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IN 1931 Sir Gerald Burrard published his remarkable work on shotguns in three volumes, The Gun, The Cartridge and The Gun and the Cartridge, all profusely illustrated with photographs and diagrams. The first book considered the design and strength of actions and the length and boring of barrels, and, in fact, every aspect of the complete weapon.

IN Great Britain the pistol has always been the Cinderella of personal weapons, and perhaps the basic reason is ignorance of the pistol's capability of precision and usefulness for purposes other than crime. Howlers in the Press and often in the cinema are the rule rather than the exception. All Pistols are revolvers and sometimes the descriptions used of them are quite laughable. It is certain that this attitude springs from the settled and law-abiding nature of this country over a long period, where the only common use of the weapon in the last two centuries was for duelling.

Bacteria from phyla lacking cultivated representatives are widespread in natural systems and some have very small genomes. Here we test the hypothesis that these cells are small and thus might be enriched by filtration for coupled genomic and ultrastructural characterization. Metagenomic analysis of groundwater that passed through a ~0.2-μm filter reveals a wide diversity of bacteria from the WWE3, OP11 and OD1 candidate phyla. Cryogenic transmission electron microscopy demonstrates that, despite morphological variation, cells consistently have small cell size (0.009±0.002 μm 3 ). Ultrastructural features potentially related to cell and genome size minimization include tightly packed spirals inferred to be DNA, few densely packed ribosomes and a variety of pili-like structures that might enable inter-organism interactions that compensate for biosynthetic capacities inferred to be missing from genomic data. The results suggest that extremely small cell size is associated with these relatively common, yet little known organisms. Little is known about certain bacterial phyla because of our current inability to grow them in the lab. Here, Luef et al. combine metagenomics and ultrastuctural analyses to show that some of these bacteria have a very small cell size, tightly packed DNA, few ribosomes and diverse pili-like structures.

In this 3-year multicenter trial, patients with suboptimal glycated hemoglobin levels while receiving metformin and sulfonylurea therapy were randomly assigned to add biphasic, prandial, or basal insulin. During the first year, sulfonylurea therapy was replaced by additional insulin for unacceptable hyperglycemia or subsequently for a glycated hemoglobin level of more than 6.5%. Basal- or prandial-based insulin regimens more often achieved glycated hemoglobin targets. Fewer hypoglycemic episodes and less weight gain occurred with regimens initiated with basal insulin. Basal- or prandial-based insulin regimens more often achieved glycated hemoglobin targets. Fewer hypoglycemic episodes and less weight gain occurred with regimens initiated with basal insulin. Most patients with type 2 diabetes require insulin therapy when oral antidiabetic agents provide suboptimal glycemic control, since long-term glycemic improvement reduces the risks of both microvascular 1 and macrovascular 1 , 2 complications. However, different insulin regimens have varying effects on glycemic control, weight gain, and the risk of hypoglycemia. 3 In the first phase of the Treating to Target in Type 2 Diabetes (4-T) study, we evaluated patients with type 2 diabetes who had suboptimal glycemic control despite maximally tolerated doses of metformin and sulfonylurea to see whether the randomized addition of a biphasic, prandial, or basal analogue insulin would lead to . . .

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.

Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve cardiovascular and renal outcomes in patients with type 2 diabetes through distinct mechanisms. However, evidence on clinical outcomes in patients treated with both GLP-1 RA and SGLT2i is lacking. We aim to provide insight into the effects of open-label SGLT2i use in parallel with or shortly after once-weekly GLP-1 RA exenatide (EQW) on cardiorenal outcomes. Methods In the EXSCEL cardiovascular outcomes trial EQW arm, SGLT2i drop-in occurred in 8.7% of participants. These EQW+SGLT2i users were propensity-matched to: (1) placebo-arm participants not taking SGLT2i (n = 572 per group); and to (2) EQW-arm participants not taking SGLT2i (n = 575), based on their last measured characteristics before SGLT2i initiation, and equivalent study visit in comparator groups. Time-to-first major adverse cardiovascular event (MACE) and all-cause mortality (ACM) were compared using Cox regression analyses. eGFR slopes were quantified using mixed model repeated measurement analyses. Results In adjusted analyses, the risk for MACE with combination EQW+SGLT2i use was numerically lower compared with both placebo (adjusted hazard ratio 0.68, 95% CI 0.39–1.17) and EQW alone (0.85, 0.48–1.49). Risk of ACM was nominally significantly reduced compared with placebo (0.38, 0.16–0.90) and compared with EQW (0.41, 0.17–0.95). Combination EQW+SGLT2i use also nominally significantly improved estimated eGFR slope compared with placebo (+ 1.94, 95% CI 0.94–2.94 mL/min/1.73 m 2 /year) and EQW alone (+ 2.38, 1.40–3.35 mL/min/1.73 m 2 /year). Conclusions This post hoc analysis supports the hypothesis that combinatorial EQW and SGLT2i therapy may provide benefit on cardiovascular outcomes and mortality. Trial registration Clinicaltrials.gov, Identifying number: NCT01144338, Date of registration: June 15, 2010.

In an open-label trial, patients with type 2 diabetes with a suboptimal glycated hemoglobin level while receiving a maximally tolerated dose of metformin and sulfonylurea were randomly assigned to receive biphasic, prandial, or basal insulin. The addition of a single analogue-insulin formulation resulted in a glycated hemoglobin level of 6.5% or less in a minority of patients at 1 year. Regimens of biphasic or prandial insulin had greater efficacy than did the basal regimen but were associated with greater risks of hypoglycemia and weight gain. The addition of a single analogue-insulin formulation resulted in a glycated hemoglobin level of 6.5% or less in a minority of patients at 1 year. Regimens of biphasic or prandial insulin had greater efficacy than did the basal regimen but were associated with greater risks of hypoglycemia and weight gain. Type 2 diabetes mellitus is a progressive condition in which the glycated hemoglobin level rises inexorably over time and the function of beta cells declines. 1 , 2 The maintenance of nearly normal glycemic levels reduces the risk of diabetic complications 3 – 5 but is difficult to achieve, despite the administration of escalating doses of oral antidiabetic drugs, such as metformin, sulfonylureas, and thiazolidinediones. 6 – 8 Most patients eventually require insulin, 6 which usually is added when glycemic control with a regimen of oral antidiabetic agents becomes suboptimal. 9 The addition of insulin can result in a clinically relevant improvement in a patient's glycated hemoglobin level. . . .