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Background: Antimicrobial stewardship (AS) is an important topic in infectious diseases (ID) training, yet many ID fellowships lack formal training, and little is known about fellows' learning preferences., Methods: We conducted 24 in-depth interviews with ID fellows across the United States during 2018 and 2019 to explore their experiences with and preferences for AS education during fellowship. Interviews were transcribed, deidentified, and analyzed to identify themes., Results: Fellows had variable exposure to AS before and during fellowship, which impacted their knowledge about and attitude toward stewardship as a career; however, all fellows expressed the importance of learning general stewardship principles during fellowship. Some fellows' training included mandatory stewardship lectures and/or rotations, but most fellows felt their primary stewardship learning occurred through informal experiences in the clinical setting, such as holding the antimicrobial approval pager. Fellows expressed a preference for a standardized, structured curriculum that included in-person practical, interactive discussions with multidisciplinary faculty along with the opportunity to practice and apply their skills; however, they emphasized that time needed to be set aside for those educational activities. Although they wanted to learn the evidence and rationale for stewardship recommendations, they especially wanted training in and feedback on how to communicate stewardship recommendations to other health professionals, particularly in the setting of conflict., Conclusions: ID fellows believe that standardized AS curricula should be included in their fellowship training, and they prefer structured, practical, and interactive learning experiences., Competing Interests: Potential conflicts of interest. R. S., A. L., and K. B. are employed by the Infectious Diseases Society of America and were involved in the development and evaluation of the IDSA Core Antimicrobial Stewardship Curriculum. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Antimicrobial stewardship (AS) programs are required by Centers for Medicare and Medicaid Services and should ideally have infectious diseases (ID) physician involvement; however, only 50% of ID fellowship programs have formal AS curricula. The Infectious Diseases Society of America (IDSA) formed a workgroup to develop a core AS curriculum for ID fellows. Here we study its impact., Methods: ID program directors and fellows in 56 fellowship programs were surveyed regarding the content and effectiveness of their AS training before and after implementation of the IDSA curriculum. Fellows' knowledge was assessed using multiple-choice questions. Fellows completing their first year of fellowship were surveyed before curriculum implementation ("pre-curriculum") and compared to first-year fellows who complete the curriculum the following year ("post-curriculum")., Results: Forty-nine (88%) program directors and 105 (67%) fellows completed the pre-curriculum surveys; 35 (64%) program directors and 79 (50%) fellows completed the post-curriculum surveys. Prior to IDSA curriculum implementation, only 51% of programs had a "formal" curriculum. After implementation, satisfaction with AS training increased among program directors (16% to 68%) and fellows (51% to 68%). Fellows' confidence increased in 7/10 AS content areas. Knowledge scores improved from a mean of 4.6 to 5.1 correct answers of 9 questions (P = .028). The major hurdle to curriculum implementation was time, both for formal teaching and for e-learning., Conclusions: Effective AS training is a critical component of ID fellowship training. The IDSA Core AS Curriculum can enhance AS training, increase fellow confidence, and improve overall satisfaction of fellows and program directors., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The Ending the HIV Epidemic initiative, which aims to decrease the annual incidence of HIV infections in the United States (US) by 90% over the next decade, will require growth of a limited HIV provider workforce. Existing HIV training pathways within Family Medicine (FM) and Internal Medicine (IM) residency programs may address the shortage of HIV medical providers, but their curricula and outcomes have not previously been assessed., Methods: We identified HIV residency pathways via literature review, Internet search, and snowball sampling and designed a cross-sectional study of existing HIV pathways in the US. This survey of pathway directors included 33 quantitative items regarding pathway organization, curricular content, graduate outcomes, and challenges. We used descriptive statistics to summarize responses., Results: Twenty-five residency programs with dedicated HIV pathways in the US were identified (14 FM and 11 IM), with most located in the West and Northeast. All 25 (100%) pathway directors completed the survey. Since 2006, a total of 228 residents (77 FM and 151 IM) have graduated from these HIV pathways. Ninety (39%) of 228 pathway graduates provide primary care to persons with HIV (PWH)., Conclusions: HIV pathways are effective in graduating providers who can care for PWH, but generally are not located in nor do graduates practice in the geographic areas of highest need. Our findings can inform quality improvement for existing programs, development of new pathways, and workforce development strategies. Specifically, expanding pathways in regions of greatest need and incentivizing pathway graduates to work in these regions could augment the HIV workforce., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

A needs assessment survey of infectious diseases (ID) training program directors identified gaps in educational resources for training and evaluating ID fellows in antimicrobial stewardship. An Infectious Diseases Society of America-sponsored core curriculum was developed to address that need.

Background: Challenges with any therapeutic program for children include the level of the child's engagement or adherence. Capitalizing on one of the primary learning avenues of children, play, the approach described in this article is to develop therapeutic toy and game controllers that require specific and repetitive joint movements to trigger toy/game activation., Objective: The goal of this study was to evaluate a specially designed wrist flexion and extension play controller in a cohort of children with upper extremity motor impairments (UEMIs). The aim was to understand the relationship among controller play activity, measures of wrist and forearm range of motion (ROM) and spasticity, and ratings of fun and difficulty., Design: This was a cross-sectional study of 21 children (12 male, 9 female; 4-12 years of age) with UEMIs., Methods: All children participated in a structured in-clinic play session during which measurements of spasticity and ROM were collected. The children were fitted with the controller and played with 2 toys and 2 computer games for 5 minutes each. Wrist flexion and extension motion during play was recorded and analyzed. In addition, children rated the fun and difficulty of play., Results: Flexion and extension goal movements were repeatedly achieved by children during the play session at an average frequency of 0.27 Hz. At this frequency, 15 minutes of play per day would result in approximately 1,700 targeted joint motions per week. Play activity was associated with ROM measures, specifically supination, but toy perception ratings of enjoyment and difficulty were not correlated with clinical measures., Limitations: The reported results may not be representative of children with more severe UEMIs., Conclusions: These outcomes indicate that the therapeutic controllers elicited repetitive goal movements and were adaptable, enjoyable, and challenging for children of varying ages and UEMIs., (© 2016 American Physical Therapy Association.)

Background: A strong foundational understanding of microbiology is crucial for the 21st century physician. Given recent major advances in medical microbiology, curricular changes will likely be needed. Before transforming curricula, we must first obtain a comprehensive understanding of contemporary medical student microbiology education., Methods: We disseminated a 38-question survey to microbiology course directors and curriculum deans at 142 US medical schools accredited by the Liason Committee on Medical Education. Survey questions focused on course leadership, curricular structure, course content, and educator perceptions about microbiology education locally and nationally., Results: One hundred and four (73%) of 142 schools completed the survey. Ninety-four (90%) schools identified a course director. Of these, 48% were led by microbiologists alone, 23% co-led by a microbiologist and a clinician, 20% by a clinician alone, and 8% by a laboratory medicine physician with or without a co-director. At 55 (53%) schools, the curricula were organized in a single block or course and at 47 (45%) it was integrated into other curricula. Areas of emerging importance, such as antimicrobial stewardship, global health, infection control, and the microbiome, were addressed at 66%, 65%, 64%, and 47% of institutions, respectively. Respondents reported the following concerns: challenges integrating microbiology into other courses, reduced total teaching hours, and difficulty balancing basic and clinical science topics., Conclusions: Preclinical microbiology course directors report significant challenges in meeting the needs of changing curriculum structure and content. Enhanced local collaboration between microbiologists and clinicians, as well as national collaboration among relevant societies to design best practices and support research, may be strategies for future success., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: The wrist extensors and flexors are profoundly affected in most children with hemiparetic cerebral palsy (CP) and are the major target of physical therapists' and occupational therapists' efforts to restore useful hand functions. A limitation of any therapeutic or exercise program can be the level of the child's engagement or adherence. The proposed approach capitalizes on the primary learning avenue for children: toy play., Objective: This study aimed to develop and evaluate the measurement accuracy of innovative, motion-specific play controllers that are engaging rehabilitative devices for enhancing therapy and promoting neural plasticity and functional recovery in children with CP., Design: Design objectives of the play controller included a cost-effective, home-based supplement to physical therapy, the ability to calibrate the controller so that play can be accomplished with any active range of motion, and the capability of logging play activity and wrist motion over week-long periods., Methods: Accuracy of the play controller in measuring wrist flexion-extension was evaluated in 6 children who were developing in a typical manner, using optical motion capture of the wrist and forearm as the gold standard., Results: The error of the play controller was estimated at approximately 5 degrees in both maximum wrist flexion and extension., Limitations: Measurements were taken during a laboratory session, with children without CP, and no toy or computer game was interfaced with the play controller. Therefore, the potential engagement of the proposed approach for therapy remains to be evaluated., Conclusions: This study presented the concept, development, and wrist tracking accuracy of an inexpensive approach to extremity therapy that may have a health benefit for children with hemiparesis, and potentially for patients of any age with a wide range of extremity neuromotor impairments., (© 2015 American Physical Therapy Association.)

We report the case of a 73-year-old American traveler who presented with 3 weeks of fatigue, fevers, chills, and pancytopenia. Clinical and laboratory findings were consistent with hemophagocytic lymphohystiocytosis (HLH) and bone marrow biopsy revealed amastigotes consistent with visceral leishmaniasis. The range of endemic visceral leishmaniasis transmission now extends into northern Spain and travelers to this region should use personal protective measures against sand fly exposure., (© 2014 International Society of Travel Medicine.)

Background: Cytomegalovirus (CMV) disease remains an important problem in solid-organ transplant recipients, with the greatest risk among donor CMV-seropositive, recipient-seronegative (D(+)/R(-)) patients. CMV-specific cell-mediated immunity may be able to predict which patients will develop CMV disease., Methods: We prospectively included D(+)/R(-) patients who received antiviral prophylaxis. We used the Quantiferon-CMV assay to measure interferon-γ levels following in vitro stimulation with CMV antigens. The test was performed at the end of prophylaxis and 1 and 2 months later. The primary outcome was the incidence of CMV disease at 12 months after transplant. We calculated positive and negative predictive values of the assay for protection from CMV disease., Results: Overall, 28 of 127 (22%) patients developed CMV disease. Of 124 evaluable patients, 31 (25%) had a positive result, 81 (65.3%) had a negative result, and 12 (9.7%) had an indeterminate result (negative mitogen and CMV antigen) with the Quantiferon-CMV assay. At 12 months, patients with a positive result had a subsequent lower incidence of CMV disease than patients with a negative and an indeterminate result (6.4% vs 22.2% vs 58.3%, respectively; P < .001). Positive and negative predictive values of the assay for protection from CMV disease were 0.90 (95% confidence interval [CI], .74-.98) and 0.27 (95% CI, .18-.37), respectively., Conclusions: This assay may be useful to predict if patients are at low, intermediate, or high risk for the development of subsequent CMV disease after prophylaxis., Clinical Trials Registration: NCT00817908.

Background: Since its emergence in 2000, epidemic spread of the methicillin-resistant Staphylococcus aureus (MRSA) clone USA300 has led to a high burden of skin and soft tissue infections (SSTIs) in the United States, yet its impact on MRSA bloodstream infections (BSIs) is poorly characterized., Methods: To assess clonality of the MRSA isolates causing SSTI and BSI during the epidemic period, a stratified, random sample of 1350 unique infection isolates (from a total of 7252) recovered at the Community Health Network of San Francisco from 2000 to 2008 were selected for genotyping. Risk factors and outcomes for 549 BSI cases caused by the USA300 epidemic clone and non-USA300 MRSA clones were assessed by retrospective review of patient medical records., Results: From 2000 to 2008, secular trends of USA300 SSTI and USA300 BSI were strongly correlated (Pearson r = 0.953). USA300 accounted for 55% (304/549) of BSIs as it was the predominant MRSA clone that caused community-associated (115/160), healthcare-associated community-onset (125/207), and hospital-onset (64/182) BSIs. Length of hospitalization after BSI diagnosis and mortality rates for USA300 and non-USA300 were similar. Two independent risk factors for USA300 BSI were identified: concurrent SSTI (adjusted relative risk, 1.4 [95% confidence interval {CI}, 1.2-1.6]) and anti-MRSA antimicrobial use in the preceding 30 days (0.7 [95% CI, .6-.8]). Isolates from concurrent SSTI were indistinguishable genotypically from the USA300 isolates that caused BSI., Conclusions: USA300 SSTIs serve as a source for BSI. Strategies to control the USA300 SSTI epidemic may lessen the severity of the concurrent USA300 BSI epidemic.

Background:  International travel poses a risk of destination-specific illness and may contribute to the global spread of infectious diseases. Despite this, little is known about the health characteristics and pretravel healthcare of US international travelers, particularly those at higher risk of travel-associated illness., Methods:  We formed a national consortium (Global TravEpiNet) of 18 US clinics registered to administer yellow fever vaccination. We collected data regarding demographic and health characteristics, destinations, purpose of travel, and pretravel healthcare from 13235 international travelers who sought pretravel consultation at these sites from January 2009 through January 2011., Results:  The destinations and itineraries of Global TravEpiNet travelers differed from those of the overall population of US international travelers. The majority of Global TravEpiNet travelers were visiting low- or lower-middle-income countries, and Africa was the most frequently visited region. Seventy-five percent of travelers were visiting malaria-endemic countries, and 38% were visiting countries endemic for yellow fever. Fifty-nine percent of travelers reported ≥1 medical condition. Atovaquone/proguanil was the most commonly prescribed antimalarial drug, and most travelers received an antibiotic for self-treatment of travelers' diarrhea. Hepatitis A and typhoid were the most frequently administered vaccines., Conclusions:  Data from Global TravEpiNet provide insight into the characteristics and pretravel healthcare of US international travelers who are at increased risk of travel-associated illness due to itinerary, purpose of travel, or existing medical conditions. Improved understanding of this epidemiologically significant population may help target risk-reduction strategies and interventions to limit the spread of infections related to global travel.

Pregnancy is an established risk factor for the development of severe and disseminated coccidioidomycosis, particularly when infection is acquired during the later stages of gestation. Although recent studies suggest that the incidence of symptomatic coccidioidomycosis during pregnancy is decreasing and that outcome has improved, management is complicated by the observations that azole antifungal agents can be teratogenic when given to some women, particularly at high doses, early in pregnancy. This article summarizes the data on these issues and offers guidance on the management of coccidioidomycosis during pregnancy.

The safety of high-dose oseltamivir during treatment of 2009 H1N1 influenza A infection for critically ill patients is unknown. Here we report on a case patient with severe, delayed-onset neuropsychiatric symptoms after administration of high-dose oseltamivir. Clinicians should be vigilant to the possible increased risk of complications associated with high-dose oseltamivir therapy for 2009 H1N1 influenza A infection.

Before the 1970s, today's older Americans were exposed to high levels of lead in the environment. The authors previously reported that lifetime cumulative lead dose was associated with lower cognitive test performance in older adults. Experiments suggest that environmental stress may intensify the detrimental influence of lead. No large, population-based studies of this question have been done. The authors evaluated whether cross-sectional associations of tibia lead with cognitive function were modified by neighborhood psychosocial hazards in the Baltimore Memory Study (2001-2005), a longitudinal cohort study of determinants of cognitive decline. Tibia lead was measured via (109)Cd-induced K-shell X-ray fluorescence. Neighborhood psychosocial hazards were measured independently of study subjects. Complete data were available among 1,001 demographically diverse adults aged 50-70 years, randomly selected from 65 contiguous neighborhoods in Baltimore City. Hierarchical mixed-effects regression models showed that neighborhood psychosocial hazards exacerbated the adverse associations of tibia lead in 3 of 7 cognitive domains after adjustment for age, sex, race/ethnicity, education, testing technician, and time of day (language, P = 0.039; processing speed, P = 0.067; executive functioning, P = 0.025). The joint occurrence of environmental stress and lead exposure across the life span may partially explain persistent racial/ethnic and socioeconomic disparities in cognitive function in late life.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) infections have become a major public health problem in both the community and hospitals. Few studies have characterized the incidence and clonal composition of disease-causing strains in an entire population. Our objective was to perform a population-based survey of the clinical and molecular epidemiology of MRSA disease in San Francisco, California., Methods: We prospectively collected 3985 MRSA isolates and associated clinical and demographic information over a 12-month period (2004-2005) at 9 San Francisco-area medical centers. A random sample of 801 isolates was selected for molecular analysis., Results: The annual incidence of community-onset MRSA disease among San Francisco residents was 316 cases per 100,000 population, compared with 31 cases per 100,000 population for hospital-onset disease. Persons who were aged 35-44 years, were men, and were black had the highest incidence of community-onset disease. The USA300 MRSA clone accounted for 234 cases of community-onset disease and 15 cases of hospital-onset disease per 100,000 population, constituting an estimated 78.5% and 43.4% of all cases of MRSA disease, respectively. Patients with community-onset USA300 MRSA versus non-USA300 MRSA disease were more likely to be male, be of younger age, and have skin and soft-tissue infections. USA300 strains were generally more susceptible to multiple antibiotics, although decreased susceptibility to tetracycline was observed in both community-onset (P = .008) and hospital-onset (P = .03) USA300 compared to non-USA300 strains., Conclusions: The annual incidence of community-onset MRSA disease in San Francisco is substantial, surpassing that of hospital-onset disease. USA300 is the predominant clone in both the community and hospitals. The dissemination of USA300 from the community into the hospital setting has blurred its distinction as a community-associated pathogen.

The authors used cross-sectional data (2001-2003) to consider the pathway through which past occupational lead exposure impacts cognitive function. They were motivated by studies linking cumulative lead dose with brain volumes, volumes with cognitive function, and lead dose with cognitive function. It was hypothesized that the brain regions associated with lead mediate a portion of the relation between lead dose and cognitive function. Data were derived from an ongoing US study of 513 former organolead manufacturing workers. Magnetic resonance imaging was used to perform a novel analysis to investigate mediation. Volumes associated with cognitive function and lead dose were derived by using registered images and were used in a subsequent mediation analysis. Cumulative lead dose was associated with adverse function in the visuo-construction, executive function, and eye-hand coordination domains. Regarding these domains, there was strong evidence of volumetric mediation of lead's effect on cognition in the visuo-construction domain and a moderate amount for executive function and eye-hand coordination. A second path-analysis-based approach was also used. To address the possibility that chance associations explained these findings, a permuted analysis was conducted, the results of which supported the mediation inferences. The approach to evaluating volumetric mediation may have general applicability in epidemiologic neuroimaging settings.

Homocysteine levels are associated with peripheral arterial disease (PAD) in observational studies. Lead and cadmium are risk factors for PAD that affect thiol metabolism, and they may partly explain the association of homocysteine with PAD. To evaluate the roles of lead and cadmium exposure in confounding the association between homocysteine and PAD, the authors performed a cross-sectional study among 4,447 persons aged > or = 40 years who participated in the 1999-2002 National Health and Nutrition Examination Survey (NHANES). PAD was defined as an ankle-brachial blood pressure index less than 0.90 in at least one leg. After adjustment for sociodemographic variables, the odds ratio for PAD in the highest quintile of homocysteine compared with the lowest was 1.92 (p(trend) = 0.004). Adjusting for blood lead and cadmium levels reduced this odds ratio to 1.37 (p(trend) = 0.13), and further adjusting for estimated glomerular filtration rate and smoking reduced it to 0.89 (p(trend) = 0.87). Adjustment for other risk factors did not affect this association. In the general population, the association of homocysteine level with PAD can be completely explained by confounding due to smoking, increased blood lead and cadmium levels, and impaired renal function. The association of lead and cadmium with PAD risk deserves further investigation.

Few studies have compared associations of blood lead and tibia lead with blood pressure and hypertension, and associations have differed in samples with occupational exposure compared with those with mainly environmental lead exposure. African Americans have been underrepresented in prior studies. The authors performed a cross-sectional analysis of 2001-2002 data from a community-based cohort in Baltimore, Maryland, of 964 men and women aged 50-70 years (40% African American, 55% White, 5% other race/ethnicity) to evaluate associations of blood lead and tibia lead with systolic and diastolic blood pressure and hypertension while adjusting for a large set of potential confounding variables. Blood lead was a strong and consistent predictor of both systolic and diastolic blood pressure in models adjusted and not adjusted for race/ethnicity and socioeconomic status. Tibia lead was associated with hypertension status before adjustment for race/ethnicity and socioeconomic status (p = 0.01); after such adjustment, the association was borderline significant (p = 0.09). Propensity score analysis suggested that standard regression analysis may have exaggerated the attenuation. These findings are discussed in the context of complex causal pathways. The data suggest that lead has an acute effect on blood pressure via recent dose and a chronic effect on hypertension risk via cumulative dose.

Arsenic exposure is a likely cause of blackfoot disease and a potential risk factor for atherosclerosis. The authors performed a systematic review of the epidemiologic evidence on the association between arsenic and cardiovascular outcomes. The search period was January 1966 through April 2005. Thirteen studies conducted in general populations (eight in high-arsenic areas in Taiwan, five in other countries) and 16 studies conducted in occupational populations were identified. Exposure was assessed ecologically in most studies. In Taiwan, relative risks comparing the highest arsenic exposure category with the lowest ranged from 1.59 to 4.90 for coronary disease, from 1.19 to 2.69 for stroke, and from 1.66 to 4.28 for peripheral arterial disease. In other general populations, relative risks ranged from 0.84 to 1.54 for coronary disease, from 0.69 to 1.53 for stroke, and from 0.61 to 1.58 for peripheral arterial disease. In occupational populations, relative risks ranged from 0.40 to 2.14 for coronary disease mortality and from 0.30 to 1.33 for stroke mortality. Methodologic limitations, however, limited interpretation of the moderate-to-strong associations between high arsenic exposure and cardiovascular outcomes in Taiwan. In other populations or in occupational settings, the evidence was inconclusive. Because of the high prevalence of arsenic exposure, carefully performed studies of arsenic and cardiovascular outcomes should be a research priority.

The authors attempted to determine whether a targeted educational intervention in an area with endemic Lyme disease could increase knowledge, positive attitudes, and reported behaviors related to tick bite prevention and consequently decrease tick bites, as measured by a biomarker of tick bites. Between April and September of 1999, 317 subjects in Baltimore County, Maryland, were randomized to receive either tick-related or general health-related educational materials bimonthly through the mail. At each of three clinic visits, participants completed a self-administered questionnaire and provided a serum sample. Anti-recombinant tick calreticulin antibody (ARTCA), measured in ng/ micro l, was used as a biomarker of tick bites. Linear and logistic regression analyses were used to determine 1) whether the educational intervention was associated with a change in knowledge, attitudes, and behaviors (KAB) and 2) whether change in KAB predicted change in ARTCA levels. Proportions of desired responses increased significantly among intervention subjects versus the comparison group on KAB measures related to examining the body for ticks and insect repellent use. Levels of ARTCA were low among all study subjects. Only six of 37 models exhibited a significant relation between change in a KAB variable and change in ARTCA levels over time. The behavioral intervention was associated with an increase in the KAB measures in the intervention group, but this change was not associated with change in ARTCA levels.

Lead can replace calcium in enzyme assays that measure protein kinase C activity and lead activates protein kinase C in human erythrocytes after exposure to lead in vitro. To examine the relevance of these observations to lead exposure in humans, we studied the associations of lead found in blood or tibia with activation of protein kinase C in erythrocytes isolated from workers in the lead industry. We examined erythrocytes among 212 lead workers, with a mean (+/-SD) age of 39.1 (10.0) years and exposure duration of 8.1 (6.5) years and measured protein kinase C activation by an in vitro back-phosphorylation assay. After adjustment for potential confounding factors (age and sex), tibia lead and exposure duration were significantly associated with erythrocyte protein kinase C activation (both p values < 0.05). No associations were observed between protein kinase C activation and blood-lead or zinc-protoporphyrin levels. These findings suggest that human exposure to lead results in activation of erythrocyte protein kinase C, which may be directly relevant to the neurotoxicity of lead.

Lead is associated with elevated blood pressure, although the mechanism of action is unknown. Genetic differences in sodium-potassium adenosine triphosphatase (Na(+)-K(+)ATPase) could explain some of the variation in the strength of the blood pressure-blood lead relation that has been observed in previous studies. In 1996-1997, the authors studied the association of blood pressure, hypertension prevalence, and polymorphisms in the gene for the alpha 2 subunit of Na(+)-K(+)ATPase (ATP1A2) among 220 former organolead manufacturing workers from New Jersey. Subjects were genotyped for a restriction fragment length polymorphism (RFLP) on the ATP1A2 gene. The association between blood lead and blood pressure was stronger among persons who were homozygous for the variant allele. Genotype was also associated with hypertension (adjusted odds ratio = 7.7; 95% confidence interval: 1.9, 31.4). Finally, the variant allele was 1.8 times more common among African Americans than among Caucasians. The RFLP may indicate susceptibility to the effect of lead on blood pressure. Moreover, the alpha 2 gene (or a closely linked gene) may contribute to the pathophysiology of hypertension. However, because the number of subjects (especially African Americans) with the susceptible genotype in this study was small, these observations should be considered preliminary.

The authors performed a cross-sectional study to evaluate associations between blood lead, tibia lead, and dimercaptosuccinic acid (DMSA)-chelatable lead and measures of neurobehavioral and peripheral nervous system function among 803 lead-exposed workers and 135 unexposed controls in South Korea. The workers and controls were enrolled in the study between October 1997 and August 1999. Central nervous system function was assessed with a modified version of the World Health Organization Neurobehavioral Core Test Battery. Peripheral nervous system function was assessed by measuring pinch and grip strength and peripheral vibration thresholds. After adjustment for covariates, the signs of the beta coefficients for blood lead were negative for 16 of the 19 tests and blood lead was a significant predictor of worse performance on eight tests. On average, for the eight tests that were significantly associated with blood lead levels, an increase in blood lead of 5 microg/dl was equivalent to an increase of 1.05 years in age. In contrast, after adjustment for covariates, tibia lead level was not associated with neurobehavioral test scores. Associations with DMSA-chelatable lead were similar to those for blood lead. In these currently exposed workers, blood lead was a better predictor of neurobehavioral performance than was tibia or DMSA-chelatable lead, mainly in the domains of executive abilities, manual dexterity, and peripheral motor strength.

The activity and sterility of reconstituted alteplase solution and the effectiveness of an alteplase dose-escalation protocol for the clearance of midline-catheter and central-venous-access device occlusions were studied. Reconstituted alteplase solution was stored at -70, -25, or 2 degrees C at concentrations of 0.5, 1, or 2 mg/mL. Durations of storage in the freezer were 0, 7, and 14 days, and durations of storage in the refrigerator were 0, 48, and 72 hours and 7 and 14 days. Samples were also assayed and cultured without prior freezing after refrigeration at 2 degrees C for 0, 48, and 72 hours and 7, 14, and 28 days. Fifty-eight pediatric and adult patients were enrolled in a separate study in which catheter clearance was initiated with alteplase 0.5 mg, and the dose was escalated to 1 and 2 mg sequentially until the catheter was cleared. The primary endpoint was restoration of catheter patency, and the secondary endpoint was the occurrence of bleeding episodes within 24 hours of alteplase administration. Catheter removal due to failure to restore patency was also documented. The activity and sterility of alteplase were maintained under all conditions studied. Fifty catheters (86.2%) were cleared with alteplase 0.5 mg, 5 (8.6%) after dose escalation to 1 mg, and 1 (1.7%) after escalation to 2 mg. The alteplase solution did not clear the occlusion in 2 catheters (3.4%): 1 had a mechanical obstruction and 1 cleared two hours after the 1-mg dose was deemed a failure. None of the six catheter removals was due to recalcitrant clots. Bleeding observed was not considered to be the result of alteplase administration. For use in clearing occlusions of venous-access devices, alteplase 0.5, 1, and 2 mg/mL retained sufficient fibrinolytic activity when stored for up to 14 days at 2 degrees C (28 days for the 0.5-mg/mL dilution) and when stored for 14 days at -70 or -25 degrees C followed by up to 14 days at 2 degrees C. The dose-escalation protocol was effective.

The antibody responses of subjects who presented with a definite Ixodes scapularis (Say) tick bite were measured to determine the utility of the antibody response against recombinant tick calreticulin (rTC) as a biologic marker of tick exposure. Subjects bitten by I. scapularis evidenced an increase in anti-rTC antibody levels between visit 1 and visit 2 from 24.3 to 27.1 ng/microl serum (n = 88, p = 0.003), and levels remained elevated at visit 3 (p = 0.005). These anti-rTC antibody levels during visits 2 and 3 were significantly higher than those in four non-exposed controls. Tick engorgement indices, measured on the biting ticks, were found to be correlated with anti-rTC antibody levels (e.g., for visit 3: Pearson's r = 0.357, p = 0.001). Tick engorgement index (TEI), ratio of body length to scutal width, was identified to be the only independent predictor of anti-rTC antibody levels in linear regression models. Logistic regression revealed that a bite from an I. scapularis tick that became engorged (TEI >3.4) was a risk factor for anti-rTC antibody seropositivity (adjusted odds ratio for age and bite location = 7.4 (95% confidence interval 2.1-26.4)). The anti-rTC antibody test had a sensitivity of 0.50 and a specificity of 0.86 for a bite from I. scapularis that became engorged. Immunoblotting revealed that subjects made a specific anti-rTC antibody response.

Understanding of the animal antibody response to tick salivary gland proteins is necessary to identify candidate antibodies that may have use as species- and feeding-duration-specific biomarkers of tick exposure in humans. The kinetics of the humoral immune response of rabbits to challenge feeding by 2 tick species [Amblyomma americanum (L.) and Dermacentor variabilis (Say)] was characterized by both enzyme-linked immunosorbent assay and immunoblot. Western blot analysis revealed that rabbits produced antibodies against both A. americanum and D. variabilis tick salivary gland antigens, with molecular weights ranging from 12.2 to 125 kDa; the antibody response against the saliva of both tick species possessed both unique and common aspects. The presence of antibody against low-molecular-mass (< 20 kDa) salivary gland antigens of A. americanum may be specific for A. americanum exposure. Antibodies directed against D. variabilis salivary gland antigens of 111, 86.3, and 85 kDa may be specific for D. variabilis exposure. The data suggest that host antibodies directed against specific tick salivary gland proteins might have use as species-specific biologic markers of tick exposure.

The goal of this study was to demonstrate that male lone star ticks, Amblyomma americanum (L.), actively feed on rabbits during attachment and that the host is capable of mounting an immune response against male salivary gland proteins. During attachment, it was shown that male ticks salivary glands hypertrophy. An enzyme-linked immunosorbent assay was used to detect rabbit serum proteins in the midgut of previously attached male ticks. SDS-polyacrylamide gel electrophoresis showed that the proteins expressed in the male tick salivary gland changed during feeding, with several new proteins in the 15- to 50-kDa range synthesized during attachment. Rabbits mounted a detectable antibody response against male tick salivary gland proteins after 2 sequential feedings of male ticks. The antibodies were directed against a spectrum of male salivary gland proteins ranging from 18 to 160 kDa. Several of these proteins were not recognized by antibodies directed against female tick saliva proteins, and thus may be specific male salivary gland components. This evidence indicates that male A. americanum ticks actively feed during attachment, that their salivary gland proteins change during feeding, and that male salivary gland proteins are immunogenic.

Previous studies have suggested that polymorphisms in delta-aminolevulinic acid dehydratase (ALAD), a heme synthetic enzyme, may be associated with differences in blood lead levels, perhaps due to differential binding of lead in erythrocytes. The authors examined associations of ALAD genotype with blood lead and zinc protoporphyrin (ZPP) levels, exposure duration, sex, and plant in 308 currently exposed lead workers in three lead storage battery manufacturing plants in the Republic of Korea in 1993. The overall prevalence of the variant allele, ALAD2, was 11%, but prevalence varied by plant (p = 0.02: 8.6% in plant A, 20% in plant B, and 22% in plant C). While ALAD2 was not associated with mean blood lead levels, the allele was associated with blood lead levels greater than or equal to 40 micrograms/dl (crude odds ratio (OR) = 2.6, 95% confidence interval (CI) 1.1-6.3; adjusted OR = 2.3, 95% CI 0.8-6.2, with adjustment for sex, plant, and exposure duration) and with exposure durations greater than 6 years (adjusted OR = 2.5, 95% CI 1.2-5.4, with adjustment for blood lead, sex, and plant). Among workers in plant C, the highest exposure plant, ALAD2 was associated with lower ZPP levels when controlling for blood lead levels. These data suggest that lead toxicokinetics may be modified by ALAD genotype and that ALAD2 may be protective for the health effects of lead. ALAD genotype also appears to have been a selection factor for current lead exposure status in the studied workers.

From 1988 to 1991, annual questionnaires and serosurveys were performed in a cohort of outdoor workers in New Jersey at high risk for Lyme disease to 1) evaluate temporal trends in seroprevalence and seroconversion of antibody to Borrelia burgdorferi; 2) identify risk factors for B. burgdorferi seroconversion during these years; and 3) examine associations between such seroconversion in 1989-1990 and anti-tick saliva antibody (ATSA, a biologic marker of tick exposure) seropositivity in 1990. A total of 1,519 workers participated in at least 1 year of the study. Lyme disease seroprevalence and seroconversion increased from 1988 to 1990 and then decreased in 1991. Years at residence, rural residence, and a history of medical problems were observed to be risk factors for seroconversion from 1988 to 1991. An interaction between pet ownership and rural residence was observed in that rural residents were only at an elevated risk if they owned pets. B. burgdorferi seroconversion from 1989 to 1990 was associated with ATSA seropositivity in 1990; in subjects reporting low tick exposure, the odds ratio was 8.2 (95% confidence interval 1.5-44.7). Associations between ATSA and B. burgdorferi serologic status suggested that educational programs may have contributed to the decline in Lyme seroprevalence and seroconversion in 1991.

In 1990, 222 current employees of a chemical facility in the eastern United States that manufactured tetraethyl lead were administered a neurobehavioral test battery, tests of olfactory function and peripheral vibration threshold, and questionnaires that assessed neuropsychiatric symptoms. A cumulative variable of exposure to inorganic and organic lead was derived from 12 years of personal industrial hygiene sampling data and an occupational history interview that assessed work in each of 29 exposure zones in the lead area. The range of assigned exposure intensities in these 29 zones was 4-119 micrograms/m3 for organic lead and 1-56 micrograms/m3 for inorganic lead. Cumulative lead exposure and exposure duration were defined as categorical variables (four groups) in multiple linear regression models. The adjusted mean differences in neurobehavioral test scores were estimated by comparing the average scores of the moderate, high, and highest exposure groups with the low exposure (reference) group. After adjustment for premorbid intellectual ability, age, race, and alcohol consumption, neurobehavioral test scores were poorer as measures of both cumulative lead exposure and exposure duration increased; many of the associations evidenced dose-response relations. Associations were observed in most cognitive and functional domains tested, but were most common in two domains: manual dexterity and verbal memory/learning. On the affected neuropsychologic measures, the groups with the highest exposure averaged scores 5-22% lower than those of the reference groups. Overall, the data revealed generally consistent and coherent associations between two measures of lead exposure and poorer neurobehavioral test performance.

Anti-tick saliva antibody (ATSA) has potential as a biologic marker of exposure to tick bites. In 1989, we conducted a cross-sectional study of 304 outdoor workers in Monmouth County, New Jersey, to evaluate associations between self-reported tick exposure, ATSA status, and Lyme disease antibody status. ATSA levels 1) were correlated with an index of tick exposure on the basis of three self-reported measures of tick exposure and outdoor hours worked per week (p = 0.01); 2) were consistently higher in pet owners compared with persons without pets (p = 0.03); and 3) when examined by duration since last tick bite, peaked at 3-5 weeks after tick bite and then declined (p = 0.06). ATSA levels dichotomized at the 75th percentile (approximately two standard deviations above the mean ATSA optical density of 25 subjects who denied recent tick exposure) were associated with self-reported tick exposure: adjusted odds ratios for high ATSA levels were 4.2 (95% confidence interval (CI) 0.9-18.9) for moderate (versus none) tick exposure and 5.8 (95% CI 1.2-27.2) for high (versus none) tick exposure. Finally, high ATSA levels were associated with Lyme disease seropositivity, with an adjusted odds ratio of 3.2 (95% CI 1.3-7.6). The data suggest that ATSA is a biologic marker of tick exposure that is a risk factor for Lyme disease seropositivity.

In 1988, antibodies to arthropod (Ixodes dammini, Dermacentor variabilis, and Aedes aegypti) salivary gland proteins and to Borrelia burgdorferi were measured by enzyme-linked immunosorbent assay in 53 high-risk outdoor workers from the New Jersey Department of Environmental Protection. Lyme disease seropositives had significantly higher anti-I. dammini antibody levels than seronegative controls (p = 0.006). Anti-B. burgdorferi antibody (enzyme-linked immunosorbent assay) and anti-I. dammini antibody titers were highly correlated in these workers (r = 0.49, p = 0.0002). Quantitative self-reported tick exposure (tick bites in the past year) and anti-I. dammini antibody titers were significantly correlated (r = 0.27, p = 0.05), and persons without tick exposure had lower anti-I. dammini antibody levels (p = 0.009) than persons with known exposure. A second serum sample obtained 3 months after the first after a period of decreased tick exposure (the winter) revealed that the anti-I. dammini antibody levels had significantly declined (p = 0.0004). Additional experiments revealed that the antibody was not completely specific for I. dammini but was relatively specific for the two tick species examined compared with A. aegypti. The data hold promise that this antibody may be a useful tool in Lyme disease research as a biologic marker of tick exposure.

A statewide cross-sectional study of risk factors for seropositivity for antibody to Borrelia burgdorferi in outdoor workers in New Jersey was performed in September and October 1988. The crude odds ratio associated with exposure to ticks on the primary state job was 2.2 (95% confidence interval (CI) 0.7-9.0). After adjustment for multiple confounding variables with logistic regression, the adjusted occupational tick exposure odds ratio was 5.1 (95% CI 1.1-23.6). Additional analyses revealed that any use of insect repellent or antibiotics may have decreased the risk of Lyme disease in these workers (adjusted odds ratios for not using insect repellent or antibiotics were 2.0 (95% CI 1.0-4.0) and 2.3 (95% CI 0.8-6.7), respectively). These data suggest that Lyme disease is a hazard of outdoor work and that increased recognition of this fact will be necessary to prevent Lyme disease in these workers.