely examine the relationship between tea consumption and breast cancer risk is warranted.
Despite a successful surgical procedure and adherence to current recommendations, postoperative left ventricular (LV) dysfunction after mitral valve repair (MVr) for organic mitral regurgitation (MR) ...may still occur. New approaches are therefore needed to detect subclinical preoperative LV dysfunction. LV global longitudinal strain (GLS), assessed with speckle-tracking echocardiographic analysis, has been proposed as a novel measure to better depict latent LV dysfunction. The aim of this study was to investigate the value of GLS to predict long-term LV dysfunction after MVr.
A total of 233 patients (61% men, 61 ± 12 years) with moderate-severe organic MR who underwent successful MVr between 2000 and 2009 were included. Echocardiography was performed at baseline and long-term follow-up (34 ± 20 months) after MVr. LV dysfunction at follow-up was defined as LV ejection fraction (EF) <50% and was present in 29 (12%) patients. A cut-off value of -19.9% of GLS showed a sensitivity and specificity of 90 and 79% to predict long-term LV dysfunction. By univariate logistic regression analysis, baseline LVEF ≤60%, LV end-systolic diameter (ESD) ≥40 mm, atrial fibrillation, presence of symptoms, and GLS >-19.9% were predictors of long-term LV dysfunction. By multivariate analysis, GLS remained an independent predictor of LV dysfunction (odds ratio 23.16, 95% confidence interval: 6.53-82.10, P < 0.001), together with LVESD.
In a large series of patients operated within the last decade, MVr resulted in a low incidence of long-term LV dysfunction. A GLS of >-19.9% demonstrated to be a major independent predictor of long-term LV dysfunction after adjustment for parameters currently implemented into guidelines.
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In this work a continuous direct compression process was developed for a low-dosed drug product. Each unit operation of the GEA CDC-50 system was thoroughly investigated. This paper ...aimed to tackle the macroscopic and microscopic blend uniformity challenges inherently associated with continuous direct compression of cohesive and agglomerated APIs formulated at low dose. Density, compressibility and flow were identified as key material properties at the feeding stage. The screw speed coupled with powder flow regulated the gravimetric feeding performance. The impact of process and design variables was elucidated at the blending stage. The impeller configuration (number and pattern of radial mixing blades) and speed were key variables to steer the residence time distribution at the blending stage. An impeller configuration with distributed radial mixing blades could sufficiently filter the steady state feeding variability at low mixer speed, but exerted limited strain and shear on the blend. Hence micro-agglomerates persisted through the blending process and occasionally resulted in super potent tablets. Therefore, a new configuration was evaluated with more radial mixing blades centered on the impeller. This configuration resulted in a long mixing time at high tip speed which induced a maximized strain and shear. Consequently, excellent uniformity of the blend and tablets at macroscopic and microscopic level was achieved. Besides, this impeller improved robustness towards feeding disturbances, changes in process settings and variable blend properties. Next, it was demonstrated that the lubrication step requires critical attention during the design of the equipment, formulation and process. This study provided abundant evidence that an optimized continuous direct compression process allows direct compression of challenging low-dose drug products.
In recent years water companies have started to adopt catchment management to reduce diffuse pollution in drinking water supply areas. The heterogeneity of catchments and the range of pollutants that ...must be removed to meet the EU Drinking Water Directive (98/83/EC) limits make it difficult to prioritise areas of a catchment for intervention. Thus conceptual frameworks are required that can disaggregate the components of pollutant risk and help water companies make decisions about where to target interventions in their catchments to maximum effect. This paper demonstrates the concept of generalising pollutants in the same framework by reviewing key pollutant processes within a source-mobilisation-delivery context. From this, criteria are developed (with input from water industry professionals involved in catchment management) which highlights the need for a new water industry specific conceptual framework. The new CaRPoW (Catchment Risk to Potable Water) framework uses the Source-Mobilisation-Delivery concept as modular components of risk that work at two scales, source and mobilisation at the field scale and delivery at the catchment scale. Disaggregating pollutant processes permits the main components of risk to be ascertained so that appropriate interventions can be selected. The generic structure also allows for the outputs from different pollutants to be compared so that potential multiple benefits can be identified. CaRPow provides a transferable framework that can be used by water companies to cost-effectively target interventions under current conditions or under scenarios of land use or climate change.
•Water companies must mitigate multiple pollutant risks in water supply catchments.•A review of catchment processes highlights links between multiple pollutants.•No current framework is able to identify and compare multiple pollutant risks.•The new CaRPoW framework disaggregates and compares risks for measure selection.•CaRPoW allows water companies to more effectively select and target measures.
The energies of valley-orbit states in silicon quantum dots are determined by an as yet poorly understood interplay between interface roughness, orbital confinement, and electron interactions. Here, ...we report measurements of one- and two-electron valley-orbit state energies as the dot potential is modified by changing gate voltages, and we calculate these same energies using full configuration interaction calculations. The results enable an understanding of the interplay between the physical contributions and enable a new probe of the quantum well interface.
The benefits of reducing blood pressure on the risks of major cardiovascular disease are well established, but uncertainty remains about the comparative effects of different blood-pressure-lowering ...regimens. We aimed to estimate effects of strategies based on different drug classes (angiotensin-converting-enzyme ACE inhibitors, calcium antagonists, angiotensin-receptor blockers ARBs, and diuretics or β blockers) or those targeting different blood pressure goals, on the risks of major cardiovascular events and death.
We did seven sets of prospectively-designed overviews with data from 29 randomised trials (n=162 341). The trial eligibility criteria, primary outcomes, and main hypotheses were specified before the result of any contributing trial was known.
In placebo-controlled trials the relative risks of total major cardiovascular events were reduced by regimens based on ACE inhibitors (22%; 95% CI 17–27) or calcium antagonists (18%; 5–29). Greater risk reductions were produced by regimens that targeted lower blood pressure goals (15%; 5–24). ARB-based regimens reduced the risks of total major cardiovascular events (10%; 4–17) compared with control regimens. There were no significant differences in total major cardiovascular events between regimens based on ACE inhibitors, calcium antagonists, or diuretics or β blockers, although ACE-inhibitor-based regimens reduced blood pressure less. There was evidence of some differences between active regimens in their effects on cause-specific outcomes. For every outcome other than heart failure, the difference between randomised groups in achieved blood pressure reduction was directly related to the observed difference in risk.
Treatment with any commonly-used regimen reduces the risk of total major cardiovascular events, and larger reductions in blood pressure produce larger reductions in risk.
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