Biology subjects

Goldstein, E.

Publications and source records attributed to Goldstein, E..

14 recordsLinked to original sources

bioRxiv2026

Tetrahydrobiopterin restores oligodendrocyte maturation after hypoxic white matter injury by reprogramming translational output

Complex congenital heart defects (CHDs) are frequently associated with chronic cerebral hypoxemia, leading to impaired white matter maturation. One proposed mechanism involves hypoxia-induced disruption of the nitric oxide synthase cofactor tetrahydrobiopterin (BH4), resulting in oxidative stress and impaired oligodendrocyte (OL) development. While our previous studies found BH4 supplementation improves hypoxia-induced white matter dysmaturation, the molecular mechanisms remain incompletely understood. Because OL maturation requires coordinated translational control, we hypothesized that BH4 promotes white matter maturation by restoring translation programs disrupted by hypoxia.Translating Ribosome Affinity Purification sequencing (TRAP-seq) was performed on OL lineage cells isolated from transgenic ribosomal reporter mice exposed to chronic hypoxia with or without daily BH4 treatment. Differential translation, weighted gene co-expression network analysis, pathway enrichment, RNAscope, and immunohistochemistry identified translational programs associated with hypoxia and BH4-mediated rescue. Developmental hypoxia extensively altered the OL translatome, suppressing transcripts associated with OL maturation while enriching pathways related to translational regulation and cellular stress. Network analyses identified BH4-responsive gene modules enriched for OL maturation, protein metabolism, and translation-related processes. BH4 partially reversed hypoxia-induced translational changes, restored OL maturation gene expression, and normalized nuclear localization of the lineage regulator OLIG1, consistent with recovery of maturation-associated regulatory programs. Developmental hypoxia disrupts OL maturation through coordinated alterations in ribosome-associated gene expression and post-transcriptional regulatory pathways. BH4 promotes recovery of OL maturation programs, including restoration of translation-related networks and OLIG1 nuclear localization, providing mechanistic insight into BH4-supported white matter maturation under chronic hypoxic conditions.

neuroscience↗

bioRxiv2025

Changes in body size with age do not follow the temperature-size rule

The temperature size-rule is often described as a reduction in ectothermic body size with warming. This coincides with the expectation that faster growth under warming would lead to larger sizes early in life but smaller sizes later in life. Here, we use > 99,000 observations of weight-at-age of four commercially-important fishes over 25 years to ask whether changes in size and growth can be explained by temperature. We also examine whether oxygen, a key part of a proposed mechanism behind the temperature size-rule, explains patterns of weight-at-age better than temperature. Changes in weight-at-age over time were more related to temperature than oxygen but the effect of temperature on weight was small and did not vary by age, counter to the temperature size-rule. Importantly, these results were sensitive to how the relationship between weight-at-age and temperature was modeled. While the functional form (linear or polynomial) mattered little, how space was included in the model led to different conclusions regarding how temperature affects size and growth. Assuming that spatial and spatiotemporal random effects - those that account for the higher degree of similarity between observations collected closer in space and time - are shared across ages led to different results compared to allowing these effects to vary by age. Models with shared effects suggested weight for younger ages had positive relationships with temperature and negative relationships for older ages. However, these models provided spurious support for the temperature size-rule as they had less statistical support than models that allowed spatial effects to vary by age. Overall, our work highlights that relationships among size, growth, temperature, and oxygen may not be as straightforward as theory suggests and illustrates that modeling decisions can have a large effect on tests of ecological theory, and more broadly, our ability to understand biological responses to climate change.

ecology↗

bioRxiv2025

Prematurity Reprograms Cerebellar Development and Long-Term Behavior

Preterm survivors often develop motor and socio-cognitive impairments that implicate altered cerebellar development, yet the underlying mechanisms remain poorly understood. A key challenge is that prematurity involves overlapping perinatal insults that converge on the developing brain, making their individual effects difficult to disentangle. Here, we model two major prematurity-associated insults, maternal immune activation (MIA) and neonatal hypoxia (Hx), in mice. By controlling timing and sequence, we define how these insults shape cerebellar assembly during rapid maturation. Comparative analysis with human tissue confirmed that these insults recapitulate key features of the human preterm cerebellum, establishing the translational validity of this model for dissecting insult-specific outcomes. Behavioral and kinematic profiling revealed divergent motor and social phenotypes, which we traced to insult-specific cerebellar remodelling. Hypoxia compromised both granule cell maturation in the internal granule layer and the principal excitatory afferents to Purkinje cells, a circuit state that manifested as impaired motor execution and stereotyped, sensory-disengaged social investigation. Maternal immune activation, by contrast, expanded the granule cell progenitor layer and reduced Purkinje cell dendritic complexity, a phenotype that preserved social preference but reorganized the kinematic structure of social investigation. When hypoxia followed maternal immune activation, it acted on this primed substrate to produce a distinct state in which the features established by prior inflammation were compounded by granule cell proliferative arrest, progressive mitochondrial dysfunction, and aberrant, hyper-interactive social investigation. Together, these findings reframe prematurity-associated insults as cerebellar reprogramming events shaped by both the identity and sequence of insults, linking distinct mechanistic substrates to divergent neurodevelopmental outcomes.

neuroscience↗

bioRxiv2025

ALGR: A multi-purpose agricultural landscape generator in R

O_LIAgricultural and ecological modelers commonly use maps as input for spatially explicit simulations. While real world maps are often used, they are limited by being static objects, therefore making it difficult to assess how patterns within the landscape contribute to ecological processes. Agricultural landscape generators (ALG) are a useful tool for simulating maps in a more flexible way. They can increase robustness of models that rely on landscape maps as input, they allow modelers to give spatial representation to non-spatial models, and they are a useful tool for recreating spatial patterns in agricultural-dominated landscapes. A limitation of previous ALGs is that they have rarely been designed for general use (non-open source software, not written in R, and designed for specific projects). Furthermore, they are typically either extremely general and thus oversimplified or have a high specificity for particular use cases. C_LIO_LIALGR bridges this gap by providing a general-purpose, dynamic landscape generator that balances structural realism with adaptability. ALGR generates agricultural landscapes with a three-step approach: first, outlining potential space, second, field placement inside of that space, and third, enrichment of the landscape with information. This stepwise approach ensures that ALGR generates landscapes with realistic spatial patterns while remaining adaptable to diverse regions and applications. C_LIO_LIIt is the first ALG that is specifically designed to allow a simple integration within the R programming environment and the r-spatial package environment. ALGR is designed as a general-purpose generator, which is simple to use and facilitates an easy integration in modelling workflow. C_LIO_LIWe present several examples of workflows using ALGR, to demonstrate its usefulness. Our examples include: 1) simulating different land use shares, 2) parameter tuning of ALGR to recreate real world landscape patterns 3) spatially distributing crop portfolios, and 4) using real world maps as a basis for field placement C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/646291v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@19c02c3org.highwire.dtl.DTLVardef@17975f6org.highwire.dtl.DTLVardef@12f7aa5org.highwire.dtl.DTLVardef@1cfdd0_HPS_FORMAT_FIGEXP M_FIG Visual Abstract: The three-step conceptual framework of ALGR for landscape generation C_FIG

ecology↗

bioRxiv2019

Relation between prescribing of different antibiotics and rates of bacteremia/septicemia and associated mortality in the US and England

BackgroundAntibiotic use contributes to the rates of bacteremia, sepsis and associated mortality, particularly through lack of clearance of resistant infections following antibiotic treatment. At the same time, there is limited information on the effects of prescribing of some antibiotics vs. others, of antibiotic replacement and of reduction in prescribing on the rates of severe outcomes associated with bacterial infections. MethodsFor each of several antibiotic types/classes, we looked at associations (univariate, and multivariable for the US data) between the proportions (state-specific in the US, Clinical Commissioning Group (CCG)-specific in England) of a given antibiotic type/class among all prescribed antibiotics in the outpatient setting, and rates of outcomes (mortality with septicemia, ICD-10 codes A40-41 present on the death certificate in different age groups of adults in the US, and E. coli or MSSA bacteremia in England) per unit of antibiotic prescribing (defined as the rate of outcome divided by the rate of prescribing of all antibiotics). ResultsIn the US, prescribing of penicillins was positively associated with rates of mortality with septicemia for persons aged 75-84y and 85+y between 2014-2015, while multivariable analyses also suggest an association between the percent of individuals aged 50-64y lacking health insurance, as well as the percent of individuals aged 65-84y who are African-American and rates of mortality with septicemia. In England, prescribing of penicillins other than amoxicillin/co-amoxiclav was positively associated with rates of both MSSA and E. coli bacteremia for the period between financial years 2014/15 through 2017/18. Additionally, as time progressed, correlations between prescribing for both trimethoprim and co-amoxiclav and rates of bacteremia in England decreased, while correlations between amoxicillin prescribing and rates of bacteremia increased. ConclusionsOur results suggest that prescribing of penicillins is associated with rates of E. coli and MSSA bacteremia in England, and rates of mortality with septicemia in older US adults, which agrees with our earlier findings. Those results, as well as the related epidemiological data suggest that antibiotic replacement rather than reduction in prescribing may be the more effective mechanism for reducing the rates of severe bacterial infections.

epidemiology↗

bioRxiv2019

Rise in mortality involving poisoning by medicaments other than narcotics, including poisoning by psychotropic and sedative-hypnotic drugs in different age/racial groups in the US

BackgroundIncrease in mortality involving poisoning, particularly by narcotics, is known to have been one of the factors that affected life expectancy in the US during the last two decades, especially for white Americans and Native Americans. However, the contribution of medicaments other than narcotics to mortality in different racial/age groups is less studied.\n\nMethodsWe regressed annual rates of mortality involving poisoning by medicaments but not narcotics/psychodysleptics (ICD-10 codes T36-39.xx or T41-50.8 but not T40.xx present as either underlying or contributing causes of death), as well as annual rates of mortality for certain subcategories of the above, including mortality involving poisoning by psychotropic drugs but not narcotics/psychodysleptics (ICD-10 codes T43.xx but not T40.xx present as either underlying or contributing causes of death) in different age/racial groups for both the 2000-2011 period and the 2011-2017 period against calendar year.\n\nResultsAnnual numbers of deaths involving poisoning by medicaments but not narcotics/psychodysleptics grew from 4,332 between 2000-2001 to 11,401 between 2016-2017, with the growth in the rates of those deaths being higher for the 2011-2017 period compared to the 2000-2011 period. The largest increases in the rates of mortality involving poisoning by medicaments but not narcotics/psychodysleptics were in non-elderly Non-Hispanic Native Americans, followed by Non-Hispanic whites. Most of those increases came from increases in the rates of mortality involving poisoning by psychotropic medications; the latter rates grew for the period of 2015-2017 vs. 2000-2002 by factors ranging from 2.75 for ages 35-44y to 5.37 for ages 55-64y.\n\nConclusionsThere were major increases in mortality involving poisoning by non-narcotic, particularly psychotropic medicaments, especially in non-elderly non-Hispanic whites and Native Americans. Our results, and the epidemiological data on mortality involving poisoning by different drugs and medications in the US, which are quite different from the ones in many other countries support the need for a comprehensive evaluation of the effect of various drugs, including psychotropic medications on health-related outcomes, the associated mortality the does not involve poisoning being listed on a death certificate, and the impact of medication misuse.

epidemiology↗

bioRxiv2018

Outpatient antibiotic prescribing and demographic factors associated with state-level septicemia mortality rates in US adults

BackgroundRates of septicemia/sepsis mortality and hospitalization in the US have risen significantly during the recent years, and antibiotic use may contribute to those rates through various mechanisms.\n\nMethodsWe used multivariable linear regression to relate state-specific rates of outpatient prescribing overall for fluoroquinolones, penicillins, macrolides, and cephalosporins between 2013-2014 to state-specific rates of septicemia mortality (ICD-10 codes A40-41 present as either the underlying or contributing causes of death) in each of the following age groups of adults: (18-49y, 50-64y, 65-74y, 75-84y, 85+y) between 2013-2014, adjusting for median household income, average annual temperature, age-specific percentages of state residents who (i) lived below the poverty level, (ii) were African American, (iii) lacked health insurance (in non-elderly age groups), and random effects associated with the different US Health and Human Services (HHS) regions.\n\nResultsRates of penicillin prescribing were positively associated with septicemia mortality rates in the analyses for persons aged 65-74y, 75-84y and over 85y. Rates of cephalosporin prescribing were positively associated with septicemia mortality rates in the analyses for persons aged 18-49y and 65-74y. Rates of fluoroquinolone prescribing were positively associated with septicemia mortality rates in the analyses for persons aged 18-49y. Percent African Americans in a given age group was positively associated with septicemia mortality rates in the analyses for age groups over 65y, and 18-49y. Percent of residents in a given age group living below the poverty level was positively associated with septicemia mortality rates in the analysis for persons aged 65-74y.\n\nConclusionsOur results suggest that rates of penicillin prescribing are associated with rates of septicemia mortality in older US adults, while rates of cephalosporin prescribing are associated with rates of septicemia mortality in persons aged 18-49y and 65-74y, and rates of fluoroquinolone prescribing are associated with rates of septicemia mortality in persons aged 18-49y. Further studies are needed to better understand the potential effect of antibiotic replacement in the treatment of different syndromes, such as replacement of fluoroquinolones by other antibiotics, possibly penicillins and cephalosporins following the recent US FDA guidelines on restriction of fluoroquinolone use, on the rates of sepsis mortality.

epidemiology↗

bioRxiv2018

Outpatient prescribing of four major antibiotic classes and prevalence of antimicrobial resistance in US adults

BackgroundThere is limited information on the relation between antibiotic use and antibiotic resistance in the US.\n\nMethodsWe used multivariable logistic regression to relate state-specific rates of outpatient prescribing overall for fluoroquinolones, penicillins, macrolides, and cephalosporins between 2011-2014 to state-specific prevalence of resistance for select combinations of antibiotics/bacteria among catheter-associated urinary tract infections (CAUTIs) in the CDC Patient Safety Atlas data between 2011-2014 for adults aged 65+y and 19-64y, adjusting for potential confounders.\n\nResultsRates of fluoroquinolone prescribing were positively associated with prevalence of fluoroquinolone resistance in Escherichia coli and Pseudomonas aeruginosa (both age groups), resistance to extended-spectrum (ES) cephalosporins in E. coli (aged 19-64y), and resistance to methicillin in Staphylococcus aureus (aged 19-64y). Rates of penicillin prescribing were positively associated with prevalence of resistance to fluoroquinolones in E. coli (aged 65+) and P. aeruginosa (both age groups), and resistance to ES cephalosporins in Klebsiella spp. (both age groups). Rates of cephalosporin prescribing were negatively associated with prevalence of resistance to fluoroquinolones in E. coli and resistance to ES cephalosporins in Klebsiella spp. (both age groups). Average annual temperature was positively associated with prevalence of resistance to ES cephalosporins in E. coli and P. aeruginosa, and resistance to fluoroquinolones in E. coli.\n\nConclusionsOur results suggest that prescribing of fluoroquinolones and penicillins to US adults is associated with prevalence of antibiotic resistance, including ESBLs and MRSA. Further work is needed to understand the potential benefit of replacing fluoroquinolones and penicillins by other antibiotics for reducing prevalence of antibiotic resistance.

epidemiology↗

bioRxiv2018

On the role of different age groups during pertussis epidemics in California, 2010 and 2014

BackgroundThere is limited information on the roles of different age groups in propagating pertussis outbreaks, and the temporal changes in those roles since the introduction of acellular pertussis vaccines.\n\nMethodsThe relative roles of different age groups in propagating the 2010 and the 2014 pertussis epidemics in California were evaluated using the RR statistic that measures the change in the groups proportion among all detected cases before-vs.-after the epidemic peak.\n\nResultsFor the 2010-11 epidemic, evidence for a predominant transmission age group was weak, with the largest RR estimates being 1.26(95%CI (1.08,1.46)) (aged 11-13y); 1.19(1.01,1.4) (aged 9-10y); 1.17(0.86,1.59) (aged 14-15y); 1.12(0.86,1.46) (aged 16-19y); and 1.1(0.89,1.36) (aged 7-8y). The 2014 epidemic showed a strong signal of the role of older adolescents, with the highest RR estimate being in those aged 14-15y (RR=1.83(1.61,2.07)), followed by adolescents aged 16-19y (RR=1.41(1.24,1.61)) and 11-13y (RR=1.26(1.12,1.41)), with lower RR estimates in other age groups.\n\nConclusionsAs the time following introduction of acellular pertussis vaccines in California progressed, older adolescents played an increasing role in transmission during the major pertussis outbreaks. Booster pertussis vaccination for older adolescents with vaccines effective against pertussis transmission should be considered with the aim of mitigating future pertussis epidemics in the community.

epidemiology↗

bioRxiv2018

Levels of prescribing for four major antibiotic classes and rates of septicemia hospitalization in different US states

BackgroundRates of sepsis/septicemia hospitalization in the US have risen significantly during recent years, and antibiotic resistance and use may contribute to those rates through various mechanisms.\n\nMethodsWe used multivariable linear regression to relate state-specific rates of outpatient prescribing overall for fluoroquinolones, penicillins, macrolides, and cephalosporins between 2011-2012 to state-specific rates of hospitalization with septicemia (ICD-9 codes 038.xx present anywhere on discharge diagnosis) in each of the following age groups of adults: (18-49y, 50-64y, 65-74y, 75-84y, 85+y) reported to the Healthcare Cost and Utilization Project (HCUP) between 2011-2012, adjusting for additional covariates, and random effects associated with the ten US Health and Human Services (HHS) regions.\n\nResultsRates of penicillin prescribing were positively associated with septicemia hospitalization rates in the analyses for persons aged 50-64y, 65-74y, and 74-84y. Percent African Americans in a given age group was positively associated with septicemia hospitalization rates in the analyses for persons aged 75-84y and over 85y. Average minimal daily temperature was positively associated with septicemia hospitalization rates in the analyses for persons aged 18-49y, 50-64y, 75-84y and over 85y.\n\nConclusionsOur results suggest positive associations between the rates of prescribing for penicillins and the rates of sepsis hospitalization in US adults aged 50-84y. Further studies are needed to understand the potential effect of antibiotic replacement in the treatment of various syndromes, such as replacement of fluoroquinolones by other antibiotics, possibly penicillins following the recent US FDA guidelines on restriction of fluoroquinolone use, on the rates of sepsis hospitalization.

epidemiology↗

bioRxiv2018

Antimicrobial resistance prevalence and rates of hospitalization with septicemia in the diagnosis in adults in different US states

ObjectivesRates of hospitalization with sepsis/septicemia and associated mortality in the US have risen significantly during the last two decades. Antibiotic resistance may contribute to the rates of sepsis-related outcomes through lack of clearance of bacterial infections following antibiotic treatment during different stages of infection. However, there is limited information about the relation between prevalence of resistance to various antibiotics in different bacteria and rates of sepsis-related outcomes. MethodsFor different age groups of adults (18-49y,50-64y,65-74y,75-84y,85+y) and combinations of antibiotics/bacteria, we evaluated associations between state-specific prevalence (percentage) of resistant samples for a given combination of antibiotics/bacteria among catheter-associated urinary tract infections in the CDC Antibiotic Resistance Patient Safety Atlas data between 2011-2014 and rates of hospitalization with septicemia (ICD-9 codes 038.xx present on the discharge diagnosis) reported to the Healthcare Cost and Utilization Project (HCUP), as well as rates of mortality with sepsis (ICD-10 codes A40-41.xx present on death certificate). ResultsAmong the different combinations of antibiotics/bacteria, prevalence of resistance to fluoroquinolones in E. coli had the strongest association with septicemia hospitalization rates for individuals aged over 50y, and with sepsis mortality rates for individuals aged 18-84y. A number of positive correlations between prevalence of resistance for different combinations of antibiotics/bacteria and septicemia hospitalization/sepsis mortality rates in adults were also found. ConclusionsOur findings, as well as our related work on the relation between antibiotic use and sepsis rates support the association between resistance to/use of certain antibiotics and rates of sepsis-related outcomes, suggesting the potential utility of antibiotic replacement.

epidemiology↗

bioRxiv2017

On the relative role of different age groups during epidemics associated with the respiratory syncytial virus

BackgroundWhile RSV circulation results in high burden of hospitalization, particularly among infants, young children and the elderly, little is known about the role of different age groups in propagating annual RSV epidemics in the community.\n\nMethodsDuring a communicable disease outbreak, some subpopulations may play a disproportionate role during the outbreak's ascent due to increased susceptibility and/or contact rates. Such subpopulations can be identified by considering the proportion that cases in a subpopulation represent among all cases in the population occurring before (Bp) and after the epidemic peak (Ap) to calculate the subpopulation's relative risk, RR=Bp/Ap. We estimated RR for several age groups using data on RSV hospitalizations in the US between 2001-2012 from the Healthcare Cost and Utilization Project (HCUP).\n\nResultsChildren aged 3-4y and 5-6y each had the highest RR estimate for 5/11 seasons in the data, with RSV hospitalization rates in infants being generally higher during seasons when children aged 5-6y had the highest RR estimates. Children aged 2y had the highest RR estimate during one season. RR estimates in infants and individuals aged 11y and older were mostly lower than in children aged 1-10y.\n\nConclusionsThe RR estimates suggest that preschool and young school-age children have the leading relative roles during RSV epidemics. We hope that those results will aid in the design of RSV vaccination policies.

epidemiology↗

bioRxiv2017

Pediatric hospitalizations associated with respiratory syncytial virus (RSV) and influenza, and the frequency of asthma as a secondary diagnosis

BackgroundThere is uncertainty about the burden of hospitalization associated with RSV and influenza in children, including those with underlying medical conditions. MethodsWe applied previously developed methodology (Goldstein et al., Epidemiology 2012) to HealthCare Cost and Utilization Project (HCUP) hospitalization data and additional data related to asthma diagnosis/previous history in hospitalized children to estimate RSV and influenza-associated hospitalization rates in different subpopulations of US children between 2003-2010. ResultsThe estimated average annual rates (per 100,000 children) of RSV-associated hospitalization with a respiratory cause (ICD-9 codes 460-519) present anywhere in the discharge diagnosis were 2381 (95% CI(2252,2515)) in age <1y; 710.6(609.1,809.2) (age 1y); 395(327.7,462.4) (age 2y); 211.3(154.6,266.8) (age 3y); 111.1(62.4,160.1) (age 4y); 72.3(29.3,116.4) (ages 5-6y); 35.6(9.9,62.2) (ages 7-11y); and 39(17.5,60.6) (ages 12-17y). The corresponding rates of influenza-associated hospitalization were lower, ranging from 181(142.5,220.3) in age <1y to 17.9(11.7,24.2) in ages 12-17y. The relative risks for RSV-related hospitalization associated with a prior diagnosis of asthma in age groups under 5y ranged between 3.1(2.1,4.7) (age <1y) to 6.7(4.2,11.8) (age 2y); the corresponding risks for influenza-related hospitalization ranged from 2.8(2.1,4) (age <1y) to 4.9(3.8,6.4) (age 3y). ConclusionsRSV-associated hospitalization rates in young children are high and decline rapidly with age. Young children with an asthma diagnosis should be target groups for RSV and influenza-related mitigation efforts, possibly including RSV prophylaxis for the youngest children.

epidemiology↗

bioRxiv2017

On the relative role of different age groups during influenza A epidemics in Germany, 2002-2017

BackgroundThere is limited information about the role of different age groups, particularly subgroups of school-age children and younger adults in propagating influenza epidemics.\n\nMethodsFor a communicable disease outbreak, some subpopulations may play a disproportionate role during the ascent of the outbreak due to increased susceptibility and/or contact rates. Such subpopulations can be identified by considering the proportion that cases in a subpopulation represent among all cases in the population occurring before the epidemic peak (Bp), the corresponding proportion after the epidemic peak (Ap), to calculate the relative risk for a subpopulation, RR=Bp/Ap. We estimated RR for several age groups using data on reported influenza A cases in Germany between 2002-2017.\n\nResultsChildren aged 14-17y had the highest RR estimates for 7 out of 15 influenza A epidemics in the data, including the 2009 pandemic, and the large 2016/17, 2008/09, and 2006/07 seasons. Children aged 10-13y had the highest RR estimates during 3 epidemics, including the large 2014/15 and 2004/05 seasons. Children aged 6-9y had the highest RR estimates during two epidemics, including the large 2012/13 season. Children aged 2-5y had the highest RR estimate during the moderate 2015/16 season; adults aged 18-24y had the highest RR estimate during the small 2005/06 season; adults aged 25-34y had the highest RR estimate during the large, 2002/03 season.\n\nConclusionsOur results support the prominent role of all school-age children, particularly the oldest ones, in propagating influenza epidemics in the community. We note that national vaccination coverage levels among older school-age children were lower than among younger school-age children during the recent influenza seasons in the US, and influenza vaccination program in England has not been phased in yet for secondary school students.

epidemiology↗