Cigarette smoking is the strongest independent risk factor for invasive pneumococcal disease among immunocompetent, nonelderly adults. Because of the high prevalence of smoking and the large population attributable risk, programs to reduce both smoking and exposure to environmental tobacco smoke have the potential to reduce the incidence of pneumococcal disease.

Spatial analyses of the effect of insecticide (permethrin)-treated bed nets (ITNs) on nearby households both with and without ITNs was performed in the context of a large-scale, group-randomized, controlled mortality trial in Asembo, western Kenya. Results illustrate a protective effect of ITNs on compounds lacking ITNs located within 300 meters of compounds with ITNs for child mortality, moderate anemia, high-density parasitemia, and hemoglobin levels. This community effect on nearby compounds without nets is approximately as strong as the effect observed within villages with ITNs. This implies that in areas with intense malaria transmission with high ITN coverage, the primary effect of insecticide-treated nets is via area-wide effects on the mosquito population and not, as commonly supposed, by simple imposition of a physical barrier protecting individuals from biting. The strength of the community effect depended upon the proportion of nearby compounds with treated nets. To maximize their public health impact, high coverage with treated nets is essential.

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Because of rare but serious adverse events, pharmaceutical drugs and vaccines are sometimes withdrawn from the market, either by a government agency such as the Food and Drug Administration (FDA) in the United States or by the manufacturing pharmaceutical company. In other cases, a drug may be generally safe but increase the risk for serious adverse events for certain subpopulations such as pregnant women or people with heart problems. Due to limited sample size and selected study populations, rare adverse events are often impossible to detect during phase 3 trials conducted before the drug is approved for general use. It is then important to conduct post-approval drug safety surveillance, using, for example, health insurance claims data. In such surveillance, the goal should be to detect serious adverse events as early as possible without too many false alarms, and it is then natural to use a continuous or near-continuous sequential test procedure that reevaluates the data on a daily or weekly basis.In this article, we first show that Wald's classical sequential probability ratio test (SPRT) for continuous surveillance is very sensitive to the choice of relative risk required in the specification of the alternative hypothesis, making it difficult to use for drug and vaccine safety surveillance. We instead propose the use of a maximized sequential probability ratio test (MaxSPRT) based on a composite alternative hypothesis, which works well across a range of relative risks. We illustrate the use of this method on vaccine safety surveillance and compare it with the classical SPRT. † Deceased.Received January 22, 2010, Revised September 24, 2010, October 28, 2010, Accepted October 30, 2010 Recommended by Nitis Mukhopadhyay Address correspondence to Martin Kulldorff, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care, Boston, MA 02215, USA; E-mail: martin_kulldorff@hms.harvard.edu Drug and Vaccine Safety Surveillance 59A table of critical values for the MaxSPRT is provided, covering most parameter choices relevant for vaccine and drug safety surveillance. The critical values are based on exact numerical calculations. We also calculate the statistical power, the expected time until the null hypothesis is rejected, and the average length of surveillance.

The effect of permethrin-treated bed nets (ITNs) on malaria vectors was studied as part of a large-scale, randomized, controlled trial in western Kenya. Indoor resting densities of fed Anopheles gambiae s.l. and An. funestus in intervention houses were 58.5% (P ‫ס‬ 0.010) and 94.5% (P ‫ס‬ 0.001) lower, respectively, compared with control houses. The sporozoite infection rate in An. gambiae s.l. was 0.8% in intervention areas compared with 3.4% (P ‫ס‬ 0.026) in control areas, while the sporozoite infection rates in An. funestus were not significantly different between the two areas. We estimated the overall transmission of Plasmodium falciparum in intervention areas to be 90% lower than in control areas. Permethrin resistance was not detected during the study period. As measured by densities of An. gambiae s.l., the efficacy of bed nets decreased if one or more residents did not sleep under a net or if bed nets had not been retreated within six months. These results indicate that ITNs are optimally effective if used every night and if permethrin is reapplied at least biannually.

A group-randomized controlled trial of insecticide (permethrin)-treated bed nets (ITNs) was conducted in an area of high perennial malaria transmission in western Kenya to test the effect of ITNs on all-cause mortality in children 1-59 months of age. Child deaths were monitored over a two-year period by biannual household census in Asembo (1997-1998) and in Gem (1998-1999). Overall, 1,722 deaths occurred in children 1-59 months followed for 35,932 child-years. Crude mortality rates/1,000 child-years were 51.9 versus 43.9 in control and ITN villages in children 1-59 months old. The protective efficacy (PE) (95% confidence interval) adjusted for age, study year, study site, and season was 16% (6-25%). Corresponding figures in 1-11-and 12-59-month-old children in control and ITN villages were 133.3 versus 102.3, PE ‫ס‬ 23% (11-34%) and 31.1 versus 28.7, PE ‫ס‬ 7% (-6-19%). The numbers of lives saved/1,000 child-years were 8, 31, and 2 for the groups 1-59, 1-11, and 12-59 months old, respectively. Stratified analysis by time to insecticide re-treatment showed that the PE of ITNs retreated per study protocol (every six months) was 20% (10-29%), overall and 26% (12-37%) and 14% (−1-26%) in 1-11-and 12-59-month-old children, respectively. ITNs prevent approximately one in four infant deaths in areas of intense perennial malaria transmission, but their efficacy is compromised if re-treatment is delayed beyond six months.

Adherence with permethrin-treated bed net (ITN) use and their proper deployment was directly observed in 2,178 individuals (784 households) participating in a large-scale trial of ITNs on child mortality in western Kenya. The ITNs were distributed free of charge to ensure high coverage, resulting in a ratio of 1.46 persons per ITN. Approximately 30% of ITNs present were unused. The overall percentage adherence was 72.3%. The probability of adherence by individuals depended strongly on age (relative risk [RR] ‫ס‬ 0.86, 95% confidence limit [CL] − 0.78-0.94), in which children less than five years of age were less likely to use ITNs than older individuals, and temperature, in which ITNs were more likely to be used in periods of cooler weather. A marginally significant diminution in adherence during the second year of the project was also observed (RR ‫ס‬ 0.83, 95% CL ‫ס‬ 0.68-1.01). Mosquito numbers, relative wealth, number of house occupants, and the educational level of the head of the household had no effect on adherence. In unstructured questioning of house residents, excessive heat was often cited as a reason for not deploying the child's ITN. The most important reason for non-adherence was disruption of sleeping arrangements, indicating that ITNs were not readily redeployed in the face of shifting sleeping patterns due to visitors, funerals, house construction, and other events. Challenges faced by health education programs to maximize adherence with ITN use are discussed.

Abstract. The impact of insecticide (permethrin)-treated bed nets (ITNs) on malaria in pregnancy was studied in a rural area in western Kenya with intense perennial malaria transmission. All households in 40 of 79 villages were randomized to receive ITNs by January 1997. The ITNs were distributed in control villages two years later. Complete data on birth outcome were available on 2,754 (89.6%) of 3,072 deliveries. Women (n ‫ס‬ 780) were followed monthly throughout pregnancy in 19 of 79 villages. Among gravidae 1-4, ITNs were associated with reductions of 38% (95% confidence interval [CI] ‫ס‬ 17-54%) in the incidence of malaria parasitemia and 47% (95% CI ‫ס‬ 6-71%) in the incidence of severe malarial anemia (hemoglobin level < 8 g/dL with parasitemia) during pregnancy. At the time of delivery, mean hemoglobin levels were 0.6 g/dL (95% CI ‫ס‬ 0.01-1.2 g/dL) higher, the prevalence of placental or maternal malaria was reduced by 35% (95% CI ‫ס‬ 20-47%), and the prevalence of low birth weight was reduced by 28% (95% CI ‫ס‬ 2-47%) in gravidae 1-4 from ITN villages. No beneficial impact was observed in gravidae five or higher. In areas of intense perennial malaria transmission, permethrin-treated bed nets reduce the adverse effect of malaria during the first four pregnancies.