Ian R. Hambleton

Global estimates of diabetes prevalence for 2013 and projections for 2035

INTRODUCTION Diabetes is a serious and increasing global health burden and estimates of prevalence are essential for appropriate allocation of resources and monitoring of trends. METHODS We conducted a literature search of studies reporting the age-specific prevalence for diabetes and used the Analytic Hierarchy Process to systematically select studies to generate estimates for 219 countries and territories. Estimates for countries without available source data were modelled from pooled estimates of countries that were similar in regard to geography, ethnicity, and economic development. Logistic regression was applied to generate smoothed age-specific prevalence estimates for adults 20-79 years which were then applied to population estimates for 2013 and 2035. RESULTS A total of 744 data sources were considered and 174 included, representing 130 countries. In 2013, 382 million people had diabetes; this number is expected to rise to 592 million by 2035. Most people with diabetes live in low- and middle-income countries and these will experience the greatest increase in cases of diabetes over the next 22 years. CONCLUSION The new estimates of diabetes in adults confirm the large burden of diabetes, especially in developing countries. Estimates will be updated annually including the most recent, high-quality data available.

Effect of Herpes Simplex Suppression on Incidence of HIV among Women in Tanzania

BACKGROUND Infection with herpes simplex virus type 2 (HSV-2) is associated with an increased risk of acquiring infection with the human immunodeficiency virus (HIV). This study tested the hypothesis that HSV-2 suppressive therapy reduces the risk of HIV acquisition. METHODS Female workers at recreational facilities in northwestern Tanzania who were 16 to 35 years of age were interviewed and underwent serologic testing for HIV and HSV-2. We enrolled female workers who were HIV-seronegative and HSV-2-seropositive in a randomized, double-blind, placebo-controlled trial of suppressive treatment with acyclovir (400 mg twice daily). Participants attended mobile clinics every 3 months for a follow-up period of 12 to 30 months, depending on enrollment date. The primary outcome was the incidence of infection with HIV. We used a modified intention-to-treat analysis; data for participants who became pregnant were censored. Adherence to treatment was estimated by a tablet count at each visit. RESULTS A total of 821 participants were randomly assigned to receive acyclovir (400 participants) or placebo (421 participants); 679 (83%) completed follow-up. Mean follow-up for the acyclovir and placebo groups was 1.52 and 1.62 years, respectively. The incidence of HIV infection was 4.27 per 100 person-years (27 participants in the acyclovir group and 28 in the placebo group), and there was no overall effect of acyclovir on the incidence of HIV (rate ratio for the acyclovir group, 1.08; 95% confidence interval, 0.64 to 1.83). The estimated median adherence was 90%. Genital HSV was detected in a similar proportion of participants in the two study groups at 6, 12, and 24 months. No serious adverse events were attributable to treatment with acyclovir. CONCLUSIONS These data show no evidence that acyclovir (400 mg twice daily) as HSV suppressive therapy decreases the incidence of infection with HIV. (Current Controlled Trials number, ISRCTN35385041 [controlled-trials.com].).

Population-based study of risk of venous thromboembolism associated with various oral contraceptives

BACKGROUND Four studies published since December, 1995, reported that the incidence of venous thromboembolism (VTE) was higher in women who used oral contraceptives (OCs) containing the third-generation progestagens gestodene or desogestrel than in users of OCs containing second-generation progestagens. However, confounding and bias in the design of these studies may have affected the findings. The aim of our study was to re-examine the association between risk of VTE and OC use with a different study design and analysis to avoid some of the bias and confounding of the earlier studies. METHODS We used computer records of patients from 143 general practices in the UK. The study was based on the medical records of about 540,000 women born between 1941 and 1981. All women who had a recorded diagnosis of deep-vein thrombosis, venous thrombosis not otherwise specified, or pulmonary embolus during the study period, and who had been treated with an anticoagulant were identified as potential cases of VTE. We did a cohort analysis to estimate and compare incidence of VTE in users of the main OC preparations, and a nested case-control study to calculate the odds ratios of VTE associated with use of different types of OC, after adjustment for potential confounding factors. In the case-control study, we matched cases to controls by exact year of birth, practice, and current use of OCs. We used a multiple logistic regression model that included body-mass index, number of cycles, change in type of OC prescribed within 3 months of the event, previous pregnancy, and concurrent disease. FINDINGS 85 women met the inclusion criteria for VTE, two of whom were users of progestagen-only OCs. Of the 83 cases of VTE associated with use of combined OCs, 43 were recorded as deep-vein thrombosis, 35 as pulmonary thrombosis, and five as venous thrombosis not otherwise specified. The crude rate of VTE per 10,000 woman-years was 4.10 in current users of any OC, 3.10 in users of second-generation OCs, and 4.96 in users of third-generation preparations. After adjustment for age, the rate ratio of VTE in users of third-generation relative to second-generation OCs was 1.68 (95% CI 1.04-2.75). Logistic regression showed no significant difference in the risk of VTE between users of third-generation and second-generation OCs. Among users of third-generation progestagens, the risk of VTE was higher in users of desogestrel with 20 g ethinyloestradiol than in users of gestodene or desogestrel with 30 g ethinyloestradiol. With all second-generation OCs as the reference, the odds ratios for VTE were 3.49 (1.21-10.12) for desogestrel plus 20 g ethinyloestradiol and 1.18 (0.66-2.17) for the other third-generation progestagens. INTERPRETATION The previously reported increase in odds ratio associated with third-generation OCs when compared with second-generation products is likely to have been the result of residual confounding by age. The increased odds ratio associated with products containing 20 micrograms ethinyloestradiol and desogestrel compared with the 30 micrograms product is biologically implausible, and is likely to be the result of preferential prescribing and, thus, confounding.

Survival estimates for patients with homozygous sickle-cell disease in Jamaica: a clinic-based population study

BACKGROUND Information about life expectancy of patients with homozygous sickle-cell disease is needed for research and patient counselling. Our aim was to study two Jamaican populations, one clinic-based and one birth cohort and, by careful consideration of data quality and statistical analysis, to identify ways to increase the chances of obtaining valid and generalisable results. METHODS We investigated the survival experience of 3301 patients with homozygous sickle-cell disease attending the Jamaican sickle-cell clinic between Jan 1, 1987, and Dec 31, 1996. We applied and assessed a simulation technique for incorporating early life mortality using a birth cohort, and analysed the precision of this technique. Kaplan-Meier survival estimates are produced. FINDINGS 290 of the 3301 patients died. Median survival calculated with the excess mortality rate simulation data was 53 years (95% CI 49.3-57.0) for men and 58.5 (55.1-67.5) for women. INTERPRETATION Our simulation technique, with realistic assumptions based on empirical evidence, offers a new estimate of median survival for patients with homozygous sickle-cell disease. We present the precision of these survival estimates, which introduces an important level of uncertainty. The inherent biases of clinically ascertained populations of patients, and the assumptions underlying analysis techniques are crucial features of survival studies in sickle-cell disease, and can modify summary statistics substantially.

Outcome of pregnancy in homozygous sickle cell disease.

OBJECTIVE: Previous reports on pregnancy in homozygous sickle cell (SS) disease are biased by hospital-based, more severely affected subjects and may have underestimated recurrent early pregnancy losses. We report pregnancy outcome in a representative sample of SS subjects subsequently referred to as “subjects” or “sickle cell subjects,” and matched normal controls followed from birth. METHODS: The outcomes of 94 pregnancies in 52 subjects and 157 pregnancies in 68 controls followed in a cohort study from birth are presented. Outcome measures included the age at menarche, interval to first pregnancy, outcome of pregnancy, and maternal complications. Possible predictors of low birth weight are assessed. Outcomes were compared by the Kaplan-Meier analysis for interval to first pregnancy and by Student t test, χ2 test, or Fisher exact test, as appropriate. Correction was made for multiple testing, and multiple linear regression was used for analysis of birth weight. RESULTS: Compared with controls, SS subjects had later menarche (median age 15.4 versus 13.0 years) and first pregnancy (median age 23.7 versus 20.1 years), and more spontaneous abortions (36% versus 10%). Babies of SS subjects had a lower gestational age (P < .001) and lower birth weight (P < .001), the latter being significantly affected by sickle-related events in pregnancy. There was no difference in pregnancy-induced hypertension, preeclampsia, or antepartum or postpartum hemorrhage, but a retained placenta was marginally more common in SS subjects (Fisher exact test, P = .007 after adjustment for multiple testing). Two SS subjects died, a mortality rate of 2.1%. CONCLUSION: The increased fetal loss and maternal morbidity in mothers with homozygous sickle cell disease is confirmed. LEVEL OF EVIDENCE: II-2

Red cell antibodies in patients with homozygous sickle cell disease: a comparison of patients in Jamaica and the United Kingdom

The transfusion history and frequency of red cell antibodies in patients with homozygous sickle cell (SS) disease have been compared in 190 subjects from the Jamaican cohort study and 37 patients attending a sickle cell clinic in Manchester, England. The proportion of patients transfused did not differ between the groups although the number of units transfused and the frequency of red cell antibodies were significantly greater in the Manchester group. Immune antibodies occurred in three Jamaicans (2·6% of those transfused) and 16 UK subjects (76% of those transfused). Multiple antibodies occurred in 10 (63%) UK subjects but in no Jamaicans. Indications for transfusion also differed between the groups, Jamaican patients typically receiving 1–2 units for acute anaemia or acute chest syndrome, whereas UK patients frequently had multiple transfusions in preoperative exchange or prophylaxis programmes. The greater red cell alloimmunization among UK patients probably reflects both the greater use of transfusion and the disparity between donor and recipient populations in the UK.

Gallstones in sickle cell disease: observations from The Jamaican Cohort study.

The prevalence, incidence, risk factors, clinical associations, and morbidity of gallstones were studied in 311 patients with homozygous sickle cell disease and 167 patients with sickle cell-hemoglobin C disease in a cohort study from birth. Gallstones developed in 96 patients with homozygous sickle cell disease and 18 patients with sickle cell-hemoglobin C disease; specific symptoms necessitating cholecystectomy occurred in only 7 patients with homozygous sickle cell disease.

All-Cause Mortality After Diabetes-Related Amputation in Barbados: A prospective case-control study

OBJECTIVE—To determine the mortality rate after diabetes-related lower-extremity amputation (LEA) in an African-descent Caribbean population. RESEARCH DESIGN AND METHODS—We conducted a prospective case-control study. We recruited case subjects (with diabetes and LEA) and age-matched control subjects (with diabetes and no LEA) between 1999 and 2001. We followed these groups for 5 years to assess mortality risk and causes. RESULTS—There were 205 amputations (123 minor and 82 major). The 1-year and 5-year survival rates were 69 and 44% among case subjects and 97 and 82% among control subjects (case-control difference, P < 0.001). The mortality rates (per 1,000 person-years) were 273.9 (95% CI 207.1–362.3) after a major amputation, 113.4 (85.2–150.9) after a minor amputation, and 36.4 (25.6–51.8) among control subjects. Sepsis and cardiac disease were the most common causes of death. CONCLUSIONS—These mortality rates are the highest reported worldwide. Interventions to limit sepsis and complications from cardiac disease offer a huge potential for improving post-LEA survival in this vulnerable group.

Recurrent infections in homozygous sickle cell disease

The characteristics of 214 episodes of invasive bacterial infection among 176 patients with homozygous sickle cell (SS) disease were examined. Streptococcus pneumoniaeoccurred in 81 episodes, Salmonella spp in 70, Haemophilus influenzae type b in 30,Escherichia coli in 24, andKlebsiella spp in nine. The cumulative incidence showed that S pneumoniaeand H influenzae occurred predominantly before 5 years of age and were uncommon thereafter,Salmonella spp increased almost linearly with age, and Klebsiella spp andE coli predominated in patients over 10 years of age. Escherichia coli had a different epidemiology—it was found in older children, almost entirely girls. Excluding this organism from an analysis of recurrent bacterial infections, the standardised incidence rates for second and third infections were 4.8 and 15.8 times greater, respectively, than the SS population average. This implies that the susceptibility to infection is characteristic of a subgroup of patients with SS disease and that sick patients with previous bacteraemia should be investigated early and aggressively for further infection.

Haematological response to parvovirus B19 infection in homozygous sickle- cell disease

Infection with human parvovirus B19 is known to cause aplastic crises in patients with homozygous sickle-cell disease. We studied the haematological consequences of parvovirus B19 infection in 280 such patients who had been followed up from birth in Jamaica. Evidence of seroconversion was routinely sought with a baculovirus-based, enzyme immunoassay in serum samples taken during aplastic crises and in all stored annual serum samples. 70% of patients had seroconverted by age 20 years; of 177 infections, haematological change was typical of aplastic crises in 118 (67%), minor in 16 (9%), and not discernible in 43 (24%). This assay increased the detection of unsuspected seroconversion-an observation important in planning a strategy for parvovirus B19 immunisation.