Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2

A panel of members of the 2009 International Myeloma Workshop developed guidelines for risk stratification in multiple myeloma. The purpose of risk stratification is not to decide time of therapy but to prognosticate. There is general consensus that risk stratification is applicable to newly diagnosed patients; however, some genetic abnormalities characteristic of poor outcome at diagnosis may suggest poor outcome if only detected at the time of relapse. Thus, in good-risk patients, it is necessary to evaluate for high-risk features at relapse. Although detection of any cytogenetic abnormality is considered to suggest higher-risk disease, the specific abnormalities considered as poor risk are cytogenetically detected chromosomal 13 or 13q deletion, t(4;14) and del17p, and detection by fluorescence in situ hybridization of t(4;14), t(14;16), and del17p. Detection of 13q deletion by fluorescence in situ hybridization only, in absence of other abnormalities, is not considered a high-risk feature. High serum β(2)-microglobulin level and International Staging System stages II and III, incorporating high β(2)-microglobulin and low albumin, are considered to predict higher risk disease. There was a consensus that the high-risk features will change in the future, with introduction of other new agents or possibly new combinations.     

Triple-combination antiviral drug for pandemic H1N1 influenza virus infection in critically ill patients on mechanical ventilation

A recent in vitro study showed that the three compounds of antiviral drugs with different mechanisms of action (amantadine, ribavirin, and oseltamivir) could result in synergistic antiviral activity against influenza virus. However, no clinical studies have evaluated the efficacy and safety of combination antiviral therapy in patients with severe influenza illness. A total of 245 adult patients who were critically ill with confirmed pandemic influenza A/H1N1 2009 (pH1N1) virus infection and were admitted to one of the intensive care units of 28 hospitals in Korea were reviewed. Patients who required ventilator support and received either triple-combination antiviral drug (TCAD) therapy or oseltamivir monotherapy were analyzed. A total of 127 patients were included in our analysis. Among them, 24 patients received TCAD therapy, and 103 patients received oseltamivir monotherapy. The 14-day mortality was 17% in the TCAD group and 35% in the oseltamivir group (P = 0.08), and the 90-day mortality was 46% in the TCAD group and 59% in the oseltamivir group (P = 0.23). None of the toxicities attributable to antiviral drugs occurred in either group of our study, including hemolytic anemia and hepatic toxicities related to the use of ribavirin. Logistic regression analysis indicated that the odds ratio for the association of TCAD with 90-day mortality was 0.58 (95% confidence interval, 0.24 to 1.42; P = 0.24). Although this study was retrospective and did not provide virologic outcomes, our results suggest that the treatment outcome of the triple combination of amantadine, ribavirin, and oseltamivir was comparable to that of oseltamivir monotherapy.     

Glycemic thresholds for diabetes-specific retinopathy: implications for diagnostic criteria for diabetes

OBJECTIVE

To re-evaluate the relationship between glycemia and diabetic retinopathy.

RESEARCH DESIGN AND METHODS

We conducted a data-pooling analysis of nine studies from five countries with 44,623 participants aged 20–79 years with gradable retinal photographs. The relationship between diabetes-specific retinopathy (defined as moderate or more severe retinopathy) and three glycemic measures (fasting plasma glucose [FPG; n = 41,411], 2-h post oral glucose load plasma glucose [2-h PG; n = 21,334], and A1C [n = 28,010]) was examined.

RESULTS

When diabetes-specific retinopathy was plotted against continuous glycemic measures, a curvilinear relationship was observed for FPG and A1C. Diabetes-specific retinopathy prevalence was low for FPG <6.0 mmol/l and A1C <6.0% but increased above these levels. Based on vigintile (20 groups with equal numbers) distributions, glycemic thresholds for diabetes-specific retinopathy were observed over the range of 6.4–6.8 mmol/l for FPG, 9.8–10.6 mmol/l for 2-h PG, and 6.3–6.7% for A1C. Thresholds for diabetes-specific retinopathy from receiver-operating characteristic curve analyses were 6.6 mmol/l for FPG, 13.0 mmol/l for 2-h PG, and 6.4% for A1C.

CONCLUSIONS

This study broadens the evidence based on diabetes diagnostic criteria. A narrow threshold range for diabetes-specific retinopathy was identified for FPG and A1C but not for 2-h PG. The combined analyses suggest that the current diabetes diagnostic level for FPG could be lowered to 6.5 mmol/l and that an A1C of 6.5% is a suitable alternative diagnostic criterion.The current diagnostic cut points for diabetes (fasting plasma glucose [FPG] of 7.0 mmol/l and 2-h post oral glucose load plasma glucose [2-h PG] of 11.1 mmol/l) are largely based on glycemic levels associated with a substantially increased risk of diabetes-associated microvascular complications, particularly retinopathy, above these levels (1,2). These cut points were derived from cross-sectional epidemiological studies that examined retinopathy across a range of glycemic levels. The datasets used for this purpose were from Pima Indians, an Egyptian study, and unpublished data from the Third National Health and Nutrition Examination Survey (NHANES) (2).Other studies (3–5) also have examined this relationship, but the results have been inconsistent. All studies reported to date have had limited statistical power to examine this relationship in detail and have adopted a very broad definition of retinopathy that included many cases of mild retinopathy, now known to have causes other than hyperglycemia (6). A more clinically relevant end point is diabetes-specific retinopathy (moderate or more severe levels of retinopathy) that is invariably attributed to hyperglycemia. Also different statistical methods have been used in previous studies, which has an important effect on derived cut points (5,7).Several new datasets with retinopathy data have become available since the original studies used to derive current diabetes diagnostic cut points (1,2). The DETECT-2 collaboration has pooled these datasets to examine and re-evaluate the relationship between retinopathy and three glycemic measures: FPG, 2-h PG, and A1C. The size of the DETECT-2 dataset has allowed us to focus on the relationship between measures of glycemia and diabetes-specific retinopathy (i.e., moderate or more severe levels of retinopathy). These analyses were designed to inform current deliberations on possible revisions to the diagnostic criteria for diabetes.     

Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study)

OBJECTIVE

This study evaluated the effects of testosterone replacement therapy (TRT) on insulin resistance, cardiovascular risk factors, and symptoms in hypogonadal men with type 2 diabetes and/or metabolic syndrome (MetS).

RESEARCH DESIGN AND METHODS

The efficacy, safety, and tolerability of a novel transdermal 2% testosterone gel was evaluated over 12 months in 220 hypogonadal men with type 2 diabetes and/or MetS in a multicenter, prospective, randomized, double-blind, placebo-controlled study. The primary outcome was mean change from baseline in homeostasis model assessment of insulin resistance (HOMA-IR). Secondary outcomes were measures of body composition, glycemic control, lipids, and sexual function. Efficacy results focused primarily on months 0−6 (phase 1; no changes in medication allowed). Medication changes were allowed in phase 2 (months 6−12).

RESULTS

TRT reduced HOMA-IR in the overall population by 15.2% at 6 months (P = 0.018) and 16.4% at 12 months (P = 0.006). In type 2 diabetic patients, glycemic control was significantly better in the TRT group than the placebo group at month 9 (HbA_1c: treatment difference, −0.446%; P = 0.035). Improvements in total and LDL cholesterol, lipoprotein a (Lpa), body composition, libido, and sexual function occurred in selected patient groups. There were no significant differences between groups in the frequencies of adverse events (AEs) or serious AEs. The majority of AEs (>95%) were mild or moderate.

CONCLUSIONS

Over a 6-month period, transdermal TRT was associated with beneficial effects on insulin resistance, total and LDL-cholesterol, Lpa, and sexual health in hypogonadal men with type 2 diabetes and/or MetS.Low serum testosterone is common in men with type 2 diabetes and/or metabolic syndrome (MetS) and numerous studies have reported an association between testosterone deficiency and visceral obesity, insulin resistance (IR) and dyslipidemia (1–4). In men with type 2 diabetes, low testosterone is associated with a high prevalence of symptomatic hypogonadism (3), frequently due to hypogonadotrophic hypogonadism (5).Small studies have demonstrated that testosterone replacement therapy (TRT) in hypogonadal men with and without type 2 diabetes is associated with reductions in IR, waist circumference, cholesterol, glycated hemoglobin (HbA_1c), and fasting plasma glucose (FPG) concentrations (6–9). Conversely, withdrawal of TRT in hypogonadal men leads to decreased insulin sensitivity (10). Furthermore, androgen suppression therapy for prostate cancer can result in alterations of individual cardiovascular risk factors and increases the occurrence of incident diabetes, myocardial infarction and sudden cardiac death (11,12). Epidemiologic studies have reported that low testosterone in men is associated with increased all-cause and cardiovascular mortality (13).The TIMES2 (Testosterone replacement In hypogonadal men with either MEtabolic Syndrome or type 2 diabetes) study investigated the effects of transdermal TRT on IR, selected cardiovascular risk factors, and symptoms in hypogonadal men with MetS and/or type 2 diabetes. The safety and tolerability of a novel, metered-dose, transdermal 2% testosterone gel were also examined.     

Prevalence of and risk factors for hepatic steatosis and nonalcoholic Fatty liver disease in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study

OBJECTIVE

Type 2 diabetes is an established risk factor for development of hepatic steatosis and nonalcoholic fatty liver disease (NAFLD). We aimed to determine the prevalence and clinical correlates of these conditions in a large cohort of people with type 2 diabetes.

RESEARCH DESIGN AND METHODS

A total of 939 participants, aged 61–76 years, from the Edinburgh Type 2 Diabetes Study (ET2DS)—a large, randomly selected population of people with type 2 diabetes—underwent liver ultrasonography. Ultrasound gradings of steatosis were compared with magnetic resonance spectroscopy in a subgroup. NAFLD was defined as hepatic steatosis in the absence of a secondary cause (screened by questionnaire assessing alcohol and hepatotoxic medication use, plasma hepatitis serology, autoantibodies and ferritin, and record linkage to determine prior diagnoses of liver disease). Binary logistic regression was used to analyze independent associations of characteristics with NAFLD.

RESULTS

Hepatic steatosis was present in 56.9% of participants. After excluding those with a secondary cause for steatosis, the prevalence of NAFLD in the study population was 42.6%. Independent predictors of NAFLD were BMI, lesser duration of diabetes, HbA_1c, triglycerides, and metformin use. These remained unchanged after exclusion of participants with evidence of hepatic fibrosis from the group with no hepatic steatosis.

CONCLUSIONS

Prevalences of hepatic steatosis and NAFLD were high in this unselected population of older people with type 2 diabetes, but lower than in studies in which ultrasound gradings were not compared with a gold standard. Associations with features of the metabolic syndrome could be used to target screening for this condition.Nonalcoholic fatty liver disease (NAFLD), defined as hepatic steatosis in the absence of a secondary cause, is the commonest cause of liver disease in westernized countries, affecting up to 33% of the general population (1,2) and up to 75% in some subgroups such as obese patients (3). An association between NAFLD and type 2 diabetes is well established. Diabetes has been shown to be a risk factor for the development of NAFLD and its progression to more advanced liver disease including fibrosis, cirrhosis, and hepatocellular carcinoma (4,5). Furthermore, data suggest that some classes of antidiabetic agents (6,7) may be used as treatments in NAFLD.Despite the recognized association between type 2 diabetes and NAFLD, few large-scale studies of the prevalence of NAFLD in unselected populations of people with type 2 diabetes are available. Studies estimating the prevalence using liver ultrasound have been performed in secondary care rather than community setting and have generally examined small numbers of patients (8). A large study in Italian outpatients with type 2 diabetes reported that 85% had hepatic steatosis and that 70% met the criteria for NAFLD (defined in that study as hepatic steatosis without evidence of excess alcohol consumption, viral hepatitis, or causative medications) (9). This study, however, was confined to patients attending a hospital clinic and also failed to systematically identify and exclude participants with less common causes of liver disease such as autoimmune hepatitis. Furthermore, ultrasound measurements were not compared with a gold standard in the population studied—an important factor given the variable sensitivity and specificity of ultrasound assessment for hepatic steatosis (10).Given the rising incidence and prevalence of type 2 diabetes, an accurate estimate of the prevalence of NAFLD, as well as its clinical correlates, is important to predict the number of patients who will require to be monitored for more advanced liver disease or who may benefit from future disease-modifying agents. The aim of the current study was to determine the prevalence of NAFLD in a large, randomly selected population of older people with type 2 diabetes, using magnetic resonance spectroscopy (MRS) to confirm ultrasound grading classifications and thorough screening for secondary causes of liver disease, and to examine the correlation of NAFLD with clinical and biochemical characteristics.     

Impact of natriuretic peptide clearance receptor (NPR3) gene variants on blood pressure in type 2 diabetes

OBJECTIVE

Hypertension in diabetes is characterized by abnormal sodium homeostasis, suggesting a particular role of natriuretic peptide pathway. Natriuretic peptides can affect blood pressure (BP) through their plasma concentrations, which are dependent on their receptor activities. We thus assessed the association between nine NPR3 gene polymorphisms and BP levels in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Nine single nucleotide polymorphisms (SNPs) tagging the haplotype structure of the NPR3 gene were genotyped in the 3,126 French Non-insulin-dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) trial participants. We then used a second population (Diabete de type 2, Nephropathie et Genetique [DIAB2NEPHROGENE]/Survie, Diabete de type 2 et Genetique [SURDIAGENE] study) of 2,452 patients for the purpose of replication. Finally, we separately investigated subjects selected according to their rs 2270915SNP genotypes for their BP response to salt restriction.

RESULTS

In DIABHYCAR patients, three SNPs (rs6889608, rs1173773, and rs2270915) were significantly associated with systolic BP (SBP). The effect of the rs2270915 was replicated in the second step population: AA homozygotes had a lower SBP than G carriers (137.4 ± 19.1 vs. 140.0 ± 20.2 mmHg, P = 0.004). The rs2270915 influenced the response of SBP to salt reduction, with AA homozygous patients showing greater reductions after restriction of salt intake compared with G carriers: −20 mmHg (−43 to −8) vs. −3 (−20 to +7); P = 0.006.

CONCLUSIONS

We found a consistent and significant association between the rs2270915 polymorphism of the NPR3 gene and SBP in diabetic patients. This genetic variation may affect pressure response to changes in dietary sodium.Hypertension and type 2 diabetes are two chronic conditions associated epidemiologically and pathophysiologically. Hypertension is a well-known risk factor for diabetic vascular complications in type 1 diabetes and type 2 diabetes, and is a complex trait with an established heritability (1). Genome-wide association studies are complementary to a candidate gene approach and have helped to identify new genetic pathways involved in blood pressure (BP). However, only a few genetic associations have been clearly identified and replicated to date, leaving some impetus to search for new candidate genes.Diabetic patients differ from nondiabetic patients by having an increase in total body sodium (2,3), renal tubular sodium reabsorption, and an impaired ability to excrete a sodium load (4). These factors suggest that natriuretic peptides (NPs) may play a key role in the pathophysiology of hypertension in the diabetic population.The NP system regulates BP and fluid homeostasis by modifying glomerular filtration rate (GFR) and sodium urinary excretion. This system consists of a family of three peptidic hormones (A-type NP, B-type NP [BNP], and C-type NP) that interact with three receptors (NP receptor A, NP receptor B, and NP clearance receptor [NPRC]). The NPRC is encoded by the NPR3 gene and is a determinant of NP plasma concentration. Local expression of NPRC is linked to NP activity in the kidney (5,6). The intracellular domain of NPRC modulates the contraction/relaxation properties of smooth muscle cells (5). Genetic variation in the NPR3 may therefore affect the activity of NP through affecting plasma levels or NPRC-mediated vascular effects. The NPR3 is located on chromosome 5p14-p13. It spans ∼70 kb and contains eight exons and seven introns. Within the general population, allelic variants of the NPR3 gene have been reported to be associated with hypertension (6–8).This study aimed to assess the influence of genetic polymorphisms within NPR3 on BP in patients with type 2 diabetes. We first used a candidate gene approach in two independent large populations. We then completed our investigation with a sodium restriction functional study.     

Evaluation of molecular assays for rapid detection of methicillin-resistant Staphylococcus aureus

The diagnostic sensitivities of the BD GeneOhm and Cepheid Xpert assays were compared using culture on log-serial dilutions of well-characterized methicillin-resistant Staphylococcus aureus (MRSA) and non-MRSA strains and on nasal and groin swabs from patients with histories of MRSA carriage. The sensitivities of GeneOhm and Xpert were high at 10(3)-CFU/ml MRSA concentrations (92.3% and 96.3%, respectively) although decreased considerably (<35%) at a 1-log-lower concentration. Unexpectedly, both assays also detected select coagulase-negative staphylococci, which requires further evaluation.     

Risk scores for type 2 diabetes can be applied in some populations but not all

OBJECTIVE: Risk scores based on phenotypic characteristics to identify individuals at high risk of having undiagnosed diabetes have been developed in Caucasian populations. The impact of known risk factors on having undiagnosed type 2 diabetes differs between populations from different ethnic origin, and risk scores developed in Caucasians may not be applicable to other ethnic groups. This study evaluated the performance of one risk score in nine populations of diverse ethnic origin. RESEARCH DESIGN AND METHODS: Data provided by centers from around the world to the DETECT-2 project were used. The database includes population-based surveys with information on at least 500 people without known diabetes having a 75-g oral glucose tolerance test. To date, 52 centers have contributed data on 190,000 individuals from 34 countries. In this analysis, nine cross-sectional studies were selected representing diverse ethnic and regional backgrounds. The risk score assessed uses information on age, sex, blood pressure treatment, and BMI. RESULTS: This analysis included 29,758 individuals; 1,805 individuals had undiagnosed diabetes. The performance of the risk score varied widely, with sensitivity, specificity, and percentage needing further testing ranging between 12 and 57%, 72 and 93%, and 2 and 25%, respectively, with the worse performance in non-Caucasian populations. This variation in performance was related to differences in the association between prevalence of undiagnosed diabetes and components of the risk score. CONCLUSIONS: A typical risk score developed in Caucasian populations cannot be applied to other populations of diverse ethnic origins.