Systematic Review of Neighborhood Factors Impacting HIV Care Continuum Participation in the United States.

Social determinants have been increasingly implicated in accelerating HIV vulnerability, particularly for disenfranchised communities. Among these determinants, neighborhood factors play an important role in undermining HIV prevention. However, there has been little research comprehensively examining the impact of neighborhood factors on HIV care continuum participation in the US. To address this, we conducted a systematic review (PROSPERO registration number CRD42022359787) to determine neighborhood factors most frequently associated with diminished HIV care continuum participation. Peer-reviewed studies were included if published between 2013 - 2022, centralized in the US, and analyzed a neighborhood factor with at least one aspect of the HIV care continuum. The review was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. Study quality was guided by LEGEND (Let Evidence Guide Every New Decision) evaluation guidelines. Systematic review analysis was conducted using Covidence software. There were 3,192 studies identified for initial screening. Forty-four were included for review after eliminating duplicates, title/abstract screening, and eligibility assessment. Social and economic disenfranchisement of neighborhoods negatively impacts HIV care continuum participation among persons living with HIV. In particular, five key neighborhood factors (socioeconomic status, segregation, social disorder, stigma, and care access) were associated with challenged HIV care continuum participation. Race moderated relationships between neighborhood quality and HIV care continuum participation. Structural interventions addressing neighborhood social and economic challenges may have favorable downstream effects for improving HIV care continuum participation.

Post-traumatic stress disorder symptoms and PrEP intentions among Black American young adults at high-risk for HIV.

OBJECTIVES: Black Americans bear the greatest burden of HIV, accounting for 43% of new diagnoses. Yet Black Americans also evidence the lowest utilization rates of Pre-Exposure Prophylaxis (PrEP), a highly effective biomedical strategy for preventing HIV infection. Predictors of PrEP acceptance vary; however, little is known about psychological distress, such as post-traumatic stress disorder (PTSD) symptoms, as a predictor. DESIGN: In this cross-sectional study, n = 195 Black Americans, evidencing behaviors found in the research literature to heighten risk for contracting HIV (e.g. sex work, injection drug use) ages 18-29, 55% cisgender women, 39.5% cisgender men, 3% transgender/non-binary, completed audio-computer-assisted self-interviews. RESULTS: Bivariate analyses indicated significant positive associations between PTSD symptoms and PrEP acceptance and self-confidence. In multinomial logistic regression analyses, after controlling for Perceived HIV Risk, participants had a higher likelihood of responding they 'probably would' take PrEP (as opposed to 'definitely would not' take PrEP) if they reported higher levels of PTSD symptoms. Post-hoc analyses revealed a curvilinear relationship between PTSD symptoms and PrEP acceptance with those reporting the highest level of PTSD in the sample having slightly lower PrEP acceptance than those reporting moderately high levels of PTSD. CONCLUSION: Findings are discussed in the context of the negative impacts of high levels of PTSD and potential positive adaptations subsequent to moderate levels of PTSD that could be relevant to advances in HIV prevention efforts.

Trends in Maternal Mortality and Severe Maternal Morbidity During Delivery-Related Hospitalizations in the United States, 2008 to 2021.

Importance: Maternal mortality and severe maternal morbidity (SMM) are important focus areas in public health. Further understanding trends, health disparities, and risk factors for these adverse outcomes is vital to public health decision-making. Objective: To describe trends and risk factors for delivery-related maternal deaths and SMM in the United States. Design, Setting, and Participants: This is a retrospective cross-sectional study using data from a large, geographically diverse, all-payer hospital administrative database. Hospital discharges from January 2008 to December 2021 with any Medicare Severity Diagnosis Related Group, International Classification of Diseases, Ninth Revision, Clinical Modification, or International Classification of Diseases, Tenth Revision, Clinical Modification delivery diagnosis or procedure code were included. Data analysis took place from February 2021 to March 2023. Exposures: Year, quarter (Q), age, race and ethnicity, delivery method. Main Outcomes and Measures: Maternal mortality, SMM during delivery-related hospitalization. Results: Overall, 11 628 438 unique hospital discharges were analyzed, with a mean (SD) age of 28 (6) years. There were 437 579 (3.8%) Asian, 92 547 (0.8%) American Indian, 1 640 355 (14.1%) Black, 1 762 392 (15.2%) Hispanic, 83 189 (0.7%) Pacific Islander, and 6 194 139 (53.3%) White patients. Regression-adjusted maternal mortality per 100 000 discharges declined from 10.6 deaths in Q1 2008 to 4.6 deaths in Q4 2021. Mortality was significantly higher among patients with advanced maternal age (eg, age 35-44 years vs 25-34 years: adjusted odds ratio [aOR], 1.49; 95% CI, 1.22-1.84). Other significant risk factors for mortality included cesarean delivery, comorbid conditions, complications, and COVID-19 diagnosis (eg, cesarean delivery: aOR, 2.28; 95% CI, 1.87-2.79). The prevalence of any SMM increased from 146.8 per 10 000 discharges in Q1 of 2008 to 179.8 per 10 000 discharges in Q4 of 2021. SMM risk factors included age 24 years or younger or age 35 years or older, belonging to a racial or ethnic minority group, cesarean delivery, Medicaid insurance, and having 1 or more comorbidities (eg, age 10-19 years: aOR, 1.39; 95% CI, 1.36-1.42). Conclusions and Relevance: This cross-sectional study found that delivery-related mortality in US hospitals decreased for all racial and ethnic groups, age groups, and modes of delivery during 2008 to 2021, likely demonstrating the impact of national strategies focused on improving maternal quality of care provided during delivery-related hospitalizations. SMM prevalence increased for all patients, with higher rates for racial and ethnic minority patients of any age. Advanced maternal age, racial or ethnic minority group status, cesarean delivery, and comorbidities were associated with higher odds of mortality and SMM.

Socio-Ecological Influences on HIV Care Engagement: Perspectives of Young Black Men Who Have Sex with Men Living with HIV in the Southern US.

Young Black men who have sex with men (MSM) living with HIV evidence the lowest rates of linkage to care and viral suppression of all US MSM. Kentucky, identified by the US Department of Health and Human Services as a "hot spot" state with elevated HIV incidence compared to the rest of the country, exhibits similar racialized outcomes. Structural, interpersonal, and individual drivers of engagement along the HIV care continuum among people living with HIV have been identified, primarily through quantitative designs. However, the mechanisms by which these factors shape HIV care engagement, and the ways they may combine or reinforce each other, as well as from the lived experience of young Black MSM living with HIV, have been studied to a lesser extent. In this study, a purposive sample of n = 29 HIV-positive young Black MSM (age M = 25 years old; 38% retained in care) residing in Kentucky participated in in-depth interviews. Factors that were most influential on engagement varied along the continuum, with health insurance status and knowledge of HIV being relatively more influential to diagnosis, and housing stability, psychological processes, and interpersonal relationships being more influential on retention. For some participants, barriers to care at multiple levels had a mutually influencing and intensifying impact on care engagement. Additional efforts to center the voices of young Black MSM living with HIV will help illuminate acceptable and sustainable interventions for increasing their care engagement and narrowing persistent racial disparities in HIV morbidity and mortality.

Evidence of the impacts of metal mining and the effectiveness of mining mitigation measures on social-ecological systems in Arctic and boreal regions: a systematic map.

Background: Mining can directly and indirectly affect social and environmental systems in a range of positive and negative ways, and may result in societal benefits, but may also cause conflicts, not least in relation to land use. Mining always affects the environment, whilst remediation and mitigation efforts may effectively ameliorate some negative environmental impacts. Social and environmental systems in Arctic and boreal regions are particularly sensitive to impacts from development for numerous reasons, not least of which are the reliance of Indigenous peoples on subsistence livelihoods and long recovery times of fragile ecosystems. With growing metal demand, mining in the Arctic is expected to increase, demanding a better understand its social and environmental impacts. We report here the results of a systematic mapping of research evidence of the impacts of metal mining in Arctic and boreal regions. Methods: We searched multiple bibliographic databases and organisational websites for relevant research using tested search strategies. We also collected evidence from stakeholders and rightsholders identified in the wider 3MK project (Mapping the impacts of Mining using Multiple Knowledges, https://osf.io/cvh3u). We screened articles at three stages (title, abstract, and full text) according to a predetermined set of inclusion criteria, with consistency checks between reviewers at each level. We extracted data relating to causal linkages between actions or impacts and measured outcomes, along with descriptive information about the articles and studies. We have produced an interactive database along with interactive visualisations, and identify knowledge gaps and clusters using heat maps. Review findings: Searches identified over 32,000 potentially relevant records, which resulted in a total of 585 articles being retained in the systematic map. This corresponded to 902 lines of data on impact or mitigation pathways. The evidence was relatively evenly spread across topics, but there was a bias towards research in Canada (35% of the evidence base). Research was focused on copper (23%), gold (18%), and zinc (16%) extraction as the top three minerals, and open pit mines were most commonly studied (33%). Research most commonly focused on operation stages, followed by abandonment and post-closure, with little evidence on early stages (prospecting, exploration, construction; 2%), expansion (0.2%), or decommissioning/closure (0.3%). Mitigation measures were not frequently studied (18% articles), with groundwater mitigation most frequently investigated (54% of mitigations), followed by soil quality (12%) and flora species groups (10%). Control-impact study designs were most common (68%) with reference sites as the most frequently used comparator (43%). Only 7 articles investigated social and environmental outcomes together. the most commonly reported system was biodiversity (39%), followed by water (34%), societies (20%), and soil/geology (6%), with air the least common (1%). Conclusions: The evidence found highlights a suite of potential knowledge gaps, namely: on early stages prior to operation; effectiveness of mitigation measures; stronger causal inference study designs; migration and demography; cumulative impacts; and impacts on local and Indigenous communities. We also tentatively suggest subtopics where the number of studies could allow systematic reviews: operation, post-closure, and abandonment stages; individual faunal species, surface water quality, water sediment quality; and, groundwater mitigation measure effectiveness. Supplementary Information: The online version contains supplementary material available at 10.1186/s13750-022-00282-y.

Comparison of Resident, Advanced Practice Clinician, and Hospitalist Teams in an Academic Medical Center: Association With Clinical Outcomes and Resource Utilization.

BACKGROUND: Academic medical centers have expanded their inpatient medicine services with advanced practice clinicians (APCs) or nonteaching hospitalists in response to patient volumes, residency work hour restrictions, and recently, COVID-19. Reports of clinical outcomes, cost, and resource utilization differ among inpatient team structures. OBJECTIVE: Directly compare outcomes among resident, APC, and solo hospitalist inpatient general medicine teams. DESIGN: Retrospective cohort study using multivariable analysis adjusted for time of admission, interhospital transfer, and comorbidities that compares clinical outcomes, cost, and resource utilization. SUBJECTS: Patients 18 years or older discharged from an inpatient medicine service between July 2015 and July 2018 (N = 12,716). MAIN MEASURES: Length of stay (LOS), 30-day readmission, inpatient mortality, normalized total direct cost, discharge time, and consultation utilization. KEY RESULTS: Resident teams admitted fewer patients at night (32.0%; P < .001) than did APC (49.5%) and hospitalist (48.6%) teams. APCs received nearly 4% more outside transfer patients (P = .015). Hospitalists discharged patients 26 minutes earlier than did residents (mean hours after midnight [95% CI], 14.58 [14.44-14.72] vs 15.02 [14.97-15.08]). Adjusted consult utilization was 15% higher for APCs (adjusted mean consults per admission [95% CI], 1.00 [0.96-1.03]) and 8% higher for residents (0.93 [0.90-0.95]) than it was for hospitalists (0.85 [0.80-0.90]). No differences in LOS, readmission, mortality, or cost were observed between the teams. CONCLUSION: We observed similar costs, LOS, 30-day readmission, and mortality among hospitalist, APC, and resident teams. Our results suggest clinical outcomes are not significantly affected by team structure. The addition of APC or hospitalist teams represent safe and effective alternatives to traditional inpatient resident teams.

DNA methylation changes associated with Parkinson's disease progression: outcomes from the first longitudinal genome-wide methylation analysis in blood.

Parkinson's Disease (PD) is a common neurodegenerative disorder currently diagnosed based on the presentation of characteristic movement symptoms. Unfortunately, patients exhibiting these symptoms have already undergone significant dopaminergic neuronal loss. Earlier diagnosis, aided by molecular biomarkers specific to PD, would improve overall patient care. Epigenetic mechanisms, which are modified by both environment and disease pathophysiology, are emerging as important components of neurodegeneration. Alterations to the PD methylome have been reported in epigenome-wide association studies. However, the extent to which methylation changes correlate with disease progression has not yet been reported; nor the degree to which methylation is affected by PD medication. We performed a longitudinal genome-wide methylation study surveying ~850,000 CpG sites in whole blood from 189 well-characterized PD patients and 191 control individuals obtained at baseline and at a follow-up visit ~2 y later. We identified distinct patterns of methylation in PD cases versus controls. Importantly, we identified genomic sites where methylation changes longitudinally as the disease progresses. Moreover, we identified methylation changes associated with PD pathology through the analysis of PD cases that were not exposed to anti-parkinsonian therapy. In addition, we identified methylation sites modulated by exposure to dopamine replacement drugs. These results indicate that DNA methylation is dynamic in PD and changes over time during disease progression. To the best of our knowledge, this is the first longitudinal epigenome-wide methylation analysis for Parkinson's disease and reveals changes associated with disease progression and in response to dopaminergic medications in the blood methylome.

Dopaminergic gene methylation is associated with cognitive performance in a childhood monozygotic twin study.

Individual differences in cognitive function are due to a combination of heritable and non-heritable factors. A large body of evidence from clinical, cognitive, and pharmacological neuroscience implicates dopaminergic gene variants as modulators of cognitive functions. Neuroepigenetic studies demonstrate environmental factors also influence complex phenotypes by affecting gene expression regulation. To evaluate the mechanism of environmental influence on cognitive abilities, we examined if epigenetic regulation of dopaminergic genes plays a role in cognition. Using a DNA methylation profiling microarray, we used a monozygotic (MZ) twin difference design to evaluate if co-twin differences in methylation of CpG sites near six dopaminergic genes predicted differences in response inhibition and memory performance. Studying MZ twins allows us to assess if environmentally driven differences in methylation affect differences in phenotype while controlling for the influence of genotype and shared family environment. Response inhibition was assessed with the flanker task and short-term and working memory were assessed with digit span recall. We found MZ co-twin differences in DRD4 gene methylation predicted differences in short-term memory. MZ differences in COMT, DBH, DAT1, DRD1, and DRD2 gene methylation predicted differences in response inhibition. Taken together, findings suggest methylation status of dopaminergic genes may influence cognitive functions in a dissociable manner. Our results highlight the importance of the epigenome and environment, over and above the influence of genotype, in supporting complex cognitive functions.

Experiences of Trans Women and Two-Spirit Persons Accessing Women-Specific Health and Housing Services in a Downtown Neighborhood of Vancouver, Canada.

PURPOSE: Little is known about trans womens' experiences accessing gender-segregated health and housing services, particularly services for marginalized individuals living in poverty. As such, we conducted a qualitative investigation into experiences of accessing women-specific health and housing services among trans women and two-spirit persons in a downtown neighborhood of Vancouver, Canada. METHODS: Between June 2012 and May 2013 interviews were conducted with 32 trans women and two-spirit individuals who had accessed women-specific health and/or housing services. Participants were recruited from four open prospective cohorts of sex workers and individuals who use drugs. Interview data were analyzed using a participatory analysis approach with two participants who were hired as research assistants. RESULTS: Participants were generally able to access women-specific services in the neighborhood. However, there were reports of discrimination related to gender identity, discrimination based on gender expression (e.g., requirement of a feminine gender expression), and lack of staff intervention in harassment from other service users. CONCLUSION: Trans women and two-spirit persons in our study relied upon services for their health and safety and, therefore, exclusion from women-specific services had potentially severe adverse consequences such as homelessness and sexual violence. Recommendations to improve accessibility, including policy development and procedural recommendations, are put forth.

Next-generation profiling to identify the molecular etiology of Parkinson dementia.

OBJECTIVE: We sought to determine the underlying cortical gene expression changes associated with Parkinson dementia using a next-generation RNA sequencing approach. METHODS: In this study, we used RNA sequencing to evaluate differential gene expression and alternative splicing in the posterior cingulate cortex from neurologically normal control patients, patients with Parkinson disease, and patients with Parkinson disease with dementia. RESULTS: Genes overexpressed in both disease states were involved with an immune response, whereas shared underexpressed genes functioned in signal transduction or as components of the cytoskeleton. Alternative splicing analysis produced a pattern of immune and RNA-processing disturbances. CONCLUSIONS: Genes with the greatest degree of differential expression did not overlap with genes exhibiting significant alternative splicing activity. Such variation indicates the importance of broadening expression studies to include exon-level changes because there can be significant differential splicing activity with potential structural consequences, a subtlety that is not detected when examining differential gene expression alone, or is underrepresented with probe-limited array technology.

Truncations of xyloglucan xylosyltransferase 2 provide insights into the roles of the N- and C-terminus.

Xyloglucan is the most abundant hemicellulose in the primary cell wall of dicotyledonous plants. In Arabidopsis, three xyloglucan xylosyltransferases, XXT1, XXT2, and XXT5, participate in xylosylation of the xyloglucan backbone. Despite the importance of these enzymes, there is a lack of information on their structure and the critical residues required for substrate binding and transferase activity. In this study, the roles of different domains of XX2 in protein expression and catalytic activity were investigated by constructing a series of N- and C-terminal truncations. XXT2 with an N-terminal truncation of 31 amino acids after the predicted transmembrane domain showed the highest protein expression, but truncations of more than 31 residues decreased protein expression and catalytic activity. XXT2 constructs with C-terminal truncations showed increased protein expression but decreased activity, particularly for truncations of 44 or more amino acids. Site-directed mutagenesis was also used to investigate six positively charged residues near the C-terminus and found that four of the mutants showed decreased enzymatic activity. We conclude that the N- and C-termini of XXT2 have important roles in protein folding and enzymatic activity: the stem region (particularly the N-terminus of the catalytic domain) is critical for protein folding and the C-terminus is essential for enzymatic activity but not for protein folding.

A homology model of Xyloglucan Xylosyltransferase 2 reveals critical amino acids involved in substrate binding.

In dicotyledonous plants, xyloglucan (XyG) is the most abundant hemicellulose of the primary cell wall. The enzymes involved in XyG biosynthesis have been identified through reverse-genetics and activity was characterized by heterologous expression. Currently, there is no information on the atomic structures or amino acids involved in activity or substrate binding of any of the Golgi-localized XyG biosynthetic enzymes. A homology model of the xyloglucan xylosyltransferase 2 (XXT2) catalytic domain was built on the basis of the crystal structure of A64Rp. Molecular dynamics simulations revealed that the homology model retains the glycosyltransferase (GT)-A fold of the template structure used to build the homology model indicating that XXT2 likely has a GT-A fold. According to the XXT2 homology model, six amino acids (Phe204, Lys207, Asp228, Ser229, Asp230, His378) were selected and their contribution in catalytic activity was investigated. Site-directed mutagenesis studies show that Asp228, Asp230 and His378 are critical for XXT2 activity and are predicted to be involved in coordination of manganese ion. Lys207 was also found to be critical for protein activity and the homology model indicates a critical role in substrate binding. Additionally, Phe204 mutants have less of an impact on XXT2 activity with the largest effect when replaced with a polar residue. This is the first study that investigates the amino acids involved in substrate binding of the XyG-synthesizing xylosyltransferases and contributes to the understanding of the mechanisms of polysaccharide-synthesizing GTs and XyG biosynthesis.

Enzymatic Activity of Xyloglucan Xylosyltransferase 5.

Xyloglucan, the most abundant hemicellulosic component of the primary cell wall of flowering plants, is composed of a ß-(1,4)-glucan backbone decorated with d-xylosyl residues. Three xyloglucan xylosyltransferases (XXTs) participate in xyloglucan biosynthesis in Arabidopsis (Arabidopsis thaliana). Two of these, XXT1 and XXT2, have been shown to be active in vitro, whereas the catalytic activity of XXT5 has yet to be demonstrated. By optimizing XXT2 expression in a prokaryotic system and in vitro activity assay conditions, we demonstrate that nonglycosylated XXT2 lacking its cytosolic amino-terminal and transmembrane domain displays high catalytic activity. Using this optimized procedure for the expression of XXT5, we report, to our knowledge for the first time, that recombinant XXT5 shows enzymatic activity in vitro, although at a significantly slower rate than XXT1 and XXT2. Kinetic analysis showed that XXT5 has a 7-fold higher Km and 9-fold lower kcat compared with XXT1 and XXT2. Activity assays using XXT5 in combination with XXT1 or XXT2 indicate that XXT5 is not specific for their products. In addition, mutagenesis experiments showed that the in vivo function and in vitro catalytic activity of XXT5 require the aspartate-serine-aspartate motif. These results demonstrate that XXT5 is a catalytically active xylosyltransferase involved in xylosylation of the xyloglucan backbone.

SMG1 identified as a regulator of Parkinson's disease-associated alpha-synuclein through siRNA screening.

Synucleinopathies are a broad class of neurodegenerative disorders characterized by the presence of intracellular protein aggregates containing α-synuclein protein. The aggregated α-synuclein protein is hyperphosphorylated on serine 129 (S129) compared to the unaggregated form of the protein. While the precise functional consequences of S129 hyperphosphorylation are still being clarified, numerous in vitro and in vivo studies suggest that S129 phosphorylation is an early event in α-synuclein dysfunction and aggregation. Identifying the kinases and phosphatases that regulate this critical phosphorylation event may ultimately prove beneficial by allowing pharmacological mitigation of synuclein dysfunction and toxicity in Parkinson's disease and other synucleinopathies. We report here the development of a high-content, fluorescence-based assay to quantitate levels of total and S129 phosphorylated α-synuclein protein. We have applied this assay to conduct high-throughput loss-of-function screens with siRNA libraries targeting 711 known and predicted human kinases and 206 phosphatases. Specifically, knockdown of the phosphatidylinositol 3-kinase related kinase SMG1 resulted in significant increases in the expression of pS129 phosphorylated α-synuclein (p-syn). Moreover, SMG1 protein levels were significantly reduced in brain regions with high p-syn levels in both dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD). These findings suggest that SMG1 may play an important role in increased α-synuclein pathology during the course of PDD, DLB, and possibly other synucleinopathies.

Welfare policymaking and intersections of race, ethnicity, and gender in U.S. state legislatures.

Welfare policy in the American states has been shaped profoundly by race, ethnicity, and representation. Does gender matter as well? Focusing on state welfare reform in the mid-1990s, we test hypotheses derived from two alternative approaches to incorporating gender into the study of representation and welfare policymaking. An additive approach, which assumes gender and race/ethnicity are distinct and independent, suggests that female state legislators­regardless of race/ethnicity­will mitigate the more restrictive and punitive aspects of welfare reform, much like their African American and Latino counterparts do. In contrast, an intersectional approach, which highlights the overlapping and interdependent nature of gender and race/ethnicity, suggests that legislative women of color will have the strongest countervailing effect on state welfare reform­stronger than that of other women or men of color. Our empirical analyses suggest an intersectional approach yields a more accurate understanding of gender, race/ethnicity, and welfare politics in the states.

Triggered release of therapeutic antibodies from nanodiamond complexes.

Recent reports have revealed that detonation nanodiamonds (NDs) can serve as efficient, biocompatible, and versatile drug delivery platforms. Consequently, further investigations exploring additional therapeutic applications are warranted. Current limitations associated with the non-specific nature of intravenous drugs limit the potential of certain pharmacological agents. One such treatment that could benefit from a stable delivery platform is antibody (Ab) therapy. Determination of Ab adsorption and desorption to a ND surface was subsequently examined using the transforming growth factor ß (TGF-ß) antibody as a model therapeutic. ND-Ab complexes were found to be stable in water through enzyme-linked immunosorbent assays (ELISAs), UV-vis spectroscopy and TEM, with no Ab released after ten days. Released Abs were detected in extreme pH solutions (3.5), DMEM (+) serum with pH levels ranging from 4 to 10.5, and inorganic saline solutions. Preserved activity of Abs released in DMEM (+) serum was confirmed using an ELISA. These results suggest ND-Ab complexes are synthesized and stabilized in water and are triggered to release active Abs upon exposure to physiological conditions.

Natural product derivatives with bactericidal activity against Gram-positive pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis.

We have shown that the intentional engineering of a natural product biosynthesis pathway is a useful way to generate stereochemically complex scaffolds for use in the generation of combinatorial libraries that capture the structural features of both natural products and synthetic compounds. Analysis of a prototype library based upon nonactic acid lead to the discovery of triazole-containing nonactic acid analogs, a new structural class of antibiotic that exhibits bactericidal activity against drug resistant, Gram-positive pathogens including Staphylococcus aureus and Enterococcus faecalis.

Mixing and compatibility guide for commonly used aerosolized medications.

PURPOSE: A mixing and compatibility guide for commonly used aerosolized medications was developed. SUMMARY: Compatibility guides for injectable drugs are available as a reference for pharmacists, nurses, and medical personnel. These charts are commonly used in hospitals and other health care institutions and provide a quick, easy reference for compatibility of frequently used intravenous medications. Respiratory therapists are frequently directed to administer various aerosolized medications and are often faced with the challenge of uncertain compatibility of these drugs when mixed together. However, there appear to be limited data regarding the compatibility of these aerosolized admixtures. After a careful review of the literature, a compatibility chart was developed that should provide significant value to pharmacists, nurses, and respiratory therapists who administer aerosolized medications. The authors of a recently published evaluation of the compatibility of common inhalation solutions summarized their findings in a concise table. This table served as a template to develop a more comprehensive mixing and compatibility guide in the form of an easy-to-use reference chart, which includes additional agents, compatibility references on the chart, and compatibility information for pharmacists, nurses, physicians, and respiratory therapists. CONCLUSION: A compatibility guide for aerosolized medications was developed for use by staff who administer these agents.

Alternating pattern of stereochemistry in the nonactin macrocycle is required for antibacterial activity and efficient ion binding.

Nonactin is a polyketide antibiotic produced by Streptomyces griseus ETH A7796 and is an ionophore that is selective for K(+) ions. It is a cyclic tetraester generated from two monomers of (+)-nonactic acid and two of (-)-nonactic acid, arranged (+)-(-)-(+)-(-) so that nonactin has S4 symmetry and is achiral. To understand why achiral nonactin is the naturally generated diastereoisomer, we generated two alternate diastereoisomers of nonactin, one prepared solely from (+)-nonactic acid and one prepared solely from (-)-nonactic acid, referred to here as 'all-(+)-nonactin' and 'all-(-)-nonactin', respectively. Both non-natural diastereoisomers were 500-fold less active against gram positive organisms than nonactin confirming that the natural stereochemistry is necessary for biological activity. We used isothermal calorimetry to obtain the K(a), DeltaG, DeltaH, and DeltaS of formation for the K(+), Na(+), and NH(4)(+) complexes of nonactin and all-(-)-nonactin; the natural diastereoisomer bound K(+) 880-fold better than all-(-)-nonactin. A picrate partitioning assay confirmed that all-(-)-nonactin, unlike nonactin, could not partition K(+) ions into organic solvent. To complement the thermodynamic data we used a simple model system to show that K(+) transport was facilitated by nonactin but not by all-(-)-nonactin. Modeling of the K(+) complexes of nonactin and all-(-)-nonactin suggested that poor steric interactions in the latter complex precluded tight binding to K(+). Overall, the data show that both enantiomers of nonactic acid are needed for the formation of a nonactin diastereoisomer that can act as an ionophore and has antibacterial activity.