***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background Typical advice on the design and analysis of cluster r and omized trials ( C- RCTs ) focuses on allowance for the clustering at the level of the unit of allocation . However often C- RCTs are also organised spatially as may occur in the fields of Public Health and Primary Care where population s may even overlap . Methods We allowed for spatial effects on the error variance by a multiple membership model . These are a form of hierarchical model in which each lower level unit is a member of more than one higher level unit . Membership may be determined through adjacency or through Euclidean distance of centroids or in other ways such as the proportion of overlapping population . Such models may be estimated for Normal , binary and Poisson responses in Stata ( v10 or above ) as well as in WinBUGS or MLWin . We used this to analyse a dummy trial  and two real , previously published cluster-allocated studies ( one allocating general practice  s within one City and the other allocating general practice  s within one County ) to investigate the extent to which ignoring spatial effects affected the estimate of treatment effect , using different methods for defining membership with Akaike 's Information Criterion to determine the " best " model . Results The best fitting model included both a fixed North-South gradient and a r and om cluster effect for the dummy RCT . For one of the real RCTs the best fitting model included both a r and om practice effect plus a multiple membership spatial term , while for the other RCT the best fitting model ignored the clustering but included a fixed North-South gradient . Alternative models which fitted only slightly less well all included spatial effects in one form or another , with some variation in parameter estimates ( greater when less well fitting models were included ) . Conclusions These particular results are only illustrative . However , we believe when design ing C- RCTs in a primary care setting the possibility of spatial effects should be considered in relation to the intervention and response , as well as any explanatory effect of fixed covariates , together with any implication s for sample size and methods for planned analyses 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-r and omized , 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 Research is needed to help identify interventions that will improve the capacity or functioning of health systems and thereby contribute to achieving global health goals . Well conducted , r and omized controlled trials ( RCTs ) , insofar as they reduce bias and confounding , provide the strongest evidence for identifying which interventions delivered directly to individuals are safe and effective . When ethically feasible , they can also help reduce bias and confounding when assessing interventions targeting entire health systems . However , additional challenges emerge when research focuses on interventions that target the multiple units of organization found within health systems . Hence , one can not complacently assume that r and omization can reduce or eliminate bias and confounding to the same degree in every instance . While others have articulated arguments in favour of alternative design s , this paper is intended to help people underst and why the potential value afforded by RCTs may be threatened . Specifically , it suggests six points to be borne in mind when exploring the challenges entailed in design ing or evaluating RCTs on health system interventions : ( i ) the number of units available for r and omization ; ( ii ) the complexity of the organizational unit under study ; ( iii ) the complexity of the intervention ; ( iv ) the complexity of the cause-effect pathway , ( v ) contamination ; and ( vi ) outcome heterogeneity . The authors suggest that the latter may be informative and that the reasons behind it should be explored and not ignored . Based on improved underst and ing of the value and possible limitations of RCTs on health system interventions , the authors show why we need broader platforms of research to complement RCTs Abstract Objectives To measure the impact on the  dengue vector population  ( Aedes aegypti ) and disease transmission of window curtains and water container covers treated with insecticide . Design Cluster r and omised controlled trial based on entomological surveys and , for Trujillo only , serological survey . In addition , each site had a non-r and omised external control . Setting 18 urban sectors in Veracruz ( Mexico ) and 18 in Trujillo ( Venezuela ) . Participants 4743 inhabitants ( 1095 houses ) in Veracruz and 5306 inhabitants ( 1122 houses ) in Trujillo . Intervention Sectors were paired according to entomological indices , and one sector in each pair was r and omly allocated to receive treatment . In Veracruz , the intervention comprised curtains treated with lambdacyhalothrin and water treatment with pyriproxyfen chips ( an insect growth regulator ) . In Trujillo , the intervention comprised curtains treated with longlasting deltamethrin ( PermaNet ) plus water jar covers of the same material . Follow-up surveys were conducted at intervals , with the final survey after 12 months in Veracruz and nine months in Trujillo . Main outcome measures Reduction in entomological indices , specifically the Breteau and house indices . Results In both study sites , indices at the end of the trial were significantly lower than those at baseline , though with no significant differences between control and intervention arms . The mean Breteau index dropped from 60 % ( intervention clusters ) and 113 % ( control ) to 7 % ( intervention ) and 12 % ( control ) in Veracruz and from 38 % to 11 % ( intervention ) and from 34 % to 17 % ( control ) in Trujillo . The pupae per person and container indices showed similar patterns . In contrast , in nearby communities not in the trial the entomological indices followed the rainfall pattern . The intervention reduced mosquito population s in neighbouring control clusters ( spill-over effect ) ; and houses closer to treated houses were less likely to have infestations than those further away . This created a community effect whereby mosquito numbers were reduced throughout the study site . The observed effects were probably associated with the use of material s treated with insecticide at both sites because in Veracruz , people did not accept and use the pyriproxyfen chips . Conclusion Window curtains and domestic water container covers treated with insecticide can reduce densities of dengue vectors to low levels and potentially affect dengue transmission SUMMARY An individual 's risk of infection from an infectious agent can depend on both the individual 's own risk and protective factors and those of individuals in the same community . We hypothesize that an individual 's exposure to an infectious agent is associated with the risks of infection of those living nearby , whether their risks are modified by pharmaceutical interventions or by other factors , because of the potential for transmission from them . For example , unvaccinated individuals living in a highly vaccinated community can benefit from indirect protection , or living near more children in a typhoid-endemic region ( where children are at highest risk ) might result in more exposure to typhoid . We tested this hypothesis using data from a cluster-r and omized typhoid vaccine trial . We first estimated each individual 's relative risk of confirmed typhoid outcome using their vaccination status and age . We defined a new covariate , potential exposure , to be the sum of the relative risks of all who live within 100 m of each person . We found that potential exposure was significantly associated with an individual 's typhoid outcome , and adjusting for potential exposure affected estimates of vaccine efficacy . We suggest that it is useful and feasible to adjust for spatially heterogeneous distributions of individual-level risk factors , but further work is required to develop and test such approaches OBJECTIVES Insecticide-treated bednets ( ITNs ) are effective in preventing nocturnally transmitted vector-borne diseases , but their effect on diurnally active dengue vectors has never been studied . We investigated the efficacy of ITNs in reducing Aedes aegypti population s and dengue transmission . METHODS A cluster-r and omized trial was carried out in Leogane , Haiti between July 2003 and July 2004 . The study area ( 1017 houses ) was divided into 18 sectors ( clusters ) : nine received  ITNs ( Olyset(R ) long-lasting insecticidal bednets ) and nine were untreated controls .  Entomological surveys [ measuring Breteau ( BI ) , house ( HI ) , container ( CI ) and pupae per person ( PPI ) indices and oviposition activity ] were undertaken at baseline and at 1 and 5 months post-intervention . All houses were georeferenced to enable spatial analysis . Control sectors received ITNs at 6 months , and a final entomological and attitudinal survey was undertaken at 12 months after baseline . Anti-dengue IgM seropositivity rates were measured at baseline and after 12 months . Efficacy of ITNs  was assessed by WHO cone bioassays . RESULTS At 1-month post-intervention , entomological indices fell in all sectors , with HI and BI in the bednet sectors reduced by 6.7 ( 95 % CI -10.6 , -2.7 ; P < 0.01 ) and 8.4 ( 95 % CI -14.1 , -2.6 ; P < 0.01 ) respectively . Moreover at 1 month , ovitraps in control sectors were significantly more likely to be positive than in bednet sectors ( P < 0.01 ) . By 5 months , all indices remained low and HI , CI and BI were also significantly lower than that of baseline in the control arm . Curiously , at 5 months , HI , CI and BI were lower in the control arm than that in the bednet arm . A final survey , 12 months after the initial baseline study ( 5 months after bednets had been given to all households ) indicated that all indices were significantly lower than that at baseline ( P < 0.001 ) . Control houses located within 50 m of a bednet house had significantly lower CI ( Z = -2.67 , P = 0.008 ) and PPI ( Z = -2.19 , P = 0.028 ) at 1 month , an effect that extended to 100 m by 5 months ( Z = -2.03 , P = 0.042 and Z = -2.37 , P = 0.018 respectively ) , suggesting a spill-over effect of the bednets . An IgM serosurvey showed a 15.3 % decrease ( 95 % CI 5.0 - 25.5 % , P < 0.01 ) in the number of IgM-positive individuals from baseline to12 months later . CONCLUSIONS Insecticide-treated bednets had an immediate effect on dengue vector population s after their introduction , and over the next 5 - 12 months , the presence of ITNs may have continued to affect vector population s and dengue transmission This paper identifies spatial patterns and predictors of vaccine uptake in a cluster-r and omized controlled trial in Hue , Vietnam . Data for this study result from the integration of demographic surveillance , vaccine record , and geographic data of the study area . A multi-level cross-classified ( non-hierarchical ) model was used for analyzing the non-nested nature of individual 's ecological data . Vaccine uptake was unevenly distributed in space and there was spatial variability among predictors of vaccine uptake . Vaccine uptake was higher among students with younger , male , or not literate family heads . Students from households with higher per-capita income were less likely to participate in the trial . Residency south of the river or further from a hospital/polyclinic was associated with higher vaccine uptake .  Younger students were more likely to be vaccinated than older students in high- or low-risk areas , but not in the entire study area . The findings are important for the management of vaccine campaigns during a trial and for interpretation of disease patterns during vaccine-efficacy evaluation Effects of the distribution in space of permethrin (insecticide)-impregnated bed nets ( IIBNS ) on  child mortality  were studied in a r and omized controlled trial of IIBNs in a an area highly endemic for Plasmodium falciparum malaria in rural northern Ghana . Eight hundred sixty-two deaths occurred among children 6 - 59 months of age during 16,841 child-years-at-risk .  Mortality increased with the distance from health facilities but not with proximity to identifiable anopheline breeding sites ( reservoirs ) . The efficacy of IIBNs was independent of these distances . Mortality in users of IIBNs was independent of the proximity of nonusers , and mortality rates of nonusers and users living close to each other were similar . Poisson regression estimated a 6.7 % increase in mortality among nonusers with each 100-m shift away from the nearest compound with IIBNS , indicating that the insecticide protects nearby nonusers . High coverage of IIBNs achieves maximum impact , but users of IIBNs offer some protection to less fortunate neighbors if coverage is incomplete The effect of insecticide (permethrin)-treated bed nets ( ITNs ) on the spatial distribution of malaria vectors in neighboring villages lacking ITNs was studied during a r and omized controlled trial of ITNs in western Kenya . There was a trend of decreased abundance of Anopheles gambiae with decreasing distance from intervention villages both before ( P = 0.027 ) and after ( P = 0.002 ) introduction of ITNs , but this trend was significantly stronger after ITNs were introduced ( P = 0.05 ) . For An . funestus , no pre-intervention trend was observed ( P = 0.373 ) 
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The spatial variable approach was most common and involved st and ard statistical analysis of distance measurements .
Studies tended to demonstrate the importance of accounting for location and distribution of observations in estimating unbiased effects .