Multidrug-resistant (MDR) Shigella infections have been identified globally among men who have sex with men (MSM). The highly drug-resistant phenotype often confounds initial antimicrobial therapy, placing patients at risk for adverse outcomes, the development of more drug-resistant strains, and additional treatment failures. New macrolide-resistant Shigella strains complicate treatment further as azithromycin is a next-in-line antibiotic for MDR strains, and an antibiotic-strain combination confounded by gaps in validated clinical breakpoints for clinical laboratories to interpret macrolide resistance in Shigella We present the first high-resolution genomic analyses of 2,097 U.S. Shigella isolates, including those from MDR outbreaks. A sentinel shigellosis case in an MSM patient revealed a strain carrying 12 plasmids, of which two carried known resistance genes, the pKSR100-related plasmid pMHMC-004 and spA-related plasmid pMHMC-012. Genomic-epidemiologic analyses of isolates revealed high carriage rates of pMHMC-004 predominantly in U.S. isolates from men and not in other demographic groups. Isolates genetically related to the sentinel case further harbored elevated numbers of unique replicons, showing the receptivity of this Shigella lineage to plasmid acquisition. Findings from integrated genomic-epidemiologic analyses were leveraged to direct targeted clinical actions to improve rapid diagnosis and patient care and for public health efforts to further reduce spread.IMPORTANCE Multidrug-resistant Shigella isolates with resistance to macrolides are an emerging public health threat. We define a plasmid/pathogen complex behind infections seen in the United States and globally in vulnerable patient populations and identify multiple outbreaks in the United States and evidence of intercontinental transmission. Using new tools and sequence information, we experimentally identify the drivers of antibiotic resistance that complicate patient treatment to facilitate improvements to clinical microbiologic testing for their detection. We illustrate the use of these methods to support multiagency efforts to combat multidrug-resistant Shigella using publicly available tools, existing genomic data, and resources in clinical microbiology and public health laboratories to inform credible actions to reduce spread.

AIM: To compare the frequencies of neurosurgical procedures to treat comorbid conditions of myelomeningocele in patients who underwent fetal surgery versus postnatal surgery for closure of the placode. METHOD: By utilizing the National Spina Bifida Patient Registry in a comparative effectiveness study, 298 fetal surgery patients were matched by birthdate (±3mo) and spina bifida clinic site with one to three postnatal surgery patients (n=648). Histories were obtained by record review on enrollment and yearly subsequently. Multivariable Poisson regression was used to compare frequencies of procedures between cohorts, with adjustments for sex, ethnicity, insurance status, spinal segmental level of motor function, age at last visit recorded in the Registry, and, for shunt revision in shunted patients, age at cerebrospinal fluid (CSF) diversion. RESULTS: The median age at last visit was 4 years. In fully adjusted analyses in patients aged at least 12 months old, fetal surgery was associated with decreased frequency of CSF diversion for hydrocephalus by ventriculoperitoneal shunt insertion or endoscopic third ventriculostomy compared with postnatal surgery (46% vs 79%; incidence rate ratio=0.61; 95% confidence interval [CI] 0.53-0.71; p<0.01). Over all ages, fetal surgery was associated with decreased frequency of Chiari decompression for brainstem dysfunction (3% vs 7%; incidence rate ratio=0.41; 95% CI 0.19-0.88; p=0.02). Also over all ages, differences were not significant in frequencies of shunt revision in shunted patients (53% vs 55%; incidence rate ratio=0.87; 95% CI 0.69-1.11; p=0.27), nor tethered cord release for acquired spinal cord dysfunction (18% vs 16%; incidence rate ratio=1.11; 95% CI 0.84-1.47; p=0.46). INTERPRETATION: Even with the variations inherent in clinical practice, fetal surgery was associated with lower frequencies of CSF diversion and of Chiari decompression, independent of covariates.

PURPOSE: Neurogenic bowel dysfunction (NBD) is a common comorbidity of myelomeningocele (MMC), the most common and severe form of spina bifida. The National Spina Bifida Patient Registry (NSBPR) is a research collaboration between the CDC and Spina Bifida Clinics. Fecal continence (continence) outcomes for common treatment modalities for NBD have not been described in a large sample of individuals with MMC. NSBPR patients with MMC and NBD were studied to determine variation in continence status and their ability to perform their treatment independently according to treatment modality and individual characteristics. METHODS: Continence was defined as < 1 episode of incontinence per month. Eleven common treatments were evaluated. Inclusion criteria were established diagnoses of both MMC and NBD, as well as age ⩾ 5 years (n= 3670). Chi-square or exact statistical tests were used for bivariate analyses. Logistic regression models were used to estimate the odds of continence outcomes by age, sex, race/ethnicity, level of motor function, and insurance status. RESULTS: At total of 3670 members of the NSBPR met inclusion criteria between November 2013 and December 2017. Overall prevalence of continence was 45%. Prevalence ranged from 40-69% across different treatments. Among continent individuals, 60% achieved continence without surgery. Antegrade enemas were the most commonly used treatment and had the highest associated continence rate. Ability to carry out a treatment independently increased with age. Multivariable logistic regression showed significantly higher odds of continence among individuals aged ⩾ 12 years, female, non-Hispanic white, and with private insurance.

The development and application of physiologically based pharmacokinetic (PBPK) models in chemical toxicology have grown steadily since their emergence in the 1980s. However, critical evaluation of PBPK models to support public health decision-making across federal agencies has thus far occurred for only a few environmental chemicals. In order to encourage decision-makers to embrace the critical role of PBPK modeling in risk assessment, several important challenges require immediate attention from the modeling community. The objective of this contemporary review is to highlight 3 of these challenges, including: (1) difficulties in recruiting peer reviewers with appropriate modeling expertise and experience; (2) lack of confidence in PBPK models for which no tissue/plasma concentration data exist for model evaluation; and (3) lack of transferability across modeling platforms. Several recommendations for addressing these 3 issues are provided to initiate dialog among members of the PBPK modeling community, as these issues must be overcome for the field of PBPK modeling to advance and for PBPK models to be more routinely applied in support of public health decision-making.

BACKGROUND: Multiple agencies have developed health-based toxicity values for exposure to perfluorooctanoic acid (PFOA). Although PFOA exposure occurs in utero and through breastfeeding, current health-based toxicity values have not been derived using fetal or child dosimetry. Therefore, current values may underestimate the potential risks to fetuses and nursing infants. OBJECTIVE: Using fetal and child dosimetry, we aimed to calculate PFOA maternal human equivalent doses (HEDs), corresponding to a developmental mouse study lowest observed adverse effect level (LOAEL, 1mg/kg/day). Further, we investigated the impact of breastfeeding duration and PFOA half-life on the estimated HEDs. METHODS: First, a pharmacokinetic model of pregnancy and lactation in mice was used to estimate plasma PFOA levels in pups following a maternal exposure to 1mg PFOA/kg/day for gestational days 1-17. Four plasma PFOA concentration metrics were estimated in pups: i) average prenatal; ii) average postnatal; iii) average overall (prenatal and postnatal); and iv) maximum. Then, Monte Carlo simulations were performed using a pharmacokinetic model of pregnancy and lactation in humans to generate distributions of maternal HEDs that would result in fetal/child plasma levels equivalent to those estimated in pups using the mouse model. Median (HED50) and 1st percentile (HED01) of calculated HEDs were calculated. RESULTS: Estimated PFOA maternal HED50s ranged from 3.0x10(-4) to 1.1x10(-3)mg/kg/day and HED01s ranged from 4.7x10(-5) to 2.1x10(-4)mg/kg/day. All calculated HEDs were lower than the HED based on adult dosimetry derived by the Environmental Protection Agency (EPA) (5.3x10(-3)mg/kg/day). CONCLUSION: Our results suggest that fetal/child dosimetry should be considered when deriving health-based toxicity values for potential developmental toxicants.

On April 3, 2017, two Florida residents consumed part of the same prepackaged salad before reportedly discovering the partial remains of a bat carcass in the salad. Bats are known reservoirs for rabies virus, which causes rabies disease in both animals and humans (1). The persons who ate the salad contacted the Florida Department of Health (FLDOH), which notified CDC’s Poxvirus and Rabies Branch. CDC and FLDOH determined that the immediate concern was for potential rabies virus exposure, because approximately 6% of bats submitted to U.S. public health departments annually test positive for rabies virus (2,3). | Although percutaneous exposures are more likely to result in successful transmission of rabies virus to humans (1), transmission can occur when infectious material, such as saliva or nervous tissue from an infected animal, comes into direct contact with human mucosa (2). Infection with rabies virus causes an acute, progressive encephalitis that is nearly always fatal once clinical signs have begun. The disease is preventable if exposed persons receive timely postexposure prophylaxis (PEP), which includes human rabies immunoglobulin and 4 doses of inactivated rabies vaccine administered over 14 days (4).

Manufacturing of perfluorooctanoic acid (PFOA), a synthetic chemical with a long half-life in humans, peaked between 1970 and 2002, and has since diminished. In the United States, PFOA is detected in the blood of >99% of people tested, but serum concentrations have decreased since 1999. Much is known about exposure to PFOA in drinking water; however, the impact of non-drinking water PFOA exposure on serum PFOA concentrations is not well characterized. The objective of this research is to apply physiologically based pharmacokinetic (PBPK) modeling and Monte Carlo analysis to evaluate the impact of historic non-drinking water PFOA exposure on serum PFOA concentrations. In vitro to in vivo extrapolation was utilized to inform descriptions of PFOA transport in the kidney. Monte Carlo simulations were incorporated to evaluate factors that account for the large inter-individual variability of serum PFOA concentrations measured in individuals from North Alabama in 2010 and 2016, and the Mid-Ohio River Valley between 2005 and 2008. Predicted serum PFOA concentrations were within two-fold of experimental data. With incorporation of Monte Carlo simulations, the model successfully tracked the large variability of serum PFOA concentrations measured in populations from the Mid-Ohio River Valley. Simulation of exposure in a population of 45 adults from North Alabama successfully predicted 98% of individual serum PFOA concentrations measured in 2010 and 2016, respectively, when non-drinking water ingestion of PFOA exposure was included. Variation in serum PFOA concentrations may be due to inter-individual variability in the disposition of PFOA and potentially elevated historical non-drinking water exposures.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are considered chemicals of emerging concern, in part due to their environmental and biological persistence and the potential for widespread human exposure. In 2007, a PFAS manufacturer near Decatur, Alabama notified the United States Environmental Protection Agency (EPA) it had discharged PFAS into a wastewater treatment plant, resulting in environmental contamination and potential exposures to the local community. OBJECTIVES: To characterize PFAS exposure over time, the Agency for Toxic Substances and Disease Registry (ATSDR) collected blood and urine samples from local residents. METHODS: Eight PFAS were measured in serum in 2010 (n=153). Eleven PFAS were measured in serum, and five PFAS were measured in urine (n=45) from some of the same residents in 2016. Serum concentrations were compared to nationally representative data and change in serum concentration over time was evaluated. Biological half-lives were estimated for perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and perfluorohexane sulfonic acid (PFHxS) using a one-compartment pharmacokinetic model. RESULTS: In 2010 and 2016, geometric mean PFOA and PFOS serum concentrations were elevated in participants compared to the general U.S. POPULATION: In 2016, the geometric mean PFHxS serum concentration was elevated compared to the general U.S. POPULATION: Geometric mean serum concentrations of PFOA, PFOS, and perfluorononanoic acid (PFNA) were significantly (p≤0.0001) lower (49%, 53%, and 58%, respectively) in 2016 compared to 2010. Half-lives for PFOA, PFOS, and PFHxS were estimated to be 3.9, 3.3, and 15.5years, respectively. Concentrations of PFOA in serum and urine were highly correlated (r=0.75) in males. CONCLUSIONS: Serum concentrations of some PFAS are decreasing in this residentially exposed community, but remain elevated compared to the U.S. general population.

Sexual risk reduction interventions are often ineffective for women who drink alcohol. The present study examines whether an alcohol-related sexual risk reduction intervention successfully trains women to increase assertive communication behaviors and decrease aggressive communication behaviors. Women demonstrated their communication skills during interactive role-plays with male role-play partners. Young, unmarried, and nonpregnant African American women (N = 228, ages 18-24) reporting unprotected vaginal or anal sex and greater than three alcoholic drinks in the past 90 days were randomly assigned to a control, a sexual risk reduction, or a sexual and alcohol risk reduction (NLITEN) condition. Women in the NLITEN condition significantly increased assertive communication behavior compared to women in the control condition, yet use of aggressive communicative behaviors was unchanged. These data suggest assertive communication training is an efficacious component of a sexual and alcohol risk reduction intervention. Public health practitioners and health educators may benefit from group motivational enhancement therapy (GMET) training and adding a GMET module to existing sexual health risk reduction interventions. Future research should examine GMET's efficacy in combination with other evidence-based interventions within other populations and examine talking over and interrupting one's sexual partner as an assertive communication behavior within sexual health contexts.

Renal elimination and the resulting clearance of perfluorooctanoic acid (PFOA) from the serum exhibit pronounced sex differences in the adult rat. The literature suggests that this is largely due to hormonally regulated expression of organic anion transporters (OATs) on the apical and basolateral membranes of the proximal tubule cells that facilitate excretion and reabsorption of PFOA from the filtrate into the blood. Previously developed PBPK models of PFOA exposure in the rat have not been parameterized to specifically account for transporter-mediated renal elimination. We developed a PBPK model for PFOA in the male and female rats to explore the role of Oat1, Oat3, and Oatp1a1 in sex-specific renal reabsorption and excretion of PFOA. Descriptions of the kinetic behavior of these transporters were extrapolated from in vitro studies and the model was used to simulate time-course serum, liver, and urine data for intravenous (IV) and oral exposures in both sexes. Model predicted concentrations of PFOA in the liver, serum, and urine showed good agreement with experimental data for both the male and female rats indicating that in vitro derived physiological descriptions of transporter-mediated renal reabsorption can successfully predict sex-dependent excretion of PFOA in the rat. This study supports the hypothesis that sex-specific serum half-lives for PFOA are largely driven by expression of transporters in the kidney and contribute to the development of PBPK modeling as a tool for evaluating the role of transporters in renal clearance.

PURPOSE: Evaluating genetic susceptibility may clarify effects of known environmental factors and also identify individuals at high risk. We evaluated the association of four insulin-related pathway gene polymorphisms in insulin-like growth factor-1 (IGF-I) (CA)(n) repeat, insulin-like growth factor-2 (IGF-II) (rs680), insulin-like growth factor-binding protein-3 (IGFBP-3) (rs2854744), and adiponectin (APM1 rs1501299) with colon cancer risk, as well as relationships with circulating IGF-I, IGF-II, IGFBP-3, and C-peptide in a population-based study. METHODS: Participants were African Americans (231 cases and 306 controls) and Whites (297 cases, 530 controls). Consenting subjects provided blood specimens and lifestyle/diet information. Genotyping for all genes except IGF-I was performed by the 5'-exonuclease (Taqman) assay. The IGF-I (CA)(n) repeat was assayed by PCR and fragment analysis. Circulating proteins were measured by enzyme immunoassays. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated by logistic regression. RESULTS: The IGF-I (CA)(19) repeat was higher in White controls (50 %) than African American controls (31 %). Whites homozygous for the IGF-I (CA)(19) repeat had a nearly twofold increase in risk of colon cancer (OR = 1.77; 95 % CI = 1.15-2.73), but not African Americans (OR = 0.73, 95 % CI 0.50-1.51). We observed an inverse association between the IGF-II Apa1 A-variant and colon cancer risk (OR = 0.49, 95 % CI 0.28-0.88) in Whites only. Carrying the IGFBP-3 variant alleles was associated with lower IGFBP-3 protein levels, a difference most pronounced in Whites (p-trend <0.05). CONCLUSIONS: These results support an association between insulin pathway-related genes and elevated colon cancer risk in Whites but not in African Americans.