Health and philanthropy-the tobacco connection.

Lancet. 2010 Aug 24;

Authors: Chapman S

PMID: 20797780 [PubMed - as supplied by publisher]

Health and philanthropy-the tobacco connection.

Lancet. 2010 Aug 24;

Authors: Chapman S

PMID: 20797780 [PubMed - as supplied by publisher]

A complement to kidney disease: CFHR5 nephropathy.

Lancet. 2010 Aug 25;

Authors: Karumanchi SA, Thadhani R

PMID: 20800272 [PubMed - as supplied by publisher]

A complement to kidney disease: CFHR5 nephropathy.

Lancet. 2010 Aug 25;

Authors: Karumanchi SA, Thadhani R

PMID: 20800272 [PubMed - as supplied by publisher]

Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.

Lancet. 2010 Aug 25;

Authors: Gale DP, de Jorge EG, Cook HT, Martinez-Barricarte R, Hadjisavvas A, McLean AG, Pusey CD, Pierides A, Kyriacou K, Athanasiou Y, Voskarides K, Deltas C, Palmer A, Frémeaux-Bacchi V, de Cordoba SR, Maxwell PH, Pickering MC

BACKGROUND: Complement is a key component of the innate immune system, and variation in genes that regulate its activation is associated with renal and other disease. We aimed to establish the genetic basis for a familial disorder of complement regulation associated with persistent microscopic haematuria, recurrent macroscopic haematuria, glomerulonephritis, and progressive renal failure. METHODS: We sought patients from the West London Renal and Transplant Centre (London, UK) with unusual renal disease and affected family members as a method of identification of new genetic causes of kidney disease. Two families of Cypriot origin were identified in which renal disease was consistent with autosomal dominant transmission and renal biopsy of at least one individual showed C3 glomerulonephritis. A mutation was identified via a genome-wide linkage study and candidate gene analysis. A PCR-based diagnostic test was then developed and used to screen for the mutation in population-based samples and in individuals and families with renal disease. FINDINGS: Occurrence of familial renal disease cosegregated with the same mutation in the complement factor H-related protein 5 gene (CFHR5). In a cohort of 84 Cypriots with unexplained renal disease, four had mutation in CFHR5. Overall, we identified 26 individuals with the mutation and evidence of renal disease from 11 ostensibly unrelated kindreds, including the original two families. A mutant CFHR5 protein present in patient serum had reduced affinity for surface-bound complement. We term this renal disease CFHR5 nephropathy. INTERPRETATION: CFHR5 nephropathy accounts for a substantial burden of renal disease in patients of Cypriot origin and can be diagnosed with a specific molecular test. The high risk of progressive renal disease in carriers of the CFHR5 mutation implies that isolated microscopic haematuria or recurrent macroscopic haematuria should not be regarded as a benign finding in individuals of Cypriot descent. FUNDING: UK Medical Research Council and Wellcome Trust.

PMID: 20800271 [PubMed - as supplied by publisher]

Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.

Lancet. 2010 Aug 25;

Authors: Gale DP, de Jorge EG, Cook HT, Martinez-Barricarte R, Hadjisavvas A, McLean AG, Pusey CD, Pierides A, Kyriacou K, Athanasiou Y, Voskarides K, Deltas C, Palmer A, Frémeaux-Bacchi V, de Cordoba SR, Maxwell PH, Pickering MC

BACKGROUND: Complement is a key component of the innate immune system, and variation in genes that regulate its activation is associated with renal and other disease. We aimed to establish the genetic basis for a familial disorder of complement regulation associated with persistent microscopic haematuria, recurrent macroscopic haematuria, glomerulonephritis, and progressive renal failure. METHODS: We sought patients from the West London Renal and Transplant Centre (London, UK) with unusual renal disease and affected family members as a method of identification of new genetic causes of kidney disease. Two families of Cypriot origin were identified in which renal disease was consistent with autosomal dominant transmission and renal biopsy of at least one individual showed C3 glomerulonephritis. A mutation was identified via a genome-wide linkage study and candidate gene analysis. A PCR-based diagnostic test was then developed and used to screen for the mutation in population-based samples and in individuals and families with renal disease. FINDINGS: Occurrence of familial renal disease cosegregated with the same mutation in the complement factor H-related protein 5 gene (CFHR5). In a cohort of 84 Cypriots with unexplained renal disease, four had mutation in CFHR5. Overall, we identified 26 individuals with the mutation and evidence of renal disease from 11 ostensibly unrelated kindreds, including the original two families. A mutant CFHR5 protein present in patient serum had reduced affinity for surface-bound complement. We term this renal disease CFHR5 nephropathy. INTERPRETATION: CFHR5 nephropathy accounts for a substantial burden of renal disease in patients of Cypriot origin and can be diagnosed with a specific molecular test. The high risk of progressive renal disease in carriers of the CFHR5 mutation implies that isolated microscopic haematuria or recurrent macroscopic haematuria should not be regarded as a benign finding in individuals of Cypriot descent. FUNDING: UK Medical Research Council and Wellcome Trust.

PMID: 20800271 [PubMed - as supplied by publisher]

What makes a good doctor?

Lancet. 2010 Aug 28;376(9742):658

Authors:

PMID: 20801386 [PubMed - in process]

What makes a good doctor?

Lancet. 2010 Aug 28;376(9742):658

Authors:

PMID: 20801386 [PubMed - in process]

Chinese doctors are under threat.

Lancet. 2010 Aug 28;376(9742):657

Authors:

PMID: 20801385 [PubMed - in process]

Chinese doctors are under threat.

Lancet. 2010 Aug 28;376(9742):657

Authors:

PMID: 20801385 [PubMed - in process]

Why are drug trials in Alzheimer's disease failing?

Lancet. 2010 Aug 28;376(9742):658

Authors:

PMID: 20801387 [PubMed - in process]

Why are drug trials in Alzheimer's disease failing?

Lancet. 2010 Aug 28;376(9742):658

Authors:

PMID: 20801387 [PubMed - in process]

The unfolding human tragedy in Pakistan: fighting alone.

Lancet. 2010 Aug 28;376(9742):664-5

Authors: Bhutta ZA, Bhutta SZ

PMID: 20801388 [PubMed - in process]

The unfolding human tragedy in Pakistan: fighting alone.

Lancet. 2010 Aug 28;376(9742):664-5

Authors: Bhutta ZA, Bhutta SZ

PMID: 20801388 [PubMed - in process]

The James Lind Alliance: tackling research mismatches.

Lancet. 2010 Aug 28;376(9742):667-9

Authors: Petit-Zeman S, Firkins L, Scadding JW

PMID: 20801389 [PubMed - in process]

The James Lind Alliance: tackling research mismatches.

Lancet. 2010 Aug 28;376(9742):667-9

Authors: Petit-Zeman S, Firkins L, Scadding JW

PMID: 20801389 [PubMed - in process]

Bernard Pécoul: championing the cause of neglected diseases.

Lancet. 2010 Aug 28;376(9742):677

Authors: Shetty P

PMID: 20801392 [PubMed - in process]

Bernard Pécoul: championing the cause of neglected diseases.

Lancet. 2010 Aug 28;376(9742):677

Authors: Shetty P

PMID: 20801392 [PubMed - in process]

The potato: fertile ground for more funding.

Lancet. 2010 Aug 28;376(9742):669

Authors: Hunt C, McNamee D

PMID: 20801390 [PubMed - in process]

The potato: fertile ground for more funding.

Lancet. 2010 Aug 28;376(9742):669

Authors: Hunt C, McNamee D

PMID: 20801390 [PubMed - in process]

Extensively drug-resistant tuberculosis in South Africa.

Lancet. 2010 Aug 28;376(9742):681; author reply 681-2

Authors: Bhuniya S

PMID: 20801394 [PubMed - in process]

Extensively drug-resistant tuberculosis in South Africa.

Lancet. 2010 Aug 28;376(9742):681; author reply 681-2

Authors: Bhuniya S

PMID: 20801394 [PubMed - in process]

Extensively drug-resistant tuberculosis in South Africa.

Lancet. 2010 Aug 28;376(9742):681; author reply 681-2

Authors: Cox H, Ford N, McDermid C, van Cutsem G, Goemaere E

PMID: 20801395 [PubMed - in process]

Extensively drug-resistant tuberculosis in South Africa.

Lancet. 2010 Aug 28;376(9742):681; author reply 681-2

Authors: Cox H, Ford N, McDermid C, van Cutsem G, Goemaere E

PMID: 20801395 [PubMed - in process]

Multidrug-resistant tuberculosis in India.

Lancet. 2010 Aug 28;376(9742):682-3

Authors: Tageja N, Sharma V

PMID: 20801396 [PubMed - in process]

Multidrug-resistant tuberculosis in India.

Lancet. 2010 Aug 28;376(9742):682-3

Authors: Tageja N, Sharma V

PMID: 20801396 [PubMed - in process]

Opportunistic screening for type 2 diabetes in primary care.

Lancet. 2010 Aug 28;376(9742):683-4

Authors: Klein Woolthuis EP, de Grauw WJ, van Weel C

PMID: 20801397 [PubMed - in process]

Opportunistic screening for type 2 diabetes in primary care.

Lancet. 2010 Aug 28;376(9742):683-4

Authors: Klein Woolthuis EP, de Grauw WJ, van Weel C

PMID: 20801397 [PubMed - in process]

Where is diabetes in The Lancet's tuberculosis Series?

Lancet. 2010 Aug 28;376(9742):683

Authors: Bailey S, Godfrey-Faussett P

PMID: 20801398 [PubMed - in process]

Where is diabetes in The Lancet's tuberculosis Series?

Lancet. 2010 Aug 28;376(9742):683

Authors: Bailey S, Godfrey-Faussett P

PMID: 20801398 [PubMed - in process]

Like-with-like comparisons?

Lancet. 2010 Aug 28;376(9742):684; author reply 684-5

Authors: Bird SM

PMID: 20801400 [PubMed - in process]

Like-with-like comparisons?

Lancet. 2010 Aug 28;376(9742):684; author reply 684-5

Authors: Bird SM

PMID: 20801400 [PubMed - in process]

Preventable cancer in the USA.

Lancet. 2010 Aug 28;376(9742):685-6

Authors: Wiseman M, Allen K, McGinley-Gieser D

PMID: 20801401 [PubMed - in process]

Preventable cancer in the USA.

Lancet. 2010 Aug 28;376(9742):685-6

Authors: Wiseman M, Allen K, McGinley-Gieser D

PMID: 20801401 [PubMed - in process]

Changing doctors in changing times.

Lancet. 2010 Aug 28;376(9742):685

Authors: Rakowski KR

PMID: 20801402 [PubMed - in process]

Changing doctors in changing times.

Lancet. 2010 Aug 28;376(9742):685

Authors: Rakowski KR

PMID: 20801402 [PubMed - in process]

Endometriosis and infertility: pathophysiology and management.

Lancet. 2010 Aug 28;376(9742):730-738

Authors: de Ziegler D, Borghese B, Chapron C

Endometriosis and infertility are associated clinically. Medical and surgical treatments for endometriosis have different effects on a woman's chances of conception, either spontaneously or via assisted reproductive technologies (ART). Medical treatments for endometriosis are contraceptive. Data, mostly uncontrolled, indicate that surgery at any stage of endometriosis enhances the chances of natural conception. Criteria for non-removal of endometriomas are: bilateral cysts, history of past surgery, and altered ovarian reserve. Fears that surgery can alter ovarian function that is already compromised sparked a rule of no surgery before ART. Exceptions to this guidance are pain, hydrosalpinges, and very large endometriomas. Medical treatment-eg, 3-6 months of gonadotropin-releasing hormone analogues-improves the outcome of ART. When age, ovarian reserve, and male and tubal status permit, surgery should be considered immediately so that time is dedicated to attempts to conceive naturally. In other cases, the preference is for administration of gonadotropin-releasing hormone analogues before ART, and no surgery beforehand. The strategy of early surgery, however, seems counterintuitive because of beliefs that milder non-surgical options should be offered first and surgery last (only if initial treatment attempts fail). Weighing up the relative advantages of surgery, medical treatment and ART are the foundations for a global approach to infertility associated with endometriosis.

PMID: 20801404 [PubMed - as supplied by publisher]

Galen's "errors".

Lancet. 2010 Aug 28;376(9742):686

Authors: Retsas S

PMID: 20801403 [PubMed - in process]

Galen's "errors".

Lancet. 2010 Aug 28;376(9742):686

Authors: Retsas S

PMID: 20801403 [PubMed - in process]

A harmless high?

Lancet. 2010 Aug 28;376(9742):742

Authors: Sammler EM, Foley PL, Lauder GD, Wilson SJ, Goudie AR, O'Riordan JI

PMID: 20801405 [PubMed - in process]

Endometriosis and infertility: pathophysiology and management.

Lancet. 2010 Aug 28;376(9742):730-738

Authors: de Ziegler D, Borghese B, Chapron C

Endometriosis and infertility are associated clinically. Medical and surgical treatments for endometriosis have different effects on a woman's chances of conception, either spontaneously or via assisted reproductive technologies (ART). Medical treatments for endometriosis are contraceptive. Data, mostly uncontrolled, indicate that surgery at any stage of endometriosis enhances the chances of natural conception. Criteria for non-removal of endometriomas are: bilateral cysts, history of past surgery, and altered ovarian reserve. Fears that surgery can alter ovarian function that is already compromised sparked a rule of no surgery before ART. Exceptions to this guidance are pain, hydrosalpinges, and very large endometriomas. Medical treatment-eg, 3-6 months of gonadotropin-releasing hormone analogues-improves the outcome of ART. When age, ovarian reserve, and male and tubal status permit, surgery should be considered immediately so that time is dedicated to attempts to conceive naturally. In other cases, the preference is for administration of gonadotropin-releasing hormone analogues before ART, and no surgery beforehand. The strategy of early surgery, however, seems counterintuitive because of beliefs that milder non-surgical options should be offered first and surgery last (only if initial treatment attempts fail). Weighing up the relative advantages of surgery, medical treatment and ART are the foundations for a global approach to infertility associated with endometriosis.

PMID: 20801404 [PubMed - as supplied by publisher]

A harmless high?

Lancet. 2010 Aug 28;376(9742):742

Authors: Sammler EM, Foley PL, Lauder GD, Wilson SJ, Goudie AR, O'Riordan JI

PMID: 20801405 [PubMed - in process]

Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis.

Lancet. 2010 Aug 27;

Authors: Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T, Antman EM, Braunwald E, Sabatine MS

BACKGROUND: Clopidogrel and prasugrel are subject to efflux via P-glycoprotein (encoded by ABCB1, also known as MDR1). ABCB1 polymorphisms, particularly 3435C-->T, may affect drug transport and efficacy. We aimed to assess the effect of this polymorphism by itself and alongside variants in CYP2C19 on cardiovascular outcomes in patients treated with clopidogrel or prasugrel in TRITON-TIMI 38. We also assessed the effect of genotype on the pharmacodynamic and pharmacokinetic properties of these drugs in healthy individuals. METHODS: We genotyped ABCB1 in 2932 patients with acute coronary syndromes undergoing percutaneous intervention who were treated with clopidogrel (n=1471) or prasugrel (n=1461) in the TRITON-TIMI 38 trial. We evaluated the association between ABCB1 3435C-->T and rates of the primary efficacy endpoint (cardiovascular death, myocardial infarction, or stroke) until 15 months. We then assessed the combined effect of ABCB1 3435C-->T genotype and reduced-function alleles of CYP2C19. 321 healthy individuals were also genotyped, and we tested the association of genetic variants with reduction in maximum platelet aggregation and plasma concentrations of active drug metabolites. FINDINGS: In patients treated with clopidogrel, ABCB1 3435C-->T genotype was significantly associated with the risk of cardiovascular death, myocardial infarction, or stroke (p=0.0064). TT homozygotes had a 72% increased risk of the primary endpoint compared with CT/CC individuals (Kaplan-Meier event rates 12.9% [52 of 414] vs 7.8% [80 of 1057 participants]; HR 1.72, 95% CI 1.22-2.44, p=0.002). ABCB1 3435C-->T and CYP2C19 genotypes were significant, independent predictors of the primary endpoint, and 681 (47%) of the 1454 genotyped patients taking clopidogrel who were either CYP2C19 reduced-function allele carriers, ABCB1 3435 TT homozygotes, or both were at increased risk of the primary endpoint (HR 1.97, 95% CI 1.38-2.82, p=0.0002). In healthy participants, 3435 TT homozygotes had an absolute reduction in maximum platelet aggregation with clopidogrel that was 7.3 percentage points less than for CT/CC individuals (p=0.0127). ABCB1 genotypes were not significantly associated with clinical or pharmacological outcomes in patients with an acute coronary syndrome or healthy individuals treated with prasugrel, respectively. INTERPRETATION: Individuals with the ABCB1 3435 TT genotype have reduced platelet inhibition and are at increased risk of recurrent ischaemic events during clopidogrel treatment. In patients with acute coronary syndromes who have undergone percutaneous intervention, when both ABCB1 and CYP2C19 are taken into account, nearly half of the population carries a genotype associated with increased risk of major adverse cardiovascular events while on standard doses of clopidogrel. FUNDING: Daiichi Sankyo Company Ltd and Eli Lilly and Company.

PMID: 20801494 [PubMed - as supplied by publisher]

Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis.

Lancet. 2010 Aug 27;

Authors: Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T, Antman EM, Braunwald E, Sabatine MS

BACKGROUND: Clopidogrel and prasugrel are subject to efflux via P-glycoprotein (encoded by ABCB1, also known as MDR1). ABCB1 polymorphisms, particularly 3435C-->T, may affect drug transport and efficacy. We aimed to assess the effect of this polymorphism by itself and alongside variants in CYP2C19 on cardiovascular outcomes in patients treated with clopidogrel or prasugrel in TRITON-TIMI 38. We also assessed the effect of genotype on the pharmacodynamic and pharmacokinetic properties of these drugs in healthy individuals. METHODS: We genotyped ABCB1 in 2932 patients with acute coronary syndromes undergoing percutaneous intervention who were treated with clopidogrel (n=1471) or prasugrel (n=1461) in the TRITON-TIMI 38 trial. We evaluated the association between ABCB1 3435C-->T and rates of the primary efficacy endpoint (cardiovascular death, myocardial infarction, or stroke) until 15 months. We then assessed the combined effect of ABCB1 3435C-->T genotype and reduced-function alleles of CYP2C19. 321 healthy individuals were also genotyped, and we tested the association of genetic variants with reduction in maximum platelet aggregation and plasma concentrations of active drug metabolites. FINDINGS: In patients treated with clopidogrel, ABCB1 3435C-->T genotype was significantly associated with the risk of cardiovascular death, myocardial infarction, or stroke (p=0.0064). TT homozygotes had a 72% increased risk of the primary endpoint compared with CT/CC individuals (Kaplan-Meier event rates 12.9% [52 of 414] vs 7.8% [80 of 1057 participants]; HR 1.72, 95% CI 1.22-2.44, p=0.002). ABCB1 3435C-->T and CYP2C19 genotypes were significant, independent predictors of the primary endpoint, and 681 (47%) of the 1454 genotyped patients taking clopidogrel who were either CYP2C19 reduced-function allele carriers, ABCB1 3435 TT homozygotes, or both were at increased risk of the primary endpoint (HR 1.97, 95% CI 1.38-2.82, p=0.0002). In healthy participants, 3435 TT homozygotes had an absolute reduction in maximum platelet aggregation with clopidogrel that was 7.3 percentage points less than for CT/CC individuals (p=0.0127). ABCB1 genotypes were not significantly associated with clinical or pharmacological outcomes in patients with an acute coronary syndrome or healthy individuals treated with prasugrel, respectively. INTERPRETATION: Individuals with the ABCB1 3435 TT genotype have reduced platelet inhibition and are at increased risk of recurrent ischaemic events during clopidogrel treatment. In patients with acute coronary syndromes who have undergone percutaneous intervention, when both ABCB1 and CYP2C19 are taken into account, nearly half of the population carries a genotype associated with increased risk of major adverse cardiovascular events while on standard doses of clopidogrel. FUNDING: Daiichi Sankyo Company Ltd and Eli Lilly and Company.

PMID: 20801494 [PubMed - as supplied by publisher]

Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial.

Lancet. 2010 Aug 27;

Authors: Böhm M, Swedberg K, Komajda M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L,

BACKGROUND: Raised resting heart rate is a marker of cardiovascular risk. We postulated that heart rate is also a risk factor for cardiovascular events in heart failure. In the SHIFT trial, patients with chronic heart failure were treated with the selective heart-rate-lowering agent ivabradine. We aimed to test our hypothesis by investigating the association between heart rate and events in this patient population. METHODS: We analysed cardiovascular outcomes in the placebo (n=3264) and ivabradine groups (n=3241) of this randomised trial, divided by quintiles of baseline heart rate in the placebo group. The primary composite endpoint was cardiovascular death or hospital admission for worsening heart failure. In the ivabradine group, heart rate achieved at 28 days was also analysed in relation to subsequent outcomes. Analysis adjusted to change in heart rate was used to study heart-rate reduction as mechanism for risk reduction by ivabradine directly. FINDINGS: In the placebo group, patients with the highest heart rates (>/=87 beats per min [bpm], n=682, 286 events) were at more than two-fold higher risk for the primary composite endpoint than were patients with the lowest heart rates (70 to <72 bpm, n=461, 92 events; hazard ratio [HR] 2.34, 95% CI 1.84-2.98, p<0.0001). Risk of primary composite endpoint events increased by 3% with every beat increase from baseline heart rate and 16% for every 5-bpm increase. In the ivabradine group, there was a direct association between heart rate achieved at 28 days and subsequent cardiac outcomes. Patients with heart rates lower than 60 bpm at 28 days on treatment had fewer primary composite endpoint events during the study (n=1192; event rate 17.4%, 95% CI 15.3-19.6) than did patients with higher heart rates. The effect of ivabradine is accounted for by heart-rate reduction, as shown by the neutralisation of the treatment effect after adjustment for change of heart rate at 28 days (HR 0.95, 0.85-1.06, p=0.352). INTERPRETATION: Our analysis confirms that high heart rate is a risk factor in heart failure. Selective lowering of heart rates with ivabradine improves cardiovascular outcomes. Heart rate is an important target for treatment of heart failure. FUNDING: Servier, France.

PMID: 20801495 [PubMed - as supplied by publisher]

Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial.

Lancet. 2010 Aug 27;

Authors: Böhm M, Swedberg K, Komajda M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L,

BACKGROUND: Raised resting heart rate is a marker of cardiovascular risk. We postulated that heart rate is also a risk factor for cardiovascular events in heart failure. In the SHIFT trial, patients with chronic heart failure were treated with the selective heart-rate-lowering agent ivabradine. We aimed to test our hypothesis by investigating the association between heart rate and events in this patient population. METHODS: We analysed cardiovascular outcomes in the placebo (n=3264) and ivabradine groups (n=3241) of this randomised trial, divided by quintiles of baseline heart rate in the placebo group. The primary composite endpoint was cardiovascular death or hospital admission for worsening heart failure. In the ivabradine group, heart rate achieved at 28 days was also analysed in relation to subsequent outcomes. Analysis adjusted to change in heart rate was used to study heart-rate reduction as mechanism for risk reduction by ivabradine directly. FINDINGS: In the placebo group, patients with the highest heart rates (>/=87 beats per min [bpm], n=682, 286 events) were at more than two-fold higher risk for the primary composite endpoint than were patients with the lowest heart rates (70 to <72 bpm, n=461, 92 events; hazard ratio [HR] 2.34, 95% CI 1.84-2.98, p<0.0001). Risk of primary composite endpoint events increased by 3% with every beat increase from baseline heart rate and 16% for every 5-bpm increase. In the ivabradine group, there was a direct association between heart rate achieved at 28 days and subsequent cardiac outcomes. Patients with heart rates lower than 60 bpm at 28 days on treatment had fewer primary composite endpoint events during the study (n=1192; event rate 17.4%, 95% CI 15.3-19.6) than did patients with higher heart rates. The effect of ivabradine is accounted for by heart-rate reduction, as shown by the neutralisation of the treatment effect after adjustment for change of heart rate at 28 days (HR 0.95, 0.85-1.06, p=0.352). INTERPRETATION: Our analysis confirms that high heart rate is a risk factor in heart failure. Selective lowering of heart rates with ivabradine improves cardiovascular outcomes. Heart rate is an important target for treatment of heart failure. FUNDING: Servier, France.

PMID: 20801495 [PubMed - as supplied by publisher]

Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial.

Lancet. 2010 Aug 27;

Authors: Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, Pais P, Dans A, Eikelboom J, Oldgren J, Pogue J, Reilly PA, Yang S, Connolly SJ,

BACKGROUND: Effectiveness and safety of warfarin is associated with the time in therapeutic range (TTR) with an international normalised ratio (INR) of 2.0-3.0. In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, dabigatran versus warfarin reduced both stroke and haemorrhage. We aimed to investigate the primary and secondary outcomes of the RE-LY trial in relation to each centre's mean TTR (cTTR) in the warfarin population. METHODS: In the RE-LY trial, 18 113 patients at 951 sites were randomly assigned to 110 mg or 150 mg dabigatran twice daily versus warfarin dose adjusted to INR 2.0-3.0. Median follow-up was 2.0 years. For 18 024 patients at 906 sites, the cTTR was estimated by averaging TTR for individual warfarin-treated patients calculated by the Rosendaal method. We compared the outcomes of RE-LY across the three treatment groups within four groups defined by the quartiles of cTTR. RE-LY is registered with ClinicalTrials.gov, number NCT00262600. FINDINGS: The quartiles of cTTR for patients in the warfarin group were: less than 57.1%, 57.1-65.5%, 65.5-72.6%, and greater than 72.6%. There were no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg dabigatran (interaction p=0.89) or 150 mg dabigatran (interaction p=0.20) versus warfarin. Neither were any significant interactions recorded with cTTR with regards to intracranial bleeding with 110 mg dabigatran (interaction p=0.71) or 150 mg dabigatran (interaction p=0.89) versus warfarin. There was a significant interaction between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin (interaction p=0.03), with less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than with warfarin irrespective of cTTR. There were significant interactions between cTTR and effects of both 110 mg and 150 mg dabigatran versus warfarin on the composite of all cardiovascular events (interaction p=0.036 and p=0.0006, respectively) and total mortality (interaction p=0.066 and p=0.052, respectively) with reduced event rates at low cTTR, and similar rates at high cTTR. INTERPRETATION: The benefits of 150 mg dabigatran at reducing stroke, 110 mg dabigatran at reducing bleeding, and both doses at reducing intracranial bleeding versus warfarin were consistent irrespective of centres' quality of INR control. For all vascular events, non-haemorrhagic events, and mortality, advantages of dabigatran were greater at sites with poor INR control than at those with good INR control. Overall, these results show that local standards of care affect the benefits of use of new treatment alternatives. FUNDING: Boehringer Ingelheim.

PMID: 20801496 [PubMed - as supplied by publisher]

Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial.

Lancet. 2010 Aug 27;

Authors: Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, Pais P, Dans A, Eikelboom J, Oldgren J, Pogue J, Reilly PA, Yang S, Connolly SJ,

BACKGROUND: Effectiveness and safety of warfarin is associated with the time in therapeutic range (TTR) with an international normalised ratio (INR) of 2.0-3.0. In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, dabigatran versus warfarin reduced both stroke and haemorrhage. We aimed to investigate the primary and secondary outcomes of the RE-LY trial in relation to each centre's mean TTR (cTTR) in the warfarin population. METHODS: In the RE-LY trial, 18 113 patients at 951 sites were randomly assigned to 110 mg or 150 mg dabigatran twice daily versus warfarin dose adjusted to INR 2.0-3.0. Median follow-up was 2.0 years. For 18 024 patients at 906 sites, the cTTR was estimated by averaging TTR for individual warfarin-treated patients calculated by the Rosendaal method. We compared the outcomes of RE-LY across the three treatment groups within four groups defined by the quartiles of cTTR. RE-LY is registered with ClinicalTrials.gov, number NCT00262600. FINDINGS: The quartiles of cTTR for patients in the warfarin group were: less than 57.1%, 57.1-65.5%, 65.5-72.6%, and greater than 72.6%. There were no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg dabigatran (interaction p=0.89) or 150 mg dabigatran (interaction p=0.20) versus warfarin. Neither were any significant interactions recorded with cTTR with regards to intracranial bleeding with 110 mg dabigatran (interaction p=0.71) or 150 mg dabigatran (interaction p=0.89) versus warfarin. There was a significant interaction between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin (interaction p=0.03), with less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than with warfarin irrespective of cTTR. There were significant interactions between cTTR and effects of both 110 mg and 150 mg dabigatran versus warfarin on the composite of all cardiovascular events (interaction p=0.036 and p=0.0006, respectively) and total mortality (interaction p=0.066 and p=0.052, respectively) with reduced event rates at low cTTR, and similar rates at high cTTR. INTERPRETATION: The benefits of 150 mg dabigatran at reducing stroke, 110 mg dabigatran at reducing bleeding, and both doses at reducing intracranial bleeding versus warfarin were consistent irrespective of centres' quality of INR control. For all vascular events, non-haemorrhagic events, and mortality, advantages of dabigatran were greater at sites with poor INR control than at those with good INR control. Overall, these results show that local standards of care affect the benefits of use of new treatment alternatives. FUNDING: Boehringer Ingelheim.

PMID: 20801496 [PubMed - as supplied by publisher]

Response to antiplatelet treatment: from genes to outcome.

Lancet. 2010 Aug 27;

Authors: Giusti B, Abbate R

PMID: 20801497 [PubMed - as supplied by publisher]

Response to antiplatelet treatment: from genes to outcome.

Lancet. 2010 Aug 27;

Authors: Giusti B, Abbate R

PMID: 20801497 [PubMed - as supplied by publisher]

Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial.

Lancet. 2010 Aug 27;

Authors: Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J, Husted S, Katus H, Steg PG, Shah SH, Becker RC,

BACKGROUND: In the PLATO trial of ticagrelor versus clopidogrel for treatment of acute coronary syndromes, ticagrelor reduced the composite outcome of cardiovascular death, myocardial infarction, and stroke, but increased events of major bleeding related to non-coronary artery bypass graft (CABG). CYP2C19 and ABCB1 genotypes are known to influence the effects of clopidogrel. In this substudy, we investigated the effects of these genotypes on outcomes between and within treatment groups. METHODS: DNA samples obtained from patients in the PLATO trial were genotyped for CYP2C19 loss-of-function alleles (*2, *3, *4, *5, *6, *7, and *8), the CYP2C19 gain-of-function allele *17, and the ABCB1 single nucleotide polymorphism 3435C-->T. For the CYP2C19 genotype, patients were stratified by the presence or absence of any loss-of-function allele, and for the ABCB1 genotype, patients were stratified by predicted gene expression (high, intermediate, or low). The primary efficacy endpoint was the composite of cardiovascular death, myocardial infarction, or stroke after up to 12 months' treatment with ticagrelor or clopidogrel. FINDINGS: 10 285 patients provided samples for genetic analysis. The primary outcome occurred less often with ticagrelor versus clopidogrel, irrespective of CYP2C19 genotype: 8.6% versus 11.2% (hazard ratio 0.77, 95% CI 0.60-0.99, p=0.0380) in patients with any loss-of-function allele; and 8.8% versus 10.0% (0.86, 0.74-1.01, p=0.0608) in those without any loss-of-function allele (interaction p=0.46). For the ABCB1 genotype, event rates for the primary outcome were also consistently lower in the ticagrelor than in the clopidogrel group for all genotype groups (interaction p=0.39; 8.8%vs 11.9%; 0.71, 0.55-0.92 for the high-expression genotype). In the clopidogrel group, the event rate at 30 days was higher in patients with than in those without any loss-of-function CYP2C19 alleles (5.7%vs 3.8%, p=0.028), leading to earlier separation of event rates between treatment groups in patients with loss-of-function alleles. Patients on clopidogrel who had any gain-of-function CYP2C19 allele had a higher frequency of major bleeding (11.9%) than did those without any gain-of-function or loss-of-function alleles (9.5%; p=0.022), but interaction between treatment and genotype groups was not significant for any type of major bleeding. INTERPRETATION: Ticagrelor is a more efficacious treatment for acute coronary syndromes than is clopidogrel, irrespective of CYP2C19 and ABCB1 polymorphisms. Use of ticagrelor instead of clopidogrel eliminates the need for presently recommended genetic testing before dual antiplatelet treatment. FUNDING: AstraZeneca.

PMID: 20801498 [PubMed - as supplied by publisher]

Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial.

Lancet. 2010 Aug 27;

Authors: Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J, Husted S, Katus H, Steg PG, Shah SH, Becker RC,

BACKGROUND: In the PLATO trial of ticagrelor versus clopidogrel for treatment of acute coronary syndromes, ticagrelor reduced the composite outcome of cardiovascular death, myocardial infarction, and stroke, but increased events of major bleeding related to non-coronary artery bypass graft (CABG). CYP2C19 and ABCB1 genotypes are known to influence the effects of clopidogrel. In this substudy, we investigated the effects of these genotypes on outcomes between and within treatment groups. METHODS: DNA samples obtained from patients in the PLATO trial were genotyped for CYP2C19 loss-of-function alleles (*2, *3, *4, *5, *6, *7, and *8), the CYP2C19 gain-of-function allele *17, and the ABCB1 single nucleotide polymorphism 3435C-->T. For the CYP2C19 genotype, patients were stratified by the presence or absence of any loss-of-function allele, and for the ABCB1 genotype, patients were stratified by predicted gene expression (high, intermediate, or low). The primary efficacy endpoint was the composite of cardiovascular death, myocardial infarction, or stroke after up to 12 months' treatment with ticagrelor or clopidogrel. FINDINGS: 10 285 patients provided samples for genetic analysis. The primary outcome occurred less often with ticagrelor versus clopidogrel, irrespective of CYP2C19 genotype: 8.6% versus 11.2% (hazard ratio 0.77, 95% CI 0.60-0.99, p=0.0380) in patients with any loss-of-function allele; and 8.8% versus 10.0% (0.86, 0.74-1.01, p=0.0608) in those without any loss-of-function allele (interaction p=0.46). For the ABCB1 genotype, event rates for the primary outcome were also consistently lower in the ticagrelor than in the clopidogrel group for all genotype groups (interaction p=0.39; 8.8%vs 11.9%; 0.71, 0.55-0.92 for the high-expression genotype). In the clopidogrel group, the event rate at 30 days was higher in patients with than in those without any loss-of-function CYP2C19 alleles (5.7%vs 3.8%, p=0.028), leading to earlier separation of event rates between treatment groups in patients with loss-of-function alleles. Patients on clopidogrel who had any gain-of-function CYP2C19 allele had a higher frequency of major bleeding (11.9%) than did those without any gain-of-function or loss-of-function alleles (9.5%; p=0.022), but interaction between treatment and genotype groups was not significant for any type of major bleeding. INTERPRETATION: Ticagrelor is a more efficacious treatment for acute coronary syndromes than is clopidogrel, irrespective of CYP2C19 and ABCB1 polymorphisms. Use of ticagrelor instead of clopidogrel eliminates the need for presently recommended genetic testing before dual antiplatelet treatment. FUNDING: AstraZeneca.

PMID: 20801498 [PubMed - as supplied by publisher]

Quality of anticoagulation control in atrial fibrillation.

Lancet. 2010 Aug 27;

Authors: Lane DA, Lip GY

PMID: 20801499 [PubMed - as supplied by publisher]

Quality of anticoagulation control in atrial fibrillation.

Lancet. 2010 Aug 27;

Authors: Lane DA, Lip GY

PMID: 20801499 [PubMed - as supplied by publisher]

Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.

Lancet. 2010 Aug 27;

Authors: Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L,

BACKGROUND: Chronic heart failure is associated with high mortality and morbidity. Raised resting heart rate is a risk factor for adverse outcomes. We aimed to assess the effect of heart-rate reduction by the selective sinus-node inhibitor ivabradine on outcomes in heart failure. METHODS: Patients were eligible for participation in this randomised, double-blind, placebo-controlled, parallel-group study if they had symptomatic heart failure and a left-ventricular ejection fraction of 35% or lower, were in sinus rhythm with heart rate 70 beats per min or higher, had been admitted to hospital for heart failure within the previous year, and were on stable background treatment including a beta blocker if tolerated. Patients were randomly assigned by computer-generated allocation schedule to ivabradine titrated to a maximum of 7.5 mg twice daily or matching placebo. Patients and investigators were masked to treatment allocation. The primary endpoint was the composite of cardiovascular death or hospital admission for worsening heart failure. Analysis was by intention to treat. This trial is registered, number ISRCTN70429960. FINDINGS: 6558 patients were randomly assigned to treatment groups (3268 ivabradine, 3290 placebo). Data were available for analysis for 3241 patients in the ivabradine group and 3264 patients allocated placebo. Median follow-up was 22.9 (IQR 18-28) months. 793 (24%) patients in the ivabradine group and 937 (29%) of those taking placebo had a primary endpoint event (HR 0.82, 95% CI 0.75-0.90, p<0.0001). The effects were driven mainly by hospital admissions for worsening heart failure (672 [21%] placebo vs 514 [16%] ivabradine; HR 0.74, 0.66-0.83; p<0.0001) and deaths due to heart failure (151 [5%] vs 113 [3%]; HR 0.74, 0.58-0.94, p=0.014). Fewer serious adverse events occurred in the ivabradine group (3388 events) than in the placebo group (3847; p=0.025). 150 (5%) of ivabradine patients had symptomatic bradycardia compared with 32 (1%) of the placebo group (p<0.0001). Visual side-effects (phosphenes) were reported by 89 (3%) of patients on ivabradine and 17 (1%) on placebo (p<0.0001). INTERPRETATION: Our results support the importance of heart-rate reduction with ivabradine for improvement of clinical outcomes in heart failure and confirm the important role of heart rate in the pathophysiology of this disorder. FUNDING: Servier, France.

PMID: 20801500 [PubMed - as supplied by publisher]

Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.

Lancet. 2010 Aug 27;

Authors: Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L,

BACKGROUND: Chronic heart failure is associated with high mortality and morbidity. Raised resting heart rate is a risk factor for adverse outcomes. We aimed to assess the effect of heart-rate reduction by the selective sinus-node inhibitor ivabradine on outcomes in heart failure. METHODS: Patients were eligible for participation in this randomised, double-blind, placebo-controlled, parallel-group study if they had symptomatic heart failure and a left-ventricular ejection fraction of 35% or lower, were in sinus rhythm with heart rate 70 beats per min or higher, had been admitted to hospital for heart failure within the previous year, and were on stable background treatment including a beta blocker if tolerated. Patients were randomly assigned by computer-generated allocation schedule to ivabradine titrated to a maximum of 7.5 mg twice daily or matching placebo. Patients and investigators were masked to treatment allocation. The primary endpoint was the composite of cardiovascular death or hospital admission for worsening heart failure. Analysis was by intention to treat. This trial is registered, number ISRCTN70429960. FINDINGS: 6558 patients were randomly assigned to treatment groups (3268 ivabradine, 3290 placebo). Data were available for analysis for 3241 patients in the ivabradine group and 3264 patients allocated placebo. Median follow-up was 22.9 (IQR 18-28) months. 793 (24%) patients in the ivabradine group and 937 (29%) of those taking placebo had a primary endpoint event (HR 0.82, 95% CI 0.75-0.90, p<0.0001). The effects were driven mainly by hospital admissions for worsening heart failure (672 [21%] placebo vs 514 [16%] ivabradine; HR 0.74, 0.66-0.83; p<0.0001) and deaths due to heart failure (151 [5%] vs 113 [3%]; HR 0.74, 0.58-0.94, p=0.014). Fewer serious adverse events occurred in the ivabradine group (3388 events) than in the placebo group (3847; p=0.025). 150 (5%) of ivabradine patients had symptomatic bradycardia compared with 32 (1%) of the placebo group (p<0.0001). Visual side-effects (phosphenes) were reported by 89 (3%) of patients on ivabradine and 17 (1%) on placebo (p<0.0001). INTERPRETATION: Our results support the importance of heart-rate reduction with ivabradine for improvement of clinical outcomes in heart failure and confirm the important role of heart rate in the pathophysiology of this disorder. FUNDING: Servier, France.

PMID: 20801500 [PubMed - as supplied by publisher]

Ivabradine in heart failure-no paradigm SHIFT...yet.

Lancet. 2010 Aug 27;

Authors: Teerlink JR

PMID: 20801501 [PubMed - as supplied by publisher]

Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study.

Lancet. 2010 Aug 23;

Authors: Cheng G, Saleh MN, Marcher C, Vasey S, Mayer B, Aivado M, Arning M, Stone NL, Bussel JB

BACKGROUND: Eltrombopag is an oral thrombopoietin receptor agonist for the treatment of thrombocytopenia. We aimed to compare the response to once daily eltrombopag versus placebo in patients with chronic immune thrombocytopenia during a 6-month period. METHODS: We undertook a phase 3, double-blind, placebo-controlled study in adults with previously treated immune thrombocytopenia of more than 6 months' duration who had baseline platelet counts lower than 30 000 per muL. Patients were randomly allocated (in a 2:1 ratio) treatment with local standard of care plus 50 mg eltrombopag or matching placebo once daily for 6 months. Randomisation was done centrally with a computer-generated randomisation schedule and was stratified by baseline platelet count (</=15 000 per muL), use of treatment for immune thrombocytopenia, and splenectomy status. Patients, investigators, and those assessing data were masked to allocation. Dose modifications were made on the basis of platelet response. Patients were assessed for response to treatment (defined as a platelet count of 50 000-400 000 per muL) weekly during the first 6 weeks and at least once every 4 weeks thereafter; the primary endpoint was the odds of response to eltrombopag versus placebo. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, number NCT00370331. FINDINGS: Between Nov 22, 2006, and July 31, 2007, 197 patients were randomly allocated to treatment groups and were included in the intention-to-treat analysis (135 eltrombopag, 62 placebo). 106 (79%) patients in the eltrombopag group responded to treatment at least once during the study, compared with 17 (28%) patients in the placebo group. The odds of responding were greater in patients in the eltrombopag group compared with those in the placebo group throughout the 6-month treatment period (odds ratio 8.2, 99% CI 3.59-18.73; p<0.0001). 37 (59%) patients receiving eltrombopag reduced concomitant treatment versus ten (32%) patients receiving placebo (p=0.016). 24 (18%) patients receiving eltrombopag needed rescue treatment compared with 25 (40%) patients receiving placebo (p=0.001). Three (2%) patients receiving eltrombopag had thromboembolic events compared with none in patients on placebo. Nine (7%) eltrombopag-treated patients and two (3%) in the placebo group had mild increases in alanine aminotransferase concentration, and five (4%) eltrombopag-treated patients (vs none allocated to placebo) had increases in total bilirubin. Four (7%) patients taking placebo had serious bleeding events, compared with one (<1%) patient treated with eltrombopag. INTERPRETATION: Eltrombopag is effective for management of chronic immune thrombocytopenia, and could be particularly beneficial for patients who have not responded to splenectomy or previous treatment. These benefits should be balanced with the potential risks associated with eltrombopag treatment. FUNDING: GlaxoSmithKline.

PMID: 20739054 [PubMed - as supplied by publisher]

Lymphatic filariasis and onchocerciasis.

Lancet. 2010 Aug 23;

Authors: Taylor MJ, Hoerauf A, Bockarie M

Lymphatic filariasis and onchocerciasis are parasitic helminth diseases that constitute a serious public health issue in tropical regions. The filarial nematodes that cause these diseases are transmitted by blood-feeding insects and produce chronic and long-term infection through suppression of host immunity. Disease pathogenesis is linked to host inflammation invoked by the death of the parasite, causing hydrocoele, lymphoedema, and elephantiasis in lymphatic filariasis, and skin disease and blindness in onchocerciasis. Most filarial species that infect people co-exist in mutualistic symbiosis with Wolbachia bacteria, which are essential for growth, development, and survival of their nematode hosts. These endosymbionts contribute to inflammatory disease pathogenesis and are a target for doxycycline therapy, which delivers macrofilaricidal activity, improves pathological outcomes, and is effective as monotherapy. Drugs to treat filariasis include diethylcarbamazine, ivermectin, and albendazole, which are used mostly in combination to reduce microfilariae in blood (lymphatic filariasis) and skin (onchocerciasis). Global programmes for control and elimination have been developed to provide sustained delivery of drugs to affected communities to interrupt transmission of disease and ultimately eliminate this burden on public health.

PMID: 20739055 [PubMed - as supplied by publisher]

Sustaining platelet counts in chronic ITP.

Lancet. 2010 Aug 23;

Authors: Nurden AT

PMID: 20739056 [PubMed - as supplied by publisher]

Niger's hunger crisis: a legacy of lessons unlearned.

Lancet. 2010 Aug 21;376(9741):579-81

Authors: Loewenberg S

PMID: 20734465 [PubMed - in process]

Donald Berwick takes charge of Medicare and Medicaid.

Lancet. 2010 Aug 21;376(9741):582

Authors: Bristol N

PMID: 20734466 [PubMed - in process]

Overcoming the social death of dementia through language.

Lancet. 2010 Aug 21;376(9741):586-7

Authors: George DR

PMID: 20734467 [PubMed - in process]

Analysis of factors that affect outcome after transplantation of kidneys donated after cardiac death in the UK: a cohort study.

Lancet. 2010 Aug 18;

Authors: Summers DM, Johnson RJ, Allen J, Fuggle SV, Collett D, Watson CJ, Bradley JA

BACKGROUND: A third of all kidneys from deceased donors in the UK are donated after cardiac death, but concerns have been raised about the long-term outcome of such transplants. We aimed to establish these outcomes for kidneys donated after controlled cardiac death versus brain death, and to identify the factors that affect graft survival and function. METHODS: We used data from the UK transplant registry to select a cohort of deceased kidney donors and the corresponding transplant recipients (aged >/=18 years) for transplantations done between Jan 1, 2000, and Dec 31, 2007. Kaplan-Meier estimates were used to assess graft survival, and multivariate analyses were used to identify factors associated with graft survival and with long-term renal function, which was measured from estimated glomerular filtration rate (eGFR). FINDINGS: 9134 kidney transplants were done in 23 centres; 8289 kidneys were donated after brain death and 845 after controlled cardiac death. First-time recipients of kidneys from cardiac-death donors (n=739) or brain-death donors (n=6759) showed no difference in graft survival up to 5 years (hazard ratio 1.01, 95% CI 0.83 to 1.19, p=0.97), or in eGFR at 1-5 years after transplantation (at 12 months -0.36 mL/min per 1.73 m(2), 95% CI -2.00 to 1.27, p=0.66). For recipients of kidneys from cardiac-death donors, increasing age of donor and recipient, repeat transplantation, and cold ischaemic time of more than 12 h were associated with worse graft survival; grafts from cardiac-death donors that were poorly matched for HLA had an association with inferior outcome that was not significant, and delayed graft function and warm ischaemic time had no effect on outcome. INTERPRETATION: Kidneys from controlled cardiac-death donors provide good graft survival and function up to 5 years in first-time recipients, and are equivalent to kidneys from brain-death donors. Allocation policy for kidneys from cardiac-death donors should reduce cold ischaemic time, avoid large age mismatches between donors and recipients, and restrict use of kidneys poorly matched for HLA in young recipients. FUNDING: UK National Health Service Blood and Transplant, and Cambridge National Institute for Health Research Biomedical Research Centre.

PMID: 20727576 [PubMed - as supplied by publisher]

Analysis of factors that affect outcome after transplantation of kidneys donated after cardiac death in the UK: a cohort study.

Lancet. 2010 Aug 18;

Authors: Summers DM, Johnson RJ, Allen J, Fuggle SV, Collett D, Watson CJ, Bradley JA

BACKGROUND: A third of all kidneys from deceased donors in the UK are donated after cardiac death, but concerns have been raised about the long-term outcome of such transplants. We aimed to establish these outcomes for kidneys donated after controlled cardiac death versus brain death, and to identify the factors that affect graft survival and function. METHODS: We used data from the UK transplant registry to select a cohort of deceased kidney donors and the corresponding transplant recipients (aged >/=18 years) for transplantations done between Jan 1, 2000, and Dec 31, 2007. Kaplan-Meier estimates were used to assess graft survival, and multivariate analyses were used to identify factors associated with graft survival and with long-term renal function, which was measured from estimated glomerular filtration rate (eGFR). FINDINGS: 9134 kidney transplants were done in 23 centres; 8289 kidneys were donated after brain death and 845 after controlled cardiac death. First-time recipients of kidneys from cardiac-death donors (n=739) or brain-death donors (n=6759) showed no difference in graft survival up to 5 years (hazard ratio 1.01, 95% CI 0.83 to 1.19, p=0.97), or in eGFR at 1-5 years after transplantation (at 12 months -0.36 mL/min per 1.73 m(2), 95% CI -2.00 to 1.27, p=0.66). For recipients of kidneys from cardiac-death donors, increasing age of donor and recipient, repeat transplantation, and cold ischaemic time of more than 12 h were associated with worse graft survival; grafts from cardiac-death donors that were poorly matched for HLA had an association with inferior outcome that was not significant, and delayed graft function and warm ischaemic time had no effect on outcome. INTERPRETATION: Kidneys from controlled cardiac-death donors provide good graft survival and function up to 5 years in first-time recipients, and are equivalent to kidneys from brain-death donors. Allocation policy for kidneys from cardiac-death donors should reduce cold ischaemic time, avoid large age mismatches between donors and recipients, and restrict use of kidneys poorly matched for HLA in young recipients. FUNDING: UK National Health Service Blood and Transplant, and Cambridge National Institute for Health Research Biomedical Research Centre.

PMID: 20727576 [PubMed - as supplied by publisher]

Kidneys donated after cardiac death are acceptable.

Lancet. 2010 Aug 18;

Authors: Morris PJ

PMID: 20727577 [PubMed - as supplied by publisher]

Kidneys donated after cardiac death are acceptable.

Lancet. 2010 Aug 18;

Authors: Morris PJ

PMID: 20727577 [PubMed - as supplied by publisher]

Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.

Lancet. 2010 Aug 19;

Authors: Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK,

BACKGROUND: Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer. METHODS: ToGA (Trastuzumab for Gastric Cancer) was an open-label, international, phase 3, randomised controlled trial undertaken in 122 centres in 24 countries. Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Participants were randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab. Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status, chemotherapy regimen, extent of disease, primary cancer site, and measurability of disease, implemented with a central interactive voice recognition system. The primary endpoint was overall survival in all randomised patients who received study medication at least once. This trial is registered with ClinicalTrials.gov, number NCT01041404. FINDINGS: 594 patients were randomly assigned to study treatment (trastuzumab plus chemotherapy, n=298; chemotherapy alone, n=296), of whom 584 were included in the primary analysis (n=294; n=290). Median follow-up was 18.6 months (IQR 11-25) in the trastuzumab plus chemotherapy group and 17.1 months (9-25) in the chemotherapy alone group. Median overall survival was 13.8 months (95% CI 12-16) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months (10-13) in those assigned to chemotherapy alone (hazard ratio 0.74; 95% CI 0.60-0.91; p=0.0046). The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197 [67%] vs chemotherapy alone, 184 [63%]), vomiting (147 [50%] vs 134 [46%]), and neutropenia (157 [53%] vs 165 [57%]). Rates of overall grade 3 or 4 adverse events (201 [68%] vs 198 [68%]) and cardiac adverse events (17 [6%] vs 18 [6%]) did not differ between groups. INTERPRETATION: Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. FUNDING: F Hoffmann-La Roche.

PMID: 20728210 [PubMed - as supplied by publisher]

Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.

Lancet. 2010 Aug 19;

Authors: Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK,

BACKGROUND: Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer. METHODS: ToGA (Trastuzumab for Gastric Cancer) was an open-label, international, phase 3, randomised controlled trial undertaken in 122 centres in 24 countries. Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Participants were randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab. Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status, chemotherapy regimen, extent of disease, primary cancer site, and measurability of disease, implemented with a central interactive voice recognition system. The primary endpoint was overall survival in all randomised patients who received study medication at least once. This trial is registered with ClinicalTrials.gov, number NCT01041404. FINDINGS: 594 patients were randomly assigned to study treatment (trastuzumab plus chemotherapy, n=298; chemotherapy alone, n=296), of whom 584 were included in the primary analysis (n=294; n=290). Median follow-up was 18.6 months (IQR 11-25) in the trastuzumab plus chemotherapy group and 17.1 months (9-25) in the chemotherapy alone group. Median overall survival was 13.8 months (95% CI 12-16) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months (10-13) in those assigned to chemotherapy alone (hazard ratio 0.74; 95% CI 0.60-0.91; p=0.0046). The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197 [67%] vs chemotherapy alone, 184 [63%]), vomiting (147 [50%] vs 134 [46%]), and neutropenia (157 [53%] vs 165 [57%]). Rates of overall grade 3 or 4 adverse events (201 [68%] vs 198 [68%]) and cardiac adverse events (17 [6%] vs 18 [6%]) did not differ between groups. INTERPRETATION: Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. FUNDING: F Hoffmann-La Roche.

PMID: 20728210 [PubMed - as supplied by publisher]

Pandemic influenza--(some) reasons to be cheerful?

Lancet. 2010 Aug 21;376(9741):565

Authors:

PMID: 20728735 [PubMed - in process]

Pandemic influenza--(some) reasons to be cheerful?

Lancet. 2010 Aug 21;376(9741):565

Authors:

PMID: 20728735 [PubMed - in process]

Cancer research in the global village.

Lancet. 2010 Aug 19;

Authors: Munro AJ, Niblock PG

PMID: 20728211 [PubMed - as supplied by publisher]

Cancer research in the global village.

Lancet. 2010 Aug 19;

Authors: Munro AJ, Niblock PG

PMID: 20728211 [PubMed - as supplied by publisher]

Rheumatoid arthritis: new guidelines open new doors.

Lancet. 2010 Aug 21;376(9741):566

Authors:

PMID: 20728737 [PubMed - in process]

Rheumatoid arthritis: new guidelines open new doors.

Lancet. 2010 Aug 21;376(9741):566

Authors:

PMID: 20728737 [PubMed - in process]

Do cry for Argentina.

Lancet. 2010 Aug 21;376(9741):566

Authors:

PMID: 20728736 [PubMed - in process]

Do cry for Argentina.

Lancet. 2010 Aug 21;376(9741):566

Authors:

PMID: 20728736 [PubMed - in process]

Childhood cancer survivors: stillbirth and neonatal death.

Lancet. 2010 Aug 21;376(9741):570-2

Authors: Viswanathan AN

PMID: 20728738 [PubMed - in process]

Childhood cancer survivors: stillbirth and neonatal death.

Lancet. 2010 Aug 21;376(9741):570-2

Authors: Viswanathan AN

PMID: 20728738 [PubMed - in process]

The India HPV-vaccine suspension.

Lancet. 2010 Aug 21;376(9741):572-3

Authors: Larson HJ, Brocard P, Garnett G

PMID: 20728739 [PubMed - in process]

The India HPV-vaccine suspension.

Lancet. 2010 Aug 21;376(9741):572-3

Authors: Larson HJ, Brocard P, Garnett G

PMID: 20728739 [PubMed - in process]

Is advanced renal cell carcinoma becoming a chronic disease?

Lancet. 2010 Aug 21;376(9741):574-5

Authors: Larkin J, Gore M

PMID: 20728740 [PubMed - in process]

Is advanced renal cell carcinoma becoming a chronic disease?

Lancet. 2010 Aug 21;376(9741):574-5

Authors: Larkin J, Gore M

PMID: 20728740 [PubMed - in process]

Homoeopathy waives the rules.

Lancet. 2010 Aug 21;376(9741):577

Authors: Baum M

PMID: 20728742 [PubMed - in process]

The epidemiology of mine accidents in China.

Lancet. 2010 Aug 21;376(9741):575-7

Authors: Chan EY, Griffiths SM

PMID: 20728741 [PubMed - in process]

The epidemiology of mine accidents in China.

Lancet. 2010 Aug 21;376(9741):575-7

Authors: Chan EY, Griffiths SM

PMID: 20728741 [PubMed - in process]

Homoeopathy waives the rules.

Lancet. 2010 Aug 21;376(9741):577

Authors: Baum M

PMID: 20728742 [PubMed - in process]

Nostalgia.

Lancet. 2010 Aug 21;376(9741):585

Authors: Sullivan E

PMID: 20728745 [PubMed - in process]

Nostalgia.

Lancet. 2010 Aug 21;376(9741):585

Authors: Sullivan E

PMID: 20728745 [PubMed - in process]

An interview with Nancy Davidson.

Lancet. 2010 Aug 21;376(9741):585

Authors: Davidson N

PMID: 20728744 [PubMed - in process]

An interview with Nancy Davidson.

Lancet. 2010 Aug 21;376(9741):585

Authors: Davidson N

PMID: 20728744 [PubMed - in process]

Is the UK's coalition Government serious about public health?

Lancet. 2010 Aug 21;376(9741):589

Authors: Aveyard P, Amos A, Bauld L, Britton J, Coleman T, Docherty G, Godfrey C, Hajek P, Hastings G, McNeill A, Lewis S, Munafo M, West R

PMID: 20728746 [PubMed - in process]

Is the UK's coalition Government serious about public health?

Lancet. 2010 Aug 21;376(9741):589

Authors: Aveyard P, Amos A, Bauld L, Britton J, Coleman T, Docherty G, Godfrey C, Hajek P, Hastings G, McNeill A, Lewis S, Munafo M, West R

PMID: 20728746 [PubMed - in process]

Effect of development assistance on domestic health expenditures.

Lancet. 2010 Aug 21;376(9741):589-90; author reply 592-3

Authors: Baker B

PMID: 20728747 [PubMed - in process]

Effect of development assistance on domestic health expenditures.

Lancet. 2010 Aug 21;376(9741):589-90; author reply 592-3

Authors: Baker B

PMID: 20728747 [PubMed - in process]

Effect of development assistance on domestic health expenditures.

Lancet. 2010 Aug 21;376(9741):590-1; author reply 592-3

Authors: Wright S

PMID: 20728748 [PubMed - in process]

Effect of development assistance on domestic health expenditures.

Lancet. 2010 Aug 21;376(9741):590-1; author reply 592-3

Authors: Wright S

PMID: 20728748 [PubMed - in process]

Effect of development assistance on domestic health expenditures.

Lancet. 2010 Aug 21;376(9741):590; author reply 592-3

Authors: deRiel E, Fort M, Barry D

PMID: 20728749 [PubMed - in process]

Effect of development assistance on domestic health expenditures.

Lancet. 2010 Aug 21;376(9741):590; author reply 592-3

Authors: deRiel E, Fort M, Barry D

PMID: 20728749 [PubMed - in process]

Effect of development assistance on domestic health expenditures.

Lancet. 2010 Aug 21;376(9741):591; author reply 592-3

Authors: Moatti JP, Abu-Zaineh M, Teyssier LS

PMID: 20728750 [PubMed - in process]