Imported Infections in Rural Mid-West United States - A Report from a Tertiary Care Center.

BACKGROUND: There is lack of specific data on imported infections in the mid-west United States (U.S.). METHODS: Retrospective data on demographic and geographic data of imported infections seen by the infectious diseases clinics and consultation service from 2001-2018 was collected. RESULTS: Of the 64 infections, tuberculosis(TB) was most common [20(31.3%); pulmonary(11,55%), lymphadenopathy(8,40%), gastrointestinal(4,20%), disseminated(2,10%), and 1(5%) each of genitourinary and vertebral spine infection, 4 Human immune-deficiency virus infection and 1 echinococcosis)] followed by malaria(11,17.2%). Other infections: Cysticercosis [7,10.9%], giardiasis (4,6.3%), 3 each (4.7%) Human T-lymphotrophic Virus infection and schistosomiasis, 2 each (3.1%) leprosy, strongyloidiasis, and typhoid fever, one each (1.6%) of ascariasis, brucellosis, Chagas disease, Chikungunya virus, hepatitis A virus, echinococcosis, Japanese encephalitis virus, loiasis, paratyphoid fever, Q fever, and unspecified parasitosis. Geographic origins: Africa(26,40.6%), Asia(16,25%), Central America(11,17.2%), Europe(2,3.1%), Oceania(2,3.1%), South America(2,3.1%), and Unknown(5). More cases were seen after 2015. CONCLUSIONS: With increasing tourism, it is important to educate rural mid-west healthcare professionals on travel medicine. The current COVID-19 pandemic illustrates the importance of this type of education and data accumulation now and in the future.

Exposure to disinfectant by-products and the risk of stillbirth in Massachusetts.

OBJECTIVES: We examined stillbirths in relation to disinfection by-product (DBP) exposures including chloroform, bromodichloromethane (BDCM), dibromochloromethane, bromoform, trichloroacetic acid, dichloroacetic acid (DCAA), monobromoacetic acid and summary DBP measures (trihalomethanes (THM4), haloacetic acids (HAA5), THMBr (brominated trihalomethanes) and DBP9 (sum of THM4 and HAA5)). METHODS: We randomly selected 10 controls for each of the 2460 stillbirth cases with complete quarterly 1997-2004 THM4 and HAA5 town-level drinking water data. Adjusted (aORs) were calculated based on weight-averaged second-trimester DBP exposures. RESULTS: We detected statistically significant associations for stillbirths and the upper DCAA quartiles (aOR range: 1.50-1.71). We also found positive associations for the upper four HAA5 quintiles and different stillbirth cause of death categories that were examined including unexplained stillbirth (aOR range: 1.24-1.72), compression of umbilical cord (aOR range: 1.08-1.94), prematurity (aOR range: 1.37-2.88), placental separation and haemorrhage (aOR range: 1.44-2.01) and asphyxia/hypoxia (aOR range: 1.52-1.97). Additionally, we found positive associations between stillbirths and chloroform exposure (aOR range: 1.29 - 1.36) and unexplained stillbirths and BDCM exposure (aOR range: 1.51 - 1.78). We saw no evidence of exposure-response relationships for any categorical DBP metrics. CONCLUSIONS: Consistent with some previous studies, we found associations between stillbirths and chloroform and unexplained stillbirth and BDCM exposures. These findings strengthen existing evidence of prenatal THM exposures increasing the risk of stillbirth. Additionally, we saw statistically significant associations between DCAA and stillbirth. Future research should examine cause-specific stillbirths in relation to narrower critical windows and additional DBP exposure metrics beyond trihalomethanes and haloacetic acids.

Risks of obstructive genitourinary birth defects in relation to trihalomethane and haloacetic acid exposures: expanding disinfection byproduct mixtures analyses using relative potency factors.

BACKGROUND: Some disinfection byproducts (DBPs) are teratogens based on toxicological evidence. Conventional use of predominant DBPs as proxies for complex mixtures may result in decreased ability to detect associations in epidemiological studies. OBJECTIVE: We assessed risks of obstructive genitourinary birth defects (OGDs) in relation to 12 DBP mixtures and 13 individual component DBPs. METHODS: We designed a nested registry-based case-control study (210 OGD cases; 2100 controls) in Massachusetts towns with complete quarterly 1999-2004 data on four trihalomethanes (THMs) and five haloacetic acids (HAAs). We estimated temporally-weighted average DBP exposures for the first trimester of pregnancy. We estimated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for OGD in relation to individual DBPs, unweighted mixtures, and weighted mixtures based on THM/HAA relative potency factors (RPF) from animal toxicology data for full-litter resorption, eye defects, and neural tube defects. RESULTS: We detected elevated aORs for OGDs for the highest of bromodichloromethane (aOR = 1.75; 95% CI: 1.15-2.65), dibromochloromethane (aOR = 1.71; 95% CI: 1.15-2.54), bromodichloroacetic acid (aOR = 1.56; 95%CI: 0.97-2.51), chlorodibromoacetic acid (aOR = 1.97, 95% CI: 1.23-3.15), and tribromoacetic acid (aOR = 1.90; 95%CI: 1.20-3.03). Across unweighted mixture sums, the highest aORs were for the sum of three brominated THMs (aOR = 1.74; 95% CI: 1.15-2.64), the sum of six brominated HAAs (aOR = 1.43; 95% CI: 0.89-2.31), and the sum of nine brominated DBPs (aOR = 1.80; 95% CI: 1.05-3.10). Comparing eight RPF-weighted to unweighted mixtures, the largest aOR differences were for two HAA metrics, which both were higher with RPF weighting; other metrics had reduced or minimally changed ORs in RPF-weighted models.

Engaging Clinical Partners in Curricular Initiatives to Improve Practice Readiness.

BACKGROUND: The release of the American Association of Colleges of Nursing's updated Essentials creates an opportunity for nursing programs and clinical partners to collaborate on strengthening curricula and improving new graduate practice readiness. This scoping literature review examined published models for collaborating with clinical partners on curricular initiatives to guide this process. METHOD: Three electronic databases were searched for peer-reviewed articles describing models for collaborating with clinical partners when revising nursing curricula to improve practice readiness. The final sample included seven articles representing five models developed for prelicensure undergraduate education. RESULTS: Themes identified among the models were creating a shared mission, leadership support and involvement, representative committees with regular meetings, clear role expectations, collaboratively determining concepts and competencies, and developing training and resources for consistent implementation of changes. CONCLUSION: These themes provide recommendations for engaging clinical partners in the process of integrating the new Essentials in curricula and improving graduates' practice readiness. [J Nurs Educ. 2023;62(12):706-710.].

Temporal variability in trihalomethane and haloacetic acid concentrations in Massachusetts public drinking water systems.

Previous epidemiological studies in Massachusetts have reported a risk of adverse health outcomes in relation to disinfection by-product (DBP) exposures. Measurement error due to the use of indirect exposure surrogates can lead to misclassification bias in epidemiological studies; therefore, it is important to characterize exposure variability in these populations to assess the potential for exposure misclassification. We used 19,944 trihalomethane (THM) samples and 9291 haloacetic acid (HAA) samples collected in 201 public water systems (PWSs) in Massachusetts to examine temporal variability under different drinking water sources and disinfection types. Annual and seasonal variability was also examined in 46 PWSs with complete quarterly THM4 (i.e., the sum of 4 individual THMs) data from 1995 to 2004 and 19 PWSs with complete HAA5 (i.e., the sum of 5 individual HAAs) data from 2001 to 2004. The quarterly ratio of THM4 and HAA5 and correlations between THM4, HAA5 and individual DBP species were examined to determine the adequacy of using different exposure surrogates in epidemiological studies. Individual PWSs were used to examine monthly variability in relation to quarterly averages. Based on all available matched samples (n=9003) from 1995 to 2004 data, we found a correlation of 0.52 for THM4 and HAA5. The correlation was stronger among the 62 ground water systems (r(s)=0.62) compared to the 81 surface water (r(s)=0.45) and 40 mixed water (r(s)=0.39) systems. Mean THM4 levels were fairly stable over the 10-year study period for 46 PWSs including 39 PWSs that did not change disinfection. Large reductions (∼40 µg/L) in mean THM4 data were found among seven systems that switched from chlorination to alternative disinfectants. As expected, the highest mean THM4 values were detected for Quarter 3, while the lowest values were found in Quarter 1. The highest HAA5 values were detected in Quarters 2 and 3 and the lowest was found in Quarter 4. Data from four systems showed mean differences up to 66 µg/L (67% change) in successive months and by 46 µg/L compared to quarterly mean concentrations. Although longer-term disinfection by-product temporality may be minimal in this study population, the use of monthly average concentrations for exposure assessment may be needed for some PWSs to minimize misclassification of narrow critical periods of exposure in epidemiological studies.

Disinfection By-Product Exposures and the Risk of Musculoskeletal Birth Defects.

BACKGROUND: Epidemiological studies suggest that exposure to water disinfection by-products (DBPs) may increase the risk of certain birth defects. However, evidence for musculoskeletal defects (MSDs) is limited. Previous MSD studies have not examined DBPs beyond trihalomethanes (THMs) and have not separately examined limb or diaphragm defects which may have distinct developmental etiologies. METHODS: We calculated adjusted odds ratios (aORs) in a registry-based case-control study of birth defects in Massachusetts with complete quarterly 1999-2004 data on four THMs and five haloacetic acids (HAAs). We matched 10 controls each to 187 MSD cases based on week of conception. Weight-averaged town-level first-trimester DBP exposures were individually assigned based on residence at birth. We adjusted THM models for exposure to the sum of five HAAs (HAA5), and HAA models for the sum of four THMs (THM4). RESULTS: We detected positive exposure-response associations for all grouped MSDs with THM4 quintiles (aOR range: 1.90-3.18) and chloroform quartiles (aOR range: 1.30-2.21), and for reduction of upper or lower limbs with chloroform quartiles (aOR range: 2.39-3.52). We detected elevated aORs for diaphragmatic hernia with DBP9 (sum of THM4 and HAA5), and chloroform and bromodichloromethane tertiles and an exposure-response relationship for THM4 tertiles (aOR range: 1.67-1.80). CONCLUSIONS: This is the first epidemiological study to examine HAAs in relation to MSDs. Given the indirect nature of our exposure assessment data and small case numbers, the exposure-response relationships that we detected for THM4 and chloroform warrant further investigation.

Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort.

Mutations in the DMD gene, encoding the dystrophin protein, are responsible for the dystrophinopathies Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), and X-linked Dilated Cardiomyopathy (XLDC). Mutation analysis has traditionally been challenging, due to the large gene size (79 exons over 2.2 Mb of genomic DNA). We report a very large aggregate data set comprised of DMD mutations detected in samples from patients enrolled in the United Dystrophinopathy Project, a multicenter research consortium, and in referral samples submitted for mutation analysis with a diagnosis of dystrophinopathy. We report 1,111 mutations in the DMD gene, including 891 mutations with associated phenotypes. These results encompass 506 point mutations (including 294 nonsense mutations) and significantly expand the number of mutations associated with the dystrophinopathies, highlighting the utility of modern diagnostic techniques. Our data supports the uniform hypermutability of CGA>TGA mutations, establishes the frequency of polymorphic muscle (Dp427m) protein isoforms and reveals unique genomic haplotypes associated with "private" mutations. We note that 60% of these patients would be predicted to benefit from skipping of a single DMD exon using antisense oligonucleotide therapy, and 62% would be predicted to benefit from an inclusive multiexonskipping approach directed toward exons 45 through 55.

Myroides spp. cellulitis and bacteremia: A case report.

Myroides spp., formerly Flavobacterium spp., are gram-negative, non-motile, traditionally opportunistic pathogens that are infrequent clinical isolates. Myroides spp. have been pathogenically implicated in only 52 reported cases since the discovery of the Flavobacterium genus in the 1920s. We present a case of Myroides spp. lower extremity cellulitis and bacteremia. To our knowledge, this is the 16th case of cutaneous infection caused by Myroides spp. Etiology of this patient's infection was felt to be related to exposure of his pre-existing lower extremity wounds to soil and water versus a dog lick in the context of relative immunosuppression from type 2 diabetes and chronic inhaled steroid use. Given the characteristic multi-drug resistance of Myroides spp., resistance to usual empiric antimicrobials given for cellulitis, and potential for fatal infection in cases of pan-resistance, it is important that clinicians remain alert to the possibility of this rare pathogen.

Antitumorigenic effects of peroxisome proliferator-activated receptor-gamma in non-small-cell lung cancer cells are mediated by suppression of cyclooxygenase-2 via inhibition of nuclear factor-kappaB.

Pharmacological activators of peroxisome proliferator-activated receptor-gamma (PPARgamma) inhibit growth of non-small-cell lung cancer (NSCLC) cell lines in vitro and in xenograft models. Because these agents engage off-target pathways, we have assessed the effects of PPARgamma by overexpressing the protein in NSCLC cells. We reported previously that increased PPARgamma inhibits transformed growth and invasiveness and promotes epithelial differentiation in a panel of NSCLC expressing oncogenic K-Ras. These cells express high levels of cyclooxygenase-2 (COX-2) and produce high levels of prostaglandin E(2) (PGE(2)). The goal of these studies was to identify the molecular mechanisms whereby PPARgamma inhibits tumorigenesis. Increased PPARgamma inhibited expression of COX-2 protein and promoter activity, resulting in decreased PGE(2) production. Suppression of COX-2 was mediated through increased activity of the tumor suppressor phosphatase and tensin homolog, leading to decreased levels of phospho-Akt and inhibition of nuclear factor-kappaB activity. Pharmacological inhibition of PGE(2) production mimicked the effects of PPARgamma on epithelial differentiation in three-dimensional culture, and exogenous PGE(2) reversed the effects of increased PPARgamma activity. Transgenic mice overexpressing PPARgamma under the control of the surfactant protein C promoter had reduced expression of COX-2 in type II cells and were protected against developing lung tumors in a chemical carcinogenesis model. These data indicate that high levels of PGE(2) as a result of elevated COX-2 expression are critical for promoting lung tumorigenesis and that the antitumorigenic effects of PPARgamma are mediated in part through blocking this pathway.

Associations Between Disinfection By-Product Exposures and Craniofacial Birth Defects.

OBJECTIVE: The aim of this study was to examine associations between craniofacial birth defects (CFDs) and disinfection by-product (DBP) exposures, including the sum of four trihalomethanes (THM4) and five haloacetic acids (HAA5) (ie, DBP9). METHODS: We calculated first trimester adjusted odds ratios (aORs) for different DBPs in a matched case-control study of 366 CFD cases in Massachusetts towns with complete 1999 to 2004 THM and HAA data. RESULTS: We detected elevated aORs for cleft palate with DBP9 (highest quintile aOR = 3.52; 95% CI: 1.07, 11.60), HAA5, trichloroacetic acid (TCAA), and dichloroacetic acid. We detected elevated aORs for eye defects with TCAA and chloroform. CONCLUSION: This is the first epidemiological study of DBPs to examine eye and ear defects, as well as HAAs and CFDs. The associations for cleft palate and eye defects highlight the importance of examining specific defects and DBPs beyond THM4.

Prostaglandin E2 receptor subtype 2 (EP2) null mice are protected against murine lung tumorigenesis.

BACKGROUND: Manipulating prostaglandin (PG) production modulates tumor development. Elevated PGI2 production prevents murine lung cancer, while decreasing PGE2 content protects against colon cancer. PGE2 receptor subtype 2 (EP2) -deficient mice were hypothesized to be resistant to lung tumorigenesis. MATERIALS AND METHODS: EP2 null BALB/c mice and their wild-type littermates were exposed to an initiation-promotion carcinogenesis protocol and lung tumorigenesis was examined. Chronic lung inflammation was induced to determine whether EP2 ablation influenced inflammatory cell infiltration. RESULTS: Tumor multiplicity in EP2 null mice was 34% lower than in their wild-type littermates (21.9+/-3.0 vs. 14.5+/-2.9 tumors/mouse, p<0.001). The lung tumor burden, an indicator of growth rate, also declined (57%, p<0.05). All the mice exhibited similar inflammatory cell infiltration. CONCLUSION: PGE2, acting through EP2, enhanced lung tumorigenesis through a mechanism that may be distinct from its proinflammatory activity. Thus, EP2 is a potential target for novel chemoprevention strategies.

Genetic ablation of inducible nitric oxide synthase decreases mouse lung tumorigenesis.

Inducible nitric oxide synthase (iNOS) content is elevated in human lung adenocarcinomas, and lung cancer patients exhale more nitric oxide (NO) than healthy individuals. The mechanism of this association of chronically elevated NO with tumorigenesis has not been defined. We investigated the role of iNOS in murine lung tumorigenesis, a model of human lung adenocarcinoma, using wild-type (+/+) and iNOS (-/-) mice. Genetic disruption of iNOS decreased urethane-induced lung tumor multiplicity by 80% (P < 0.0001). iNOS protein was expressed in lung tumors growing in wild-type mice and bronchiolar Clara cells isolated from normal mouse lungs, but was undetectable in whole lung extracts by immunoblotting. Because NO regulates vascular endothelial growth factor (VEGF) expression in other systems, we examined the effect of iNOS deficiency on VEGF protein concentration in mouse lung tumors. VEGF concentration was 54% lower in lung tumors isolated from iNOS (-/-) mice versus controls, implying that NO modulates angiogenesis in these tumors. Lung tumors also have elevated levels of cyclooxygenase (COX) -1 and COX-2 contents relative to normal lungs, but iNOS deficiency did not change COX expression in the tumors. Chronic inflammation predisposes mice to lung tumorigenesis; accordingly, we examined whether butylated hydroxytoluene-induced chronic lung inflammation was influenced by iNOS deficiency. Butylated hydroxytoluene-induced alveolar macrophage infiltration was unaffected by iNOS (-/-) status, suggesting that although NO is a critical mediator of mouse lung tumorigenesis, it is not essential in this model of lung inflammation. The substantial (80%) reduction in lung tumor multiplicity in iNOS (-/-) mice strongly supports examining iNOS-specific inhibitors as potential lung cancer chemopreventive agents.

Serum levels of surfactant protein D are increased in mice with lung tumors.

Most murine lung tumors are composed of differentiated epithelial cells. We have reported previously that surfactant protein (SP)-D is expressed in urethane-induced tumors. Serum levels of SP-D are increased in patients with interstitial lung disease and acute respiratory distress syndrome and in rats with acute lung injury but have not been measured in mice. In this study, we sought to determine whether SP-D could be detected in murine serum and discovered that it was increased in mice bearing lung tumors. Serum SP-D concentration was 5.0 +/- 0.2 ng/ml in normal C57BL/6 mice, essentially absent in SP-D nulls, and 63.6 +/- 9.0 ng/ml in SP-D-overexpressing mice. SP-D in serum was verified by immunoblotting. Serum SP-D was increased in mice bearing tumors induced by three different protocols, and the SP-D level correlated with tumor volume. However, in mice with a single adenoma or a few adenomas, SP-D levels were usually within the normal range. SP-D was expressed by the tumor cells, and there was also a field effect whereby type II cells near the tumor expressed more SP-D than type II cells in the remainder of the lung. Serum SP-D was also increased by lung inflammation. In airway inflammation induced by aerosolized ovalbumin in sensitized BALB/c mice, the serum levels were elevated after challenge. In conclusion, serum SP-D concentration is increased in mice bearing lung tumors and generally reflects the tumor burden but is also elevated during lung inflammation.

Integrin expression regulates neuroblastoma attachment and migration.

Neuroblastoma (NBL) is the most common malignant disease of infancy, and children with bone metastasis have a mortality rate greater than 90%. Two major classes of proteins, integrins and growth factors, regulate the metastatic process. We have previously shown that tumorigenic NBL cells express higher levels of the type I insulin-like growth factor receptor (IGF-IR) and that beta1 integrin expression is inversely proportional to tumorigenic potential in NBL. In the current study, we analyze the effect of beta1 integrin and IGF-IR on NBL cell attachment and migration. Nontumorigenic S-cells express high levels of beta1 integrin, whereas tumorigenic N-cells express little beta1 integrin. Alterations in beta1 integrin are due to regulation at the protein level, as translation is decreased in N-type cells. Moreover, inhibition of protein synthesis shows that beta1 integrin is degraded more slowly in S-type cells (SHEP) than in N-type cells (SH-SY5Y and IMR32). Inhibition of alpha5beta1 integrin prevents SHEP (but not SH-SY5Y or IMR32) cell attachment to fibronectin and increases SHEP cell migration. Increases in IGF-IR decrease beta1 integrin expression, and enhance SHEP cell migration, potentially through increased expression of alphavbeta3. These data suggest that specific classes of integrins in concert with IGF-IR regulate NBL attachment and migration.

Spatial variation of disinfection by-product concentrations: exposure assessment implications.

The use of public water system (PWS) average trihalomethane (THM) and haloacetic acid (HAA) concentrations as surrogates of "personal" exposures in epidemiological studies of disinfection by-products (DBPs) may result in exposure misclassification bias from various sources of measurement error including intra-system variation of DBPs. Using 2000-2004 data from 107 PWSs in Massachusetts, we assessed two approaches for characterizing DBP spatial variability by identifying PWSs with low spatial variability (LSV) and examining differences in LSV across DBP groups and by type of source water and primary disinfectant. We also used spatial differences to examine the association between THM concentrations and indices of social disadvantage; however, we found no correlations or statistically significant differences based on the available data. We observed similar patterns for the percentage of quarterly sampling dates with LSV across different types of source water for all DBPs but not across disinfectants. We found there was little overlap between sites classified as having LSV across different DBP groups. In the main analysis, we found moderate correlations between both approaches (φ(THM4) = 0.55; φ(BrTHM) = 0.64; φ(HAA5) = 0.67); although Method 1 (based on concentration differences between samples) may be better suited for identifying PWSs for inclusion in epidemiological studies because it is more easily adapted to study-specific exposure gradients than Method 2 (based on categorical exposure percentiles). These data reinforce the need to consider different exposure assessment approaches when examining the spatial variation of multiple DBP surrogates as they can represent different DBP mixtures.

Combination of steroids and ischial weight-bearing knee ankle foot orthoses in Duchenne's muscular dystrophy prolongs ambulation past 20 years of age--a case report.

Patients with Duchenne muscular dystrophy (DMD) lose ambulation by age 12. Long-term steroids have lengthened ambulation by 2-5 years. Ischial weight-bearing knee ankle foot orthoses prolong ambulation for 2-3 years. We report the outcome of the ambulatory status of a patient with DMD treated with daily steroid therapy and orthoses. This male patient was diagnosed with DMD at age of 2. He has been treated with daily steroids since age 7 years. He lost the ability to arise from the floor and walk up steps at age 14 and lost ambulation by age 16. He was fitted with orthoses at age 16 following surgical correction of his lower extremity contractures and regained independent ambulation. At age 20, he was able to stand independently in his orthoses and take steps with moderate support. We conclude that a combination of daily steroids and orthoses prolongs ambulation beyond that of the natural history DMD.