Particle Size, Dose, and Confinement Affect Passive Diffusion Flux through the Membrane Concentration Boundary Layer.

The authors present a steady-state-, particle-size-, and dose-dependent dissolution-permeation model that describes particle dissolution within the concentration boundary layer (CBL) adjacent to a semipermeable surface. It is critical to understand how particle size and dose affect the behavior of dissolving particles in the presence of a CBL adjacent to a semipermeable surface both in vivo and in vitro. Control of particle size is ubiquitous in the pharmaceutical industry; however, traditional pharmaceutical assumptions of particle dissolution typically ignore particle dissolution within the length scale of the CBL. The CBL does not physically prevent particles from traveling to the semipermeable surface (mucus, epithelial barrier, synthetic membrane, etc.), and particle dissolution can occur within the CBL thickness (δC) if the particle is sufficiently small (∼dparticle ≤ δC). The total flux (the time rate transport of molecules across the membrane surface per unit area) was chosen as a surrogate parameter for measuring the additional mass generated by particles dissolving within the donor CBL. Mass transfer experiments aimed to measure the total flux of drug using an ultrathin large-area membrane diffusion cell described by Sinko et al. with a silicone-based membrane ( Mol. Pharmaceutics 2020, 17, (7) 2319-2328, DOI: 10.1021/acs.molpharmaceut.0c00040). Suspensions of ibuprofen, a model weak-acid drug, with three different particle-size distributions with average particle diameters of 6.6, 37.4, and 240 µm at multiple doses corresponding to a range of suspension concentrations with dimensionless dose numbers of 2.94, 14.7, 147, and 588 were used to test the model. Experimentally measured total flux across the semipermeable membrane/CBL region agreed with the predictions from the proposed model, and at a range of relatively low suspension concentrations, dependent on the average particle size, there was a measurable effect on the flux due to the difference in δC that formed at the membrane surface. Additionally, the dose-dependent total flux across the membrane was up to 10% higher than the flux predicted by the standard Higuchi-Hiestand dissolution model where the effects of confinement were ignored as described by Wang et al. ( Mol. Pharmaceutics 2012, 9 (5), 1052-1066, DOI: 10.1021/mp2002818).

Ultrathin, Large-Area Membrane Diffusion Cell for pH-Dependent Simultaneous Dissolution and Absorption Studies.

Preclinical evaluation of modern oral dosage forms requires more advanced in vitro devices as the trend of selecting low solubility, high permeability compounds for commercial development continues. Current dissolution methodologies may not always be suitable for such compounds due to excessive fluid volume, high fluid shear rates, heterogeneity of shear rates, suboptimal fluid flow, and, ultimately, the lack of absorption ability (Gray The Science of USP 1 and 2 Dissolution: Present Challenges and Future Relevance; Pharmaceutical Research, 2009; Vol. 26; pp 1289-1302). Herein, a new dissolution apparatus is introduced in combination with an ultrathin, semipermeable polymer membrane that mimics human passive absorption for lipophilic compounds. The ultrathin large-area polydimethylsiloxane (PDMS) membrane (UTLAM) absorption system is designed to mimic the dissolution and passive transcellular diffusion process representing the oral absorption pathway. A simple spin-casting method was developed to fabricate the ultrathin highly uniform membranes. To minimize membrane resistance to diffusion and maximize transport across the polymer membrane, 10-40 µm PDMS membranes were successfully prepared. A new diffusion cell was designed and tested to support the UTLAM and incorporates a hydrofoil impeller for more desirable hydrodynamics and mixing, using ibuprofen as a model weak acidic drug. UTLAM permeability was sufficiently high that the aqueous boundary layer contributed to the overall permeability of the system. This diffusion cell system demonstrated that, when the aqueous diffusion layer contributes to the overall resistance to transport, the pH at which absorption is 50% of maximum (pH50%) shifts from the pKa to higher values, demonstrating why weak acid drugs can exhibit high absorption at pH's significantly greater than their pKa. High rates of transport across the UTLAM are possible for drugs with high partition coefficients (i.e., BCS II compounds even under mostly ionized conditions), and PDMS UTLAMs may be tailored to simulate human intestinal passive absorption rates.

Neighborhood socioeconomic characteristics, healthcare spatial access, and emergency department visits for ambulatory care sensitive conditions for elderly.

The objective of this study is to explore relationships among neighborhood socioeconomic characteristics (for example, income and ethnicity), spatial access to health care, and emergency department (ED) visits for ambulatory care sensitive conditions (ACSC) for adults aged 65 years and over. ED visit data were from 15 counties in the Texas Coastal Bend from September 1, 2009 and August 1, 2012. ED visits for ACSC that were common for elderly were estimated based on Agency for Healthcare Research and Quality's (AHRQ's) ACSC and Prevention Quality Indicators. The U.S. Census American Community Service (ACS) data provided neighborhood socioeconomic characteristics. Spatial access to general practices and to hospitals, respectively at the zip code level were estimated using the enhanced two-step floating catchment area method. Using multivariable regression models, we estimated associations of elderly ACSC ED visits with neighborhood socioeconomic characteristics and spatial accessibility of healthcare. We found higher rates of elderly ACSC ED visits are significantly associated with higher rates of elderly Hispanic and poverty at the zip code level. Spatial access to general practices and hospitals play inverse roles in the rate of elderly ACSC ED visits. Poorer access to general practices but easier access to hospitals contributes to the higher elderly ACSC ED rate at the zip code level. Neighborhood socioeconomic characteristics and spatial access to healthcare affect the rate of elderly ACSC ED visits. Research informing policy action is needed to decrease racial/ethnic and economic disadvantage and increase equitable spatial access to primary care for the elderly.

Training Public Health Advisors.

Federal public health advisors provide guidance and assistance to health departments to improve public health program work. The Centers for Disease Control and Prevention (CDC) prepares them with specialized training in administering public health programs. This article describes the evolving training and is based on internal CDC documents and interviews. The first federal public health advisors worked in health departments to assist with controlling syphilis after World War II. Over time, more CDC prevention programs hired them. To meet emerging needs, 3 major changes occurred: the Public Health Prevention Service, a fellowship program, in 1999; the Public Health Associate Program in 2007; and integration of those programs. Key components of the updated training are competency-based training, field experience, supervision, recruitment and retention, and stakeholder support. The enduring strength of the training has been the experience in a public health agency developing practical skills for program implementation and management.

Conclusion and future directions: CDC Health Disparities and Inequalities Report - United States, 2013.

The reports in this supplement document persistent disparities between some population groups in health outcomes, access to health care, adoption of health promoting behaviors, and exposure to health-promoting environments. Some improvements in overall rates and even reductions in some health disparities are noted; however, many gaps persist. These finding highlight the importance of monitoring health status, outcomes, behaviors, and exposures by population groups to assess trends and target interventions. In this report, disparities were found between race and ethnic groups across all of the health topics examined. Differences also were observed by other population characteristics. For example, persons with low socioeconomic status were more likely to be affected by diabetes, hypertension, and human immunodeficiency virus (HIV) infection and were less likely to be screened for colorectal cancer and vaccinated against influenza.

Introduction: CDC Health Disparities and Inequalities Report - United States, 2013.

This supplement is the second CDC Health Disparities and Inequalities Report (CHDIR). The 2011 CHDIR was the first CDC report to assess disparities across a wide range of diseases, behavioral risk factors, environmental exposures, social determinants, and health-care access (CDC. CDC Health Disparities and Inequalities Report-United States, 2011. MMWR 2011;60[Suppl; January 14, 2011]). The 2013 CHDIR provides new data for 19 of the topics published in 2011 and 10 new topics. When data were available and suitable analyses were possible for the topic area, disparities were examined for population characteristics that included race and ethnicity, sex, sexual orientation, age, disability, socioeconomic status, and geographic location. The purpose of this supplement is to raise awareness of differences among groups regarding selected health outcomes and health determinants and to prompt actions to reduce disparities. The findings in this supplement can be used by practitioners in public health, academia and clinical medicine; the media; the general public; policymakers; program managers; and researchers to address disparities and help all persons in the United States live longer, healthier, and more productive lives.

Risk factors associated with clinic visits during the 1999 forest fires near the Hoopa Valley Indian Reservation, California, USA.

Forest fires burned near the Hoopa Valley Indian Reservation in northern California from late August until early November in 1999. The fires generated particulate matter reaching hazardous levels. We assessed the relationship between patients seeking care for six health conditions and PM(10) exposure levels during the 1999 fires and during the corresponding period in 1998 when there were no fires. Multivariate logistic regression analysis indicated that daily PM(10) levels in 1999 were significant predictors for patients seeking care for asthma, coronary artery disease and headache after controlling for potential risk factors. Stratified multivariate logistic regression models indicated that daily PM(10) levels in 1999 were significant predictors for patients seeking care for circulatory illness among residents of nearby communities and new patients, and for respiratory illness among residents of Hoopa and those of nearby communities.

Trends in blood lead levels and blood lead testing among US children aged 1 to 5 years, 1988-2004.

OBJECTIVES: To evaluate trends in children's blood lead levels and the extent of blood lead testing of children at risk for lead poisoning from national surveys conducted during a 16-year period in the United States. METHODS: Data for children aged 1 to 5 years from the National Health and Nutrition Examination Survey III Phase I, 1988-1991, and Phase II, 1991-1994 were compared to data from the survey period 1999-2004. RESULTS: The prevalence of elevated blood lead levels, >/=10 microg/dL, among children decreased from 8.6% in 1988-1991 to 1.4% in 1999-2004, which is an 84% decline. From 1988-1991 and 1999-2004, children's geometric mean blood lead levels declined in non-Hispanic black (5.2-2.8 microg/dL), Mexican American (3.9-1.9 microg/dL), and non-Hispanic white children (3.1 microg/dL to 1.7 microg/dL). However, levels continue to be highest among non-Hispanic black children relative to Mexican American and non-Hispanic white children. Blood lead levels were distributed as follows: 14.0% were <1.0 microg/dL, 55.0% were 1.0 to <2.5 microg/dL, 23.6% were 2.5 to <5 microg/dL, 4.5% were 5 to <7.5 microg/dL, 1.5% were 7.5 to <10 microg/dL, and 1.4% were >/=10 microg/dL. Multivariable analysis indicated that residence in older housing, poverty, age, and being non-Hispanic black are still major risk factors for higher lead levels. Blood lead testing of Medicaid-enrolled children increased to 41.9% from 19.2% in 1988-1991. Only 43.0% of children with elevated blood lead levels had previously been tested. CONCLUSIONS: Children's blood lead levels continue to decline in the United States, even in historically high-risk groups for lead poisoning. To maintain progress made and eliminate remaining disparities, efforts must continue to test children at high risk for lead poisoning, and identify and control sources of lead. Coordinated prevention strategies at national, state, and local levels will help achieve the goal of elimination of elevated blood lead levels.

Screening for lead poisoning: a geospatial approach to determine testing of children in at-risk neighborhoods.

OBJECTIVE: To develop a spatial strategy to assess neighborhood risk for lead exposure and neighborhood-level blood lead testing of young children living in the city of Atlanta, Georgia. STUDY DESIGN: This ecologic study used existing blood lead results of children aged

Reduction of elevated blood lead levels in children in North Carolina and Vermont, 1996-1999.

BACKGROUND: Few studies have examined factors related to the time required for children's blood lead levels (BLLs) > or = 10 microg/dL to decline to < 10 microg/dL. OBJECTIVES: We used routinely collected surveillance data to determine the length of time and risk factors associated with reducing elevated BLLs in children below the level of concern of 10 microg/dL. METHODS: From the North Carolina and Vermont state surveillance databases, we identified a retrospective cohort of 996 children < 6 years of age whose first two blood lead tests produced levels > or = 10 microg/dL during 1996-1999. Data were stratified into five categories of qualifying BLLs and analyzed using Cox regression. Survival curves were used to describe the time until BLLs declined below the level of concern. We compared three different analytic methods to account for children lost to follow-up. RESULTS: On average, it required slightly more than 1 year (382 days) for a child's BLL to decline to < 10 microg/dL, with the highest BLLs taking even longer. The BLLs of black children [hazard ratio (HR) = 0.84; 95% confidence interval (CI), 0.71-0.99], males (HR(male) = 0.83; 95% CI, 0.71-0.98), and children from rural areas (HR(rural) = 0.83; 95% CI, 0.70-0.97) took longer to fall below 10 microg/dL than those of other children, after controlling for qualifying BLL and other covariates. Sensitivity analysis demonstrated that including censored children estimated a longer time for BLL reduction than when using linear interpolation or when excluding censored children. CONCLUSION: Children with high confirmatory BLLs, black children, males, and children from rural areas may need additional attention during case management to expedite their BLL reduction time to < 10 microg/dL. Analytic methods that do not account for loss to follow-up may underestimate the time it takes for BLLs to fall below the recommended target level.

Global approach to reducing lead exposure and poisoning.

Lead poisoning is an important environmental disease that can have life-long adverse health effects. Most susceptible are children, and most commonly exposed are those who are poor and live in developing countries. Studies of children's blood-lead levels (BLLs) are showing cognitive impairment at increasingly lower BLLs. Lead is dangerous at all levels in children. The sources of lead exposure vary among and within countries depending on past and current uses. Sources of lead may be from historic contamination, recycling old lead products, or from manufacturing new products. In all countries that have banned leaded gasoline, average population BLLs have declined rapidly. In many developing countries where leaded gasoline is no longer used, many children and workers are exposed to fugitive emissions and mining wastes. Unexpected lead threats, such as improper disposal of electronics and children's toys contaminated with lead, continue to emerge. The only medical treatment available is chelation, which can save lives of persons with very high BLLs. However, chelating drugs are not always available in developing countries and have limited value in reducing the sequelae of chronic low dose lead exposure. Therefore, the best approach is to prevent exposure to lead. Because a key strategy for preventing lead poisoning is to identify and control or eliminate lead sources, this article highlights several major sources of lead poisoning worldwide. In addition, we recommend three primary prevention strategies for lead poisoning: identify sources, eliminate or control sources, and monitor environmental exposures and hazards.

Use of the ABC care bundle to standardize guideline implementation in a cardiac surgical population: a pilot study.

A cardiac surgical progressive care unit implemented the ABC's of Cardiovascular Risk Reduction Care Bundle to determine whether the use of a packaged approach to medication prescription and lifestyle counseling would improve adherence to secondary risk-reduction guidelines in postcoronary artery bypass graft patients. A pilot study was carried out to assess changes in adherence to guideline recommendations post-Care Bundle implementation. Findings support using a systematic strategy to improve guideline adherence in this population.

Identifying housing that poisons: a critical step in eliminating childhood lead poisoning.

The purpose of our study was to develop a method to identify and prioritize "high-risk" buildings in Chicago that could be targeted for childhood lead poisoning prevention activities. We defined "high-risk" buildings as those where multiple children younger than 6 years with elevated blood lead levels (BLLs) had lived and where lead hazards were previously identified on environmental inspection. By linking 1997-2003 Chicago elevated blood lead surveillance, environmental inspection, and building footprint data, we found that 49,362 children younger than 6 years with elevated BLLs lived at 30,742 buildings. Of those, 67 were "high-risk" buildings and these were associated with 994 children with elevated BLLs. On average, 15 children with elevated BLLs had lived in each building (range: 10-53, median: 13). Almost two thirds (n = 43) of the high-risk buildings had two or more referrals for inspection to the same apartment or housing unit; of those, 40 percent (n = 17) failed to maintain lead-safe status after compliance. Linking blood lead surveillance, environmental inspection, and building footprint databases allowed us to identify individual high-risk buildings. This approach prioritizes lead hazard control efforts and may help health, housing, and environmental agencies in targeting limited resources to increase lead-safe housing for children.

Binational study of pediatric blood lead levels along the United States/Mexico border.

To evaluate lead exposure among children living in border communities, the states of Arizona and New Mexico in the United States (US), and the states of Sonora and Chihuahua in Mexico collaboratively requested that the Centers for Disease Control and Prevention (CDC) provide technical assistance to document pediatric blood lead levels (BLLs) in children living along this part of the US/Mexico border. Two studies were conducted to evaluate BLLs of children aged 1-6 years. In 1998, 1210 children were tested in the Arizona/Sonora study; in 1999, 874 children were tested in New Mexico/Chihuahua. Overall geometric mean BLL was 32.5 microg/l (95% Confidence Interval 31.5-33.5) with BLLs ranging from below limit of detection to 320.0 microg/l. Mean BLLs were higher among children living on the Mexican side of the border (43.2 microg/l) compared to those on the US side (22.3 microg/l). Mean BLLs ranged from 14.9 to 31.2 microg/l at the US sites and from 26.9 to 55.2 microg/l at the Mexican sites. This study used a convenience sample and cannot be considered representative of the general population. Nonetheless, the range of mean BLLs among the sites and especially the higher mean BLLs among children living in the border communities in Mexico suggests different exposures to lead and warrants further attention.

Blood lead levels and risk factors for lead poisoning in children and caregivers in Chuuk State, Micronesia.

Lead poisoning is a preventable environmental disease. Children and developing fetuses are especially vulnerable; even low blood lead levels (BLLs) are linked with learning and behavioral problems. We assessed children's and their caregivers' BLLs and risk factors for lead exposure in Chuuk State, Federated States of Micronesia. Children aged 2-6 years were randomly selected within 20 randomly selected villages. Children and caregivers provided venous blood, and caregivers offered information about possible risk factors for lead exposure. Mean BLLs were 39 microg/l for children and 16 microg/l for caregivers. Children with BLLs of > or = 100 microg/l (elevated) were 22.9 (95% CI: 4.5-116.0) times more likely to have a caregiver with an elevated BLL, 6.2 (95% CI: 1.4-27.3) times more likely to live on an outer island, and 3.4 (95% CI: 1.7-6.9) times more likely to have a family member who made lead fishing weights than did other children even after controlling for age and sex. For children, 61% of elevated BLLs could be attributed to making fishing weights. Caregivers with elevated BLLs were 5.9 (95% CI: 1.5-23.7) times more likely to live in a household that melted batteries than other caregivers even after controlling for age and education. For caregivers, 37% of the elevated BLLs could be attributed to melting batteries. The association of elevated BLLs in children and their caregiver suggests a common environmental exposure. Melting batteries to make fishing sinkers is a preventable source of lead exposure for children and their caregivers in Chuuk. Published by Elsevier GmbH.

Improving strategies to prevent childhood lead poisoning using local data.

Lead poisoning remains an important, yet entirely preventable, disease among children worldwide. Children's blood lead levels (BLLs) have been declining in the United States; however, nearly half a million children have BLLs > or = 10 microg/ dl, the level targeted for elimination by 2010. Attainment of this national goal will require translating knowledge into public health practice. The Centers for Disease Control and Prevention (CDC) funds state and local health departments to develop comprehensive prevention programs and surveillance. The Jefferson County, Kentucky Program, which includes Louisville, adopted CDC's recommendation for targeting lead testing to children at highest risk and used knowledge of risk factors for lead poisoning to develop prevention strategies. Blood lead testing was targeted to Louisville neighborhoods at high risk, i.e., those characterized by housing built before 1950 and valued < $50,000, which are known risk factors for BLLs > or = 10 microg/dl among children. We evaluated the impact of these and other interventions. Testing of children aged 9-24 months who were born in high risk housing increased from 64.5% to 73.7% (p-value <0.001) among the 1996 and 2000 birth cohorts. Among the 1996 and 2000 birth cohorts, there was no significant change in testing of children born in low risk housing, i.e., built after 1950 and valued at > or = $50,000 (37.0-37.5%; p-value = 0.649). This report demonstrates that applying scientific knowledge to public health practice and using surveillance and other data to evaluate practice effectively increased testing of children at high risk for lead poisoning, increased lead-safe housing, and empowered communities to protect their children from lead exposure.

A federal agency's role in fulfilling the public health core functions: the childhood lead poisoning prevention program model.

The Institute of Medicine identified 3 core functions of public health: assessment, policy development, and assurance. Federal, state, and local public health agencies all have an obligation to provide these vital functions to ensure conditions in which people can be healthy. However, the few publications that provide core function applications only focus on applications at the local or state levels. The Centers for Disease Control and Prevention's Childhood Lead Poisoning Prevention Program uses a comprehensive public health approach. This article describes the Centers for Disease Control and Prevention's leading role in applying the core public health functions to prevent childhood lead poisoning.

High-intensity targeted screening for elevated blood lead levels among children in 2 inner-city Chicago communities.

OBJECTIVES: We assessed the prevalence of elevated blood lead levels (> or = 10 micrograms of lead per deciliter of blood), risk factors, and previous blood lead testing among children in 2 high-risk Chicago, Ill, communities. METHODS: Through high-intensity targeted screening, blood lead levels were tested and risks were assessed among a representative sample of children aged 1 to 5 years who were at risk for lead exposure. RESULTS: Of the 539 children who were tested, 27% had elevated blood lead levels, and 61% had never been tested previously. Elevated blood lead levels were associated with chipped exterior house paint. CONCLUSIONS: Most of the children who lived in these communities--where the prevalence for elevated blood lead levels among children was 12 times higher than the national prevalence--were not tested for lead poisoning. Our findings highlight the need for targeted community outreach that includes testing blood lead levels in accordance with the American Academy of Pediatrics' recommendations.

Surveillance for elevated blood lead levels among children--United States, 1997-2001.

PROBLEM/CONDITION: Lead is neurotoxic and particularly harmful to the developing nervous systems of fetuses and young children. Extremely high blood lead levels (BLLs) (i.e.,> or =70 microg/dL) can cause severe neurologic problems (e.g., seizure, coma, and death). However, no threshold has been determined regarding lead's harmful effects on children's learning and behavior. In 1990, the U.S. Department of Health and Human Services established a national goal to eliminate BLLs >25 microg/dL by 2000; a new goal targets elimination of BLLs > or =10 microg/dL in children aged <6 years by 2010. REPORTING PERIOD: Information regarding children's BLLs comes from 1) National Health and Nutrition Examination Surveys (NHANES) conducted during 1976-1980, 1988-1991, 1991-1994, and 1999-2000; and 2) state child blood lead surveillance data for test results collected during 1997-2001. DESCRIPTION OF SYSTEM: CDC tracks children's BLLs in the United States by using both NHANES and state and local surveillance data. NHANES reports data regarding children aged 1-5 years; state and local surveillance systems report data regarding children aged <72 months. Because lead exposure in children varies among populations and communities, both surveys are needed to determine the burden of elevated BLLs among young children throughout the United States. NHANES uses highly standardized data-collection procedures and probability samples to gather information regarding the health and nutritional status of the civilian, noninstitutionalized U.S. population. State and local childhood lead surveillance systems are based on reports of blood lead tests from laboratories. State and local programs submit data to CDC annually. In this report, confirmed elevated BLLs are defined as one venous blood specimen > or =10 microg/dL or two capillary blood specimens > or =10 microg/dL drawn within 12 weeks of each other. RESULTS: The NHANES 1999-2000 survey estimated that 434,000 children (95% confidence interval = 189,000-846,000) or 2.2% of children aged 1-5 years had BLLs > or =10 microg/dL. For 2001, a total of 44 states, the District of Columbia (DC), and New York City (NYC) submitted child blood lead surveillance data to CDC. These jurisdictions represent 95% of the U.S. population of children aged <72 months and 97% of the nation's pre-1950 housing. The number of children tested and reported to CDC increased from 1,703,356 in 1997 (37 states, DC, and NYC reporting), to 2,422,298 in 2001 (44 states, DC, and NYC reporting). During that time, the number of children reported with confirmed elevated BLLs > or =10 microg/dL steadily decreased from 130,512 in 1997 to 74,887 in 2001. In 2000, the year targeted for national elimination of BLLs >25 microg/dL, a total of 8,723 children had BLLs > or =25 microg/dL. INTERPRETATION: Both national surveys and state surveillance data indicate children's BLLs continue to decline throughout the United States. However, thousands of children continue to be identified with elevated BLLs. The 2000 goal of eliminating BLLs >25 microg/dL was not met. Attaining the 2010 goal of eliminating BLLs > or =10 microg/dL will require intensified efforts to target areas at highest risk, evaluate preventive measures, and improve the quality of surveillance data. PUBLIC HEALTH ACTIONS: States will continue to use surveillance data to 1) promote legislation supporting lead poisoning prevention activities, 2) obtain funding, 3) identify risk groups, 4) target and evaluate prevention activities, and 5) monitor and describe progress toward elimination of BLLs > or =10 microg/dL. CDC will work with state and local programs to improve tracking systems and the collection, timeliness, and quality of surveillance data.