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With the dual onslaught of progressive β-cell failure and insulin resistance, many patients with diabetes struggle to achieve adequate glucose control despite escalation of treatment, including insulin.1 More than a third of patients who start basal insulin need more than 60 units per day to achieve target control2 but, at these doses, insulin absorption is slow and bioavailability is reduced.3 As endogenous insulin production decreases, the risk of hypoglycaemia increases,4 compounding diffi culties in achieving glycaemic targets. Patients who struggle to control their diabetes despite taking high doses of insulin (up to a third of those with type 2 diabetes) have three potential options to achieve control: treatment with glucagon-like peptide-1 receptor agonists, bariatric surgery, or continuation with increasing doses of insulin.

Glucagon-like peptide-1 receptor agonists could help to improve glucose control with mild reductions in weight

and insulin dose. A UK-wide audit of 1257 patients who continued insulin after starting treatment with glucagon-like peptide-1 receptor agonists, showed that mean total daily insulin requirements fell from 120 units per day (SD 99) to 78 units per day (SD 85) after 1 year. However, 31% of these patients discontinued glucagon-like peptide-1 receptor agonists, because of lack of effi cacy or gastrointestinal side-eff ects.5 Bariatric surgery off ers greater benefi ts in terms of weight loss and remission from diabetes,6 but not all patients are willing or able to undergo surgery; also, for older patients with established diabetes and related comorbidities, the chance of remission from diabetes is lower with a higher risk of complications and less weight loss.7 The third option is pushing the insulin doses even higher, or using alternative modes of insulin delivery. To date, a small number of before-and-after studies have been done of

Continuous subcutaneous insulin infusion for type 2 diabetesPublished Online

July 3, 2014http://dx.doi.org/10.1016/ S0140-6736(14)61098-9

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confi rmed the fi rst case of Ebola in Conakry, Guinea. Scientists from the Institut Pasteur Dakar and Paris quickly set up laboratory diagnostic facilities, including a mobile unit in Conakry (the fi rst African laboratory deployed in Guinea), and worked closely with MSF to provide validated analyses of samples of suspected cases of Ebola from Guinea, and also from Angola, Gambia, Ghana, Mali, and Senegal. With no cure or vaccine yet available for Ebola, this work underlines the crucial role of Institut Pasteur laboratory infrastructure and expertise, which off ers not only diagnostic support and epidemiological surveillance, but also case management, capacity building to support and train local staff and ensure the sustainability of expertise and capacities, and research—eg, on diagnostics and transmission dynamics.

Given the scale of the Ebola outbreak and the extensive resources of Institut Pasteur, at the symposium Kathleen Victoir, of the International Division, Paris, and Felix Rey, of the Structural Virology Unit, presented Institut Pasteur’s recently created Ebola task force to strengthen and coordinate eff orts, locally and globally. This task force will enable better coordinated support from all Instituts Pasteur to those in west and central Africa, such as in Dakar, Cameroon, Central African Republic, CÔte d’Ivoire, and Niger, and assist ministries

of health for preparedness and response. The task force’s main objectives are to provide support for timely and accurate laboratory diagnosis, training of local personnel, deployment of mobile biosafety level 4 laboratories, strain identifi cation and genome analysis, and participation in clinical trials. In the medium term, the objectives are the development of more rapid diagnostics, fi eld evaluation of new diagnostic tools, screening of compound libraries, capacity building, and research on vaccine development and treatments.

The contributions of MSF and the CDC have been vital in this Ebola outbreak, but the part played by many other partners should not be overlooked. Institut Pasteur’s work shows the importance of placing biomedical research at the forefront of this global public health eff ort.

Audrey Ceschia The Lancet, London NW1 7BY, UK

1 WHO. Ebola response roadmap update. Sept 26, 2014. Geneva: World Health Organization, 2014. http://apps.who.int/iris/bitstream/10665/135029/1/roadmapupdate26sept14_eng.pdf?ua=1 (accessed Sept 29, 2014).

2 Meltzer MI, Atkins CY, Santibanez S, et al. Estimating the future number of cases in the Ebola epidemic—Liberia and Sierra Leone, 2014–2015. MMWR Surveill Summ 2014; 63: 1–14.

3 The Lancet. Ebola: a failure of international collective action. Lancet 2014; 384: 637.

4 Baize S, Pannetier D, Oestereich L, et al. Emergence of Zaire Ebola virus disease in Guinea. N Engl J Med 2014; published online April 16. DOI:10.1056/NEJMoa1404505.

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continuous subcutaneous insulin infusion with a pump for type 2 diabetes, showing modest improvements in glycated haemoglobin. However, previous randomised controlled trials8–10 did not show any advantage of pump treatment over multiple daily injections. New approaches, such as use of higher concentrations of basal insulin or U-500 regular insulin, seem benefi cial11 for patients with very high insulin requirements, but they have not been evaluated in randomised controlled trials.

Continuous subcutaneous insulin infusion has been around for 35 years, and is recommended for patients with type 1 diabetes who are unable to achieve glycaemic targets without unacceptable hypoglycaemia.12,13 Surprisingly, very few randomised controlled trials have compared pump treatment versus optimised multiple daily injections with modern peakless basal insulin, even in type 1 diabetes.14

In The Lancet, Yves Reznik and colleagues15 report results of the OpT2mise study, which provides robust data for the clinical eff ectiveness of pump treatment in patients with type 2 diabetes. 331 patients with high insulin requirements (>0·7 units/kg per day) and suboptimum control (baseline mean glycated haemoglobin 9·0% [75 mmol/mol]) were randomly assigned to pump treatment or continued dose titration with multiple daily injections. Those in the pump treatment group achieved greater reduction in glycated haemoglobin at 6 months (1·1%, SD 1·2 [12 mmol/mol, SD 13] vs 0·4%, SD 1·1 [4 mmol/mol, SD 12]; between-group diff erence –0·7% [95% CI –0·9 to –0·4], p<0·0001), without any increase in hypoglycaemia, with the greatest benefi t in those with baseline glycated haemoglobin greater than 9·2% (78 mmol/mol).

Reznik and colleagues’ study has several key points to note. The investigators selected patients who had failed to achieve control with multiple daily injection despite high insulin doses, a point confi rmed by the 2-month run-in phase, with dose titration of basal and bolus insulin targeting pre-meal glucose of 3·9–7·2 mmol/L and post-prandial glucose of less than 10 mmol/L. During the follow-up phase, mean insulin doses were increased further in the multiple daily injection group from 106 units per day (SD 49) to 122 units per day (SD 68), showing eff orts at dose titration in this group. T he improvement in glucose control in the pump treatment group was associated with a reduction of

mean total daily dose from 112 units (SD 54) to 97 units (SD 56).

Patients in the pump treatment group did more blood glucose tests than those in the multiple daily injection group during the last 3 months of the study (3·8 vs 3·1 tests per day). Although this diff erence might have contributed to the diff erences in glycated haemoglobin results, it is possible that the use of pump treatment per se was instrumental in increasing testing through increased engagement of patients with their diabetes. Five episodes of signifi cant hyperglycaemia occurred, possibly related to blockage of the infusion set in the pump treatment group, although these episodes did not result in ketoacidosis or admission to hospital. The investigators used a simple approach with few basal rates and fi xed boluses, without the use of carbohydrate counting, and it remains to be seen whether addition of these measures would yield greater benefi ts.

OpT2mise provides a compelling case for the clinical eff ectiveness of insulin pump treatment in type 2 diabetes, suggesting that it can help improve glycaemic control in this diffi cult to treat group of patients who are unable to achieve glucose control despite increasing doses of insulin. However, cost eff ectiveness of pumps in diff erent health-care systems will need to be evaluated.

Pratik ChoudharyDiabetes Research Group, King’s College London, Weston Education Centre, London SE5 9RS, UKpratik.choudhary@kcl.ac.uk

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Idiopathic nephrotic syndrome is the most common primary glomerular disease in children. About 80% of children with idiopathic nephrotic syndrome achieve remission with corticosteroids, although most have at least one relapse.1 Of children who relapse, about 50% relapse frequently or develop steroid-dependent disease.1 Some who are initially resistant to corticosteroids will achieve complete remission with calcineurin inhibitors, but about 30% of these children will develop frequently relapsing or steroid-dependent disease.2 Various immunosuppressive agents reduce the risk of relapse.3 Nevertheless, some children continue to relapse frequently despite continuing treatment with corticosteroids and immunosuppressive agents, which can also have serious adverse eff ects.

Rituximab is a mouse–human chimaeric monoclonal antibody that binds to the CD20 antigen expressed on B cells. It was initially developed for treatment of B-cell lymphomas, but many observational studies, including those with a follow-up of 2 years or more, have shown increased duration of remission with rituximab in children with steroid-dependent nephrotic syndrome.4–6 However, children with nephrotic syndrome who receive rituximab experience serious

adverse eff ects, such as fulminant myocarditis, fatal pulmonary fi brosis, Pneumocystis jirovecii pneumonia with respiratory failure, and severe ulcerative colitis.7–10 Progressive multifocal leukoencephalopathy has been reported in some patients treated with rituximab for other disorders.11 In 2013, the US Food and Drug Administration issued a black-box warning about rituximab use after reports of fatal hepatitis B reactivation in patients with previous or chronic hepatitis B infection. Until now, just one randomised controlled trial12 has been done to investigate the effi cacy and safety of rituximab for children with steroid-sensitive nephrotic syndrome, but outcomes were assessed only at 3 months.

In The Lancet, Kazumoto Iijima and colleagues13 report the results of a randomised, placebo-controlled trial comparing rituximab (375 mg/m²) with placebo infusions (both given once weekly for 4 weeks) in children with what the investigators defi ned as complicated, frequently relapsing, or steroid-dependent nephrotic syndrome. 48 children who received at least one dose of rituximab or placebo were included in the analysis and were followed up for 1 year. The primary outcome was the median relapse-free period, which was signifi cantly longer

Rituximab for childhood-onset nephrotic syndrome

Published OnlineJune 23, 2014

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Rituximab

I have served on advisory boards and received speaker’s fees and travel support from Medtronic, Roche, and Johnson and Johnson.

1 Berkowitz SA, Meigs JB, Wexler DJ. Age at type 2 diabetes onset and glycaemic control: results from the National Health and Nutrition Examination Survey (NHANES) 2005-2010. Diabetologia 2013; 56: 2593–600.

2 Rodbard HW, Gough S, Lane W, Korsholm L, Bretler DM, Handelsman Y. Reduced risk of hypoglycemia with insulin degludec versus insulin glargine in patients with type 2 diabetes requiring high doses of basal insulin: a meta-analysis of 5 randomized begin trials. Endocr Pract 2014; 20: 285–92.

3 Gagnon-Auger M, du Souich P, Baillargeon JP, et al. Dose-dependent delay of the hypoglycemic eff ect of short-acting insulin analogs in obese subjects with type 2 diabetes: a pharmacokinetic and pharmacodynamic study. Diabetes Care 2010; 33: 2502–07.

4 UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: eff ects of treatment modalities and their duration. Diabetologia 2007; 50: 1140–47.

5 Thong KY, Jose B, Sukumar N, et al. Safety, effi cacy and tolerability of exenatide in combination with insulin in the Association of British Clinical Diabetologists nationwide exenatide audit. Diabetes Obes Metab 2011; 13: 703–10.

6 Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med 2012; 366: 1567–76.

7 Ritz P, Topart P, Benchetrit S, et al. Benefi ts and risks of bariatric surgery in patients aged more than 60 years. Surg Obes Relat Dis 2014; published online Jan 9. DOI: 10.1016/j.soard.2013.12.012.

8 Wainstein J, Metzger M, Boaz M, et al. Insulin pump therapy vs. multiple daily injections in obese type 2 diabetic patients. Diabet Med 2005; 22: 1037–46.

9 Raskin P, Bode BW, Marks JB, et al. Continuous subcutaneous insulin infusion and multiple daily injection therapy are equally eff ective in type 2 diabetes: a randomized, parallel-group, 24-week study. Diabetes Care 2003; 26: 2598–603.

10 Herman WH, Ilag LL, Johnson SL, et al. A clinical trial of continuous subcutaneous insulin infusion versus multiple daily injections in older adults with type 2 diabetes. Diabetes Care 2005; 28: 1568–73.

11 Reutrakul S, Wroblewski K, Brown RL. Clinical use of U-500 regular insulin: review and meta-analysis. J Diabetes Sci Technol 2012; 6: 412–20.

12 Nice. Diabetes insulin pump therapy. 2008. http://www.nice.org.uk/guidance/TA151 (accessed June 27, 2014).

13 Grunberger G, Bailey TS, Cohen AJ, et al. Statement by the American Association of Clinical Endocrinologists Consensus Panel on insulin pump management. Endocr Pract 2010; 16: 746–62.

14 Pickup JC, Sutton AJ. Severe hypoglycaemia and glycaemic control in type 1 diabetes: meta-analysis of multiple daily insulin injections compared with continuous subcutaneous insulin infusion. Diabet Med 2008; 25: 765–74.

15 Reznik Y, Cohen O, Aronson R, et al, for the OpT2mise Study Group. Insulin pump treatment compared with multiple daily injections for treatment of type 2 diabetes (OpT2mise): a randomised open-label controlled trial. Lancet 2014; published online July 3. http://dx.doi.org/10.1016/S0140-6736(14)61037-0.