Achromobacter cluster related to COVID-19 supply chain issues.

Isolation of an unusual organism, Achromobacter xylosoxidans, from 2 cardiac surgical patients on the same day prompted an investigation to search for cases and cause. An extensive review demonstrated a pseudo-outbreak related to practices to conserve laboratory saline due to short supply resulting from supply chain shortage from the coronavirus disease 2019 pandemic.

Suicide risk communication and intervention preferences for veterans and service members.

Despite the investment of public resources to fight staggering suicide rates among veterans, we know little about how veterans and service members in crisis communicate suicidal ideations, and what interventions they are willing to receive. We aim to identify communication and suicide intervention preferences of veterans and service members in times of crisis. Descriptive statistics were used to explore veterans communication of suicidal ideations. While 89.9% of participants indicated they were willing to speak to someone when having thoughts of suicide, less than 26% of participants indicated they were willing to bring up their thoughts with a crisis line or veterans organization. Rather, they indicate that family members (62.2%) and military friends (51.1%) would be their primary outreach. Logistic regression was used to determine whether or not preferred interventions varied by participant demographic characteristics. While the majority of participants indicated they were willing to allow intervention (88.6%), no one method was accepted by the majority of the population. The most accepted means of communication was to proactively contact a friend or family member about general life struggles (32.6%) or suicide-specific concerns (27.5%). Many participants were open to receiving resources (42.0%), suicide-specific mental health treatment (36.3%), and some sort of lethal means safety intervention (19.1%-26.4%). The age, marital status, and veterans status of participants significantly impacted what interventions they were willing to allow. We discuss the implications of these findings and the need for evidence-based, multimodal interventions in order to assist veterans in need.

Aortic valve infective endocarditis due to Streptococcus pyogenes : A case report.

Group A Streptococcus is a common cause of pharyngitis, scarlet fever, glomerulonephritis, and various skin infections. However, there have only been a few reports of Group A Streptococcus (GAS) associated with infective endocarditis. We present a case of a 31-year-old male who presented to the hospital with a few days of weakness and myalgias after recently receiving treatment with azithromycin for GAS pharyngitis as an outpatient. The patient was admitted to the intensive care unit in septic shock from Group A beta-hemolytic Streptococcus bacteremia and acute hypoxic respiratory failure. He was found to have new severe aortic insufficiency from infective endocarditis. He underwent urgent partial aortic valve annuloplasty reconstruction and incision and drainage of root abscess with intraoperative cultures growing gram positive cocci consistent with GAS. The majority of cases of infective endocarditis are caused by Staphylococcus aureus, virdians group Streptococci and Streptococcus gallolyticus, while Streptococcus pneumoniae and Streptococcus pyogenes have the lowest prevalence of infective endocarditis. Penicillin remains the first line treatment for GAS pharyngitis. However, in cases of severe penicillin allergy, macrolides should be avoided given the increasing rate of macrolide resistance GAS strains. This case emphasizes the importance of using beta-lactams as first line therapy for GAS pharyngitis to avoid harmful complications and infection recurrence.

The Best of Both Worlds: Discovery-Driven Learning through a Lab-Seminar Approach.

Microbiology courses are often designed as either a lecture class with a laboratory component or a seminar-style class. Each type of course provides students with unique learning opportunities. Lab courses allow students to perform simple experiments that relate to fundamental concepts taught in the corresponding lectures, while seminar courses challenge students to read and discuss primary literature. Microbiology courses offering a combination of seminar-style discussions and laboratory procedures are rare. Our goal in the "Microbial Diversity and Pathogenesis" undergraduate course is to integrate experiences of a seminar class with those of a discovery-driven lab course, thereby strengthening students' learning experiences through diversified didactic approaches. In the first half of the course, students read and discuss published peer-reviewed articles that cover major topics in both basic and applied microbiology, including antibiotic resistance, pathogenesis, and biotechnology applications. Complementing this primary literature, students perform microbiology experiments related to the topics covered in the readings. The assigned readings, discussions, and experiments provide a foundation in the second half of the course for inquiry-based exploratory research using student-designed transposon screens and selections. The course culminates in each student drafting a hypothesis-driven research proposal based on their literature review, their learned experimental techniques, and the preliminary data generated as a class. Through such first-hand experimental experience, students gain fundamental lab skills that are applicable beyond the realm of microbiology, such as sterile technique and learning how to support conclusions with scientific evidence. We observed a tremendous synergy between the seminar and lab aspects of our course. This unique didactic experience allows students to understand and connect primary literature to their experiments, while the discovery-driven aspect of this approach fosters active engagement of students with scientific research.

Aspergillus fumigatus endocarditis in a splenectomized patient with no risk factors.

Aspergillus endocarditis is a rare cause of culture-negative fungal endocarditis, after Candida endocarditis. Typical risk factors include intravenous drug use, immunosuppression, prior cardiac surgery or presence of prosthetic heart valves, hematopoietic stem cell or solid organ transplantation. Common presentations include signs and symptoms consistent with endocarditis but with negative bacterial blood cultures. Here, we present a case report of a 49-year-old male without known risk factors for fungal endocarditis who presented with a stroke and found to have Aspergillus endocarditis. Despite surgical intervention and antifungal treatment, the outcome was fatal. This underscores the difficulty in diagnosing Aspergillus endocarditis and its poor prognosis, necessitating the need for early diagnosis and intervention.

Ordinal dose-response modeling approach for the phthalate syndrome.

BACKGROUND: The phthalate syndrome (PS) is a collection of related male reproductive developmental effects, ranging in severity, that have been observed in rats after gestational exposure to developmentally-toxic phthalates. For statistical purposes, the PS is defined as a single endpoint and one dose-response analysis is conducted, rather than conducting multiple analyses on each individual endpoint. OBJECTIVE: To improve dose-response modeling approaches for the PS and other syndromes of effects by accounting for differing severity levels among the endpoints. METHODS: Ordinal dose-response modeling was performed on PS data from a published study of diisobutyl phthalate (DIBP) gestational exposure to male Sprague-Dawley rats. To incorporate PS endpoint severity, the endpoints were categorized into ordinal levels based on the expected impact of male developmental endpoint's on fertility. Then, a benchmark dose was estimated for each ordinal level. A bootstrap procedure was used to account for the nested nature of the data, and a sensitivity analysis was performed to assess the bootstrap results. A comparison of the estimates between the ordinal and the dichotomous model was performed. RESULTS: The ordinal version of the log-logistic model applied to the data categorized by PS endpoint severity level provided benchmark dose estimates that were closer to each other in value and had lower variability than the traditional dichotomous application. The sensitivity analysis confirmed the validity of the bootstrap results. CONCLUSION: The ordinal dose-response modeling method accounts for severity differences among dichotomous PS endpoints, can be expanded in the future to include more severity levels, and can be used in both single and cumulative phthalate risk assessments.

Methods for evaluating variability in human health dose-response characterization.

The Reference Dose (RfD) and Reference Concentration (RfC) are human health reference values (RfVs) representing exposure concentrations at or below which there is presumed to be little risk of adverse effects in the general human population. The 2009 National Research Council report Science and Decisions recommended redefining RfVs as "a risk-specific dose (for example, the dose associated with a 1 in 100,000 risk of a particular end point)." Distributions representing variability in human response to environmental contaminant exposures are critical for deriving risk-specific doses. Existing distributions estimating the extent of human toxicokinetic and toxicodynamic variability are based largely on controlled human exposure studies of pharmaceuticals. New data and methods have been developed that are designed to improve estimation of the quantitative variability in human response to environmental chemical exposures. Categories of research with potential to provide new database useful for developing updated human variability distributions include controlled human experiments, human epidemiology, animal models of genetic variability, in vitro estimates of toxicodynamic variability, and in vitro-based models of toxicokinetic variability. In vitro approaches, with further development including studies of different cell types and endpoints, and approaches to incorporate non-genetic sources of variability, appear to provide the greatest opportunity for substantial near-term advances.

Dose-Response Modeling with Summary Data from Developmental Toxicity Studies.

Dose-response analysis of binary developmental data (e.g., implant loss, fetal abnormalities) is best done using individual fetus data (identified to litter) or litter-specific statistics such as number of offspring per litter and proportion abnormal. However, such data are not often available to risk assessors. Scientific articles usually present only dose-group summaries for the number or average proportion abnormal and the total number of fetuses. Without litter-specific data, it is not possible to estimate variances correctly (often characterized as a problem of overdispersion, intralitter correlation, or "litter effect"). However, it is possible to use group summary data when the design effect has been estimated for each dose group. Previous studies have demonstrated useful dose-response and trend test analyses based on design effect estimates using litter-specific data from the same study. This simplifies the analysis but does not help when litter-specific data are unavailable. In the present study, we show that summary data on fetal malformations can be adjusted satisfactorily using estimates of the design effect based on historical data. When adjusted data are then analyzed with models designed for binomial responses, the resulting benchmark doses are similar to those obtained from analyzing litter-level data with nested dichotomous models.

A systematic evaluation of the potential effects of trichloroethylene exposure on cardiac development.

The 2011 EPA trichloroethylene (TCE) IRIS assessment, used developmental cardiac defects from a controversial drinking water study in rats (Johnson et al. [51]), along with several other studies/endpoints to derive reference values. An updated literature search of TCE-related developmental cardiac defects was conducted. Study quality, strengths, and limitations were assessed. A putative adverse outcome pathway (AOP) construct was developed to explore key events for the most commonly observed cardiac dysmorphologies, particularly those involved with epithelial-mesenchymal transition (EMT) of endothelial origin (EndMT); several candidate pathways were identified. A hypothesis-driven weight-of-evidence analysis of epidemiological, toxicological, in vitro, in ovo, and mechanistic/AOP data concluded that TCE has the potential to cause cardiac defects in humans when exposure occurs at sufficient doses during a sensitive window of fetal development. The study by Johnson et al. [51] was reaffirmed as suitable for hazard characterization and reference value derivation, though acknowledging study limitations and uncertainties.

Human Health Effects of Biphenyl: Key Findings and Scientific Issues.

BACKGROUND: In support of the Integrated Risk Information System (IRIS), the U.S. Environmental Protection Agency (EPA) has evaluated the human health hazards of biphenyl exposure. OBJECTIVES: We review key findings and scientific issues regarding expected human health effects of biphenyl. METHODS: Scientific literature from 1926 through September 2012 was critically evaluated to identify potential human health hazards associated with biphenyl exposure. Key issues related to the carcinogenicity and noncancer health hazards of biphenyl were examined based on evidence from experimental animal bioassays and mechanistic studies. DISCUSSION: Systematic consideration of experimental animal studies of oral biphenyl exposure took into account the variety of study designs (e.g., study sizes, exposure levels, and exposure durations) to reconcile differing reported results. The available mechanistic and toxicokinetic evidence supports the hypothesis that male rat urinary bladder tumors arise through urinary bladder calculi formation but is insufficient to hypothesize a mode of action for liver tumors in female mice. Biphenyl and its metabolites may induce genetic damage, but a role for genotoxicity in biphenyl-induced carcinogenicity has not been established. CONCLUSIONS: The available health effects data for biphenyl provides suggestive evidence for carcinogenicity in humans, based on increased incidences of male rat urinary bladder tumors at high exposure levels and on female mouse liver tumors. Kidney toxicity is also a potential human health hazard of biphenyl exposure. CITATION: Li Z, Hogan KA, Cai C, Rieth S. 2016. Human health effects of biphenyl: key findings and scientific issues. Environ Health Perspect 124:703-712; http://dx.doi.org/10.1289/ehp.1509730.

Human health effects of tetrachloroethylene: key findings and scientific issues.

BACKGROUND: The U.S. Environmental Protection Agency (EPA) completed a toxicological review of tetrachloroethylene (perchloroethylene, PCE) in February 2012 in support of the Integrated Risk Information System (IRIS). OBJECTIVES: We reviewed key findings and scientific issues regarding the human health effects of PCE described in the U.S. EPA's Toxicological Review of Tetrachloroethylene (Perchloroethylene). METHODS: The updated assessment of PCE synthesized and characterized a substantial database of epidemiological, experimental animal, and mechanistic studies. Key scientific issues were addressed through modeling of PCE toxicokinetics, synthesis of evidence from neurological studies, and analyses of toxicokinetic, mechanistic, and other factors (tumor latency, severity, and background rate) in interpreting experimental animal cancer findings. Considerations in evaluating epidemiological studies included the quality (e.g., specificity) of the exposure assessment methods and other essential design features, and the potential for alternative explanations for observed associations (e.g., bias or confounding). DISCUSSION: Toxicokinetic modeling aided in characterizing the complex metabolism and multiple metabolites that contribute to PCE toxicity. The exposure assessment approach-a key evaluation factor for epidemiological studies of bladder cancer, non-Hodgkin lymphoma, and multiple myeloma-provided suggestive evidence of carcinogenicity. Bioassay data provided conclusive evidence of carcinogenicity in experimental animals. Neurotoxicity was identified as a sensitive noncancer health effect, occurring at low exposures: a conclusion supported by multiple studies. Evidence was integrated from human, experimental animal, and mechanistic data sets in assessing adverse health effects of PCE. CONCLUSIONS: PCE is likely to be carcinogenic to humans. Neurotoxicity is a sensitive adverse health effect of PCE.

A "needling" problem: shoulder injury related to vaccine administration.

A 22-year-old woman with no significant medical history developed acute left shoulder pain and severe restrictions in range of motion after a seasonal influenza vaccine injection. Imaging by MRI, approximately 8 weeks after the injection, and by ultrasound, approximately 9.5 weeks after the injection demonstrated contusions on the humerus, injury of the supraspinatus, and effusion in the subacromial bursa. Her reaction was reported to the Vaccine Adverse Event Reporting System as a case of shoulder injury related to vaccine administration, likely due to injection of the influenza vaccine into the subacromial bursa. This case serves as a catalyst for discussion regarding vaccination technique and the potential to prevent complications arising from vaccine overpenetration.

Approaches to cancer assessment in EPA's Integrated Risk Information System.

The U.S. Environmental Protection Agency's (EPA) Integrated Risk Information System (IRIS) Program develops assessments of health effects that may result from chronic exposure to chemicals in the environment. The IRIS database contains more than 540 assessments. When supported by available data, IRIS assessments provide quantitative analyses of carcinogenic effects. Since publication of EPA's 2005 Guidelines for Carcinogen Risk Assessment, IRIS cancer assessments have implemented new approaches recommended in these guidelines and expanded the use of complex scientific methods to perform quantitative dose-response assessments. Two case studies of the application of the mode of action framework from the 2005 Cancer Guidelines are presented in this paper. The first is a case study of 1,2,3-trichloropropane, as an example of a chemical with a mutagenic mode of carcinogenic action thus warranting the application of age-dependent adjustment factors for early-life exposure; the second is a case study of ethylene glycol monobutyl ether, as an example of a chemical with a carcinogenic action consistent with a nonlinear extrapolation approach. The use of physiologically based pharmacokinetic (PBPK) modeling to quantify interindividual variability and account for human parameter uncertainty as part of a quantitative cancer assessment is illustrated using a case study involving probabilistic PBPK modeling for dichloromethane. We also discuss statistical issues in assessing trends and model fit for tumor dose-response data, analysis of the combined risk from multiple types of tumors, and application of life-table methods for using human data to derive cancer risk estimates. These issues reflect the complexity and challenges faced in assessing the carcinogenic risks from exposure to environmental chemicals, and provide a view of the current trends in IRIS carcinogenicity risk assessment.

Effect of lysophosphatidic acid acyltransferase-beta inhibition in acute leukemia.

Phosphatidic acid (PA) is an important component of mammalian target of rapamycin (mTOR) signaling and in the recruitment of Raf to the cell membrane. PA can be produced by several mechanisms, including by a series of lysophosphatidic acid acyl transferases (LPAATs). LPAAT-beta is an isoform that is overexpressed in some human cancers and its inhibition has been investigated as a potential targeted cancer therapy. We report that LPAAT-protein and enzyme activity in acute leukemia cell lines and blasts from patient samples are equivalent to levels in normal mononuclear cells. Treatment with the LPAAT-beta inhibitor CT-32228 (Cell Therapeutics, Seattle, WA) uniformly induces apoptosis in multiple leukemia cell lines. In patient samples, however, apoptosis was variably induced by CT-32228 and appeared to be related to the degree of cellular proliferation. The growth inhibitory effect of CT-32228 on normal hematopoietic progenitors was more pronounced in cells induced to proliferate by growth factors. These data suggest that CT-32228 may have potential in the treatment of acute leukemias, but that efficacy is more directly related to the degree of cell proliferation rather than to the level of LPAAT-beta expression or activity.

Effects of hyperthermia and boric acid on skeletal development in rat embryos.

BACKGROUND: The individual effects of boric acid (BA) and hyperthermia on the development of the axial skeleton have been reported previously. Both cause an increased incidence of axial skeletal defects including a decrease in the total number of ribs and vertebrae. Because of the similarity in the effects of the two agents, we examined their interaction when given in combination to pregnant rats on gestational day (GD) 10. METHODS: Dams were treated on GD 10 with BA (0, 250, or 500 mg/kg) and hyperthermia (37, 41, or 42 degrees C) and allowed to deliver their pups. Doses of BA were based on results from a dose-finding study. Litters were evaluated on postnatal days (PND) 1 and 3 for number, gender, and weight of pups. On PND3, pups were examined externally and viscerally, and double-stained for skeletal evaluation. RESULTS: A dose-dependent, statistically significant increase in fetal skeletal defects was seen on PND 3 with BA or hyperthermia alone with even greater effects when given in combination. Defects included rib and vertebral fusions, split vertebral centra in the thoracic and lumbar areas, and a decrease in the total number of ribs and vertebrae. CONCLUSIONS: The increased incidence of skeletal defects resulting from combined exposure to hyperthermia and BA was additive for segmentation defects and synergistic for the reduction in numbers of vertebrae.

Blood lead concentration and delayed puberty in girls.

BACKGROUND: Environmental lead exposure has been linked to alterations in growth and endocrine function. It is not known whether such exposure affects pubertal development. METHODS: We analyzed the relations between blood lead concentration and pubertal development among girls (defined as females 8 to 18 years of age) who were enrolled in a cross-sectional study (the third National Health and Nutrition Examination Survey) in which race was self-reported or proxy-reported: 600 were non-Hispanic white, 805 were non-Hispanic African-American, and 781 were Mexican-American girls. Puberty was measured on the basis of the age at menarche and Tanner stage for pubic-hair and breast development. RESULTS: Geometric mean lead concentrations were less than 3 microg per deciliter (0.144 micromol per liter) in all three groups. As compared with concentrations of 1 microg per deciliter (0.048 micromol per liter), lead concentrations of 3 microg per deciliter were associated with decreased height (P<0.001), after adjustment for age, race, and other factors, but not with body-mass index or weight. Blood lead concentrations of 3 microg per deciliter were associated with significant delays in breast and pubic-hair development in African-American and Mexican-American girls. The delays were most marked among African-American girls; in this group, the delays in reaching Tanner stages 2, 3, 4, and 5 associated with a lead concentration of 3 microg per deciliter as compared with 1 microg per deciliter were 3.8, 5.3, 5.8, and 2.1 months, respectively, for breast development and 4.0, 5.5, 6.0, and 2.2 months, respectively, for pubic-hair development; the associated delay in age at menarche was 3.6 months. In white girls, there were nonsignificant delays in all pubertal measures in association with a lead concentration of 3 microg per deciliter. CONCLUSIONS: These data suggest that environmental exposure to lead may delay growth and pubertal development in girls, although confirmation is warranted in prospective studies.