Inappropriate antimicrobial usage is a key driver of antimicrobial resistance (AMR). Low- and middle-income countries (LMICs) are disproportionately burdened by AMR and young children are especially ...vulnerable to infections with AMR-bearing pathogens. The impact of antibiotics on the microbiome, selection, persistence, and horizontal spread of AMR genes is insufficiently characterized and understood in children in LMICs. This systematic review aims to collate and evaluate the available literature describing the impact of antibiotics on the infant gut microbiome and resistome in LMICs.
In this systematic review, we searched the online databases MEDLINE (1946 to 28 January 2023), EMBASE (1947 to 28 January 2023), SCOPUS (1945 to 29 January 2023), WHO Global Index Medicus (searched up to 29 January 2023), and SciELO (searched up to 29 January 2023). A total of 4,369 articles were retrieved across the databases. Duplicates were removed resulting in 2,748 unique articles. Screening by title and abstract excluded 2,666 articles, 92 articles were assessed based on the full text, and 10 studies met the eligibility criteria that included human studies conducted in LMICs among children below the age of 2 that reported gut microbiome composition and/or resistome composition (AMR genes) following antibiotic usage. The included studies were all randomized control trials (RCTs) and were assessed for risk of bias using the Cochrane risk-of-bias for randomized studies tool. Overall, antibiotics reduced gut microbiome diversity and increased antibiotic-specific resistance gene abundance in antibiotic treatment groups as compared to the placebo. The most widely tested antibiotic was azithromycin that decreased the diversity of the gut microbiome and significantly increased macrolide resistance as early as 5 days posttreatment. A major limitation of this study was paucity of available studies that cover this subject area. Specifically, the range of antibiotics assessed did not include the most commonly used antibiotics in LMIC populations.
In this study, we observed that antibiotics significantly reduce the diversity and alter the composition of the infant gut microbiome in LMICs, while concomitantly selecting for resistance genes whose persistence can last for months following treatment. Considerable heterogeneity in study methodology, timing and duration of sampling, and sequencing methodology in currently available research limit insights into antibiotic impacts on the microbiome and resistome in children in LMICs. More research is urgently needed to fill this gap in order to better understand whether antibiotic-driven reductions in microbiome diversity and selection of AMR genes place LMIC children at risk for adverse health outcomes, including infections with AMR-bearing pathogens.
The fungal family Clavicipitaceae includes plant symbionts and parasites that produce several psychoactive and bioprotective alkaloids. The family includes grass symbionts in the epichloae clade ...(Epichloë and Neotyphodium species), which are extraordinarily diverse both in their host interactions and in their alkaloid profiles. Epichloae produce alkaloids of four distinct classes, all of which deter insects, and some-including the infamous ergot alkaloids-have potent effects on mammals. The exceptional chemotypic diversity of the epichloae may relate to their broad range of host interactions, whereby some are pathogenic and contagious, others are mutualistic and vertically transmitted (seed-borne), and still others vary in pathogenic or mutualistic behavior. We profiled the alkaloids and sequenced the genomes of 10 epichloae, three ergot fungi (Claviceps species), a morning-glory symbiont (Periglandula ipomoeae), and a bamboo pathogen (Aciculosporium take), and compared the gene clusters for four classes of alkaloids. Results indicated a strong tendency for alkaloid loci to have conserved cores that specify the skeleton structures and peripheral genes that determine chemical variations that are known to affect their pharmacological specificities. Generally, gene locations in cluster peripheries positioned them near to transposon-derived, AT-rich repeat blocks, which were probably involved in gene losses, duplications, and neofunctionalizations. The alkaloid loci in the epichloae had unusual structures riddled with large, complex, and dynamic repeat blocks. This feature was not reflective of overall differences in repeat contents in the genomes, nor was it characteristic of most other specialized metabolism loci. The organization and dynamics of alkaloid loci and abundant repeat blocks in the epichloae suggested that these fungi are under selection for alkaloid diversification. We suggest that such selection is related to the variable life histories of the epichloae, their protective roles as symbionts, and their associations with the highly speciose and ecologically diverse cool-season grasses.
Abstract This clinical report proposes a digital workflow using 2-dimensional (2D) digital photographs, a 3D extraoral facial scan, and cone beam computed tomography (CBCT) volumetric data to create ...a 3D virtual patient with craniofacial hard tissue, remaining dentition (including surrounding intraoral soft tissue), and the realistic appearance of facial soft tissue at an exaggerated smile under static conditions. The 3D virtual patient was used to assist the virtual diagnostic tooth arrangement process, providing patient with a pleasing preoperative virtual smile design that harmonized with facial features. The 3D virtual patient was also used to gain patient’s pretreatment approval (as a communication tool), design a prosthetically driven surgical plan for computer-guided implant surgery, and fabricate the computer-aided design and computer-aided manufacturing (CAD-CAM) interim prostheses.
Color changes in a graphite electrode as a function of lithiation, controlled by the voltage as shown below.
We describe the first direct
in situ measurements of Li transport in an operating cell. ...Motion of the lithiation front in the graphite electrode suggests that transport could be controlled by liquid-phase diffusion. The electrochemical (current–voltage) data are successfully modeled with a diffusion equation that contains no material or microstructural information. The model is only qualitatively successful in predicting observed Li transport rate data, suggesting that microstructural information is required and that the actual process is more complex than simply diffusion. The technique can provide data for studying Li plating and Li dendrite growth, both of which can cause battery degradation.
Microplastics are an emerging concern for the health of marine ecosystems. In the southeastern US, the filter-feeding Eastern oyster, Crassostrea virginica, is susceptible to microplastic ingestion. ...We quantified the distribution of microplastics within adult oysters (harvestable size >7.5 cm) from 28 reefs throughout a rural estuary with limited riverine inputs (St. Catherines Sound, Georgia). To determine which variables best predict microplastic concentration in oysters, we also quantified oyster recruitment, distance to ocean, fetch, and water body width. Oysters averaged 0.72 microplastic particles per individual (0.18 particles per gram wet mass); microfragments and microplastics were equally abundant. Although microplastic concentrations were low, multivariate models identified a positive effect of water body width on the site-level concentration of plastic microfibers; average microfragment length was affected by fetch. Our work informs a growing understanding of microplastic distribution in coastal estuaries, providing an important rural contrast to the urbanized estuaries that have been examined.
•Microplastic concentrations in Crassostrea virginica were low in a rural estuary.•Two plastic components—microfibers and microfragments—found at similar abundances.•Water body width correlated positively with microfiber abundance in oysters.•Fetch correlated positively with the size of microfragments in oysters.
Late-phase clinical trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumors at clinical doses. We conducted ...a clinical study integrating measurement of markers of systemic metabolism, dynamic FDG-PET-CT, transcriptomics, and metabolomics at paired time points to profile the bioactivity of metformin in primary breast cancer. We show metformin reduces the levels of mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumors. Two tumor groups are identified with distinct metabolic responses, an OXPHOS transcriptional response (OTR) group for which there is an increase in OXPHOS gene transcription and an FDG response group with increased 18-FDG uptake. Increase in proliferation, as measured by a validated proliferation signature, suggested that patients in the OTR group were resistant to metformin treatment. We conclude that mitochondrial response to metformin in primary breast cancer may define anti-tumor effect.
Display omitted
•A pharmacodynamic window study of metformin in patients with breast cancer•Metformin increases 18-FDG flux in primary breast cancer•Two distinct metabolic responses to metformin are identified in tumors•Tumors that upregulate OXPHOS genes show an increase in proliferation score
Using dynamic PET imaging, metabolomics, and transcriptomics in breast cancer patients, Lord et al. find that metformin increases 18-FDG flux into tumors and activates mitochondrial metabolism genes. Two distinct metabolic responses are observed and linked to differing proliferation signatures, suggesting that a reactive increase in OXPHOS is linked to metformin resistance.
Tumor hypoxia fuels an aggressive tumor phenotype and confers resistance to anticancer treatments. We conducted a clinical trial to determine whether the antimalarial drug atovaquone, a known ...mitochondrial inhibitor, reduces hypoxia in non-small cell lung cancer (NSCLC).
Patients with NSCLC scheduled for surgery were recruited sequentially into two cohorts: cohort 1 received oral atovaquone at the standard clinical dose of 750 mg twice daily, while cohort 2 did not. Primary imaging endpoint was change in tumor hypoxic volume (HV) measured by hypoxia PET-CT. Intercohort comparison of hypoxia gene expression signatures using RNA sequencing from resected tumors was performed.
Thirty patients were evaluable for hypoxia PET-CT analysis, 15 per cohort. Median treatment duration was 12 days. Eleven (73.3%) atovaquone-treated patients had meaningful HV reduction, with median change -28% 95% confidence interval (CI), -58.2 to -4.4. In contrast, median change in untreated patients was +15.5% (95% CI, -6.5 to 35.5). Linear regression estimated the expected mean HV was 55% (95% CI, 24%-74%) lower in cohort 1 compared with cohort 2 (
= 0.004), adjusting for cohort, tumor volume, and baseline HV. A key pharmacodynamics endpoint was reduction in hypoxia-regulated genes, which were significantly downregulated in atovaquone-treated tumors. Data from multiple additional measures of tumor hypoxia and perfusion are presented. No atovaquone-related adverse events were reported.
This is the first clinical evidence that targeting tumor mitochondrial metabolism can reduce hypoxia and produce relevant antitumor effects at the mRNA level. Repurposing atovaquone for this purpose may improve treatment outcomes for NSCLC.
In eukaryotes, the ubiquitous and abundant members of the 90 kilodalton heat-shock protein (hsp90) chaperone family facilitate the folding and conformational changes of a broad array of proteins ...important in cell signaling, proliferation, and survival. Here we describe the effects of nucleotides on the structure of full-length HtpG, the Escherichia coli hsp90 ortholog. By electron microscopy, the nucleotide-free, AMPPNP bound, and ADP bound states of HtpG adopt completely distinct conformations. Structural characterization of nucleotide-free and ADP bound HtpG was extended to higher resolution by X-ray crystallography. In the absence of nucleotide, HtpG exhibits an “open” conformation in which the three domains of each monomer present hydrophobic elements into the large cleft formed by the dimer. By contrast, ADP binding drives dramatic conformational changes that allow these hydrophobic elements to converge and shield each other from solvent, suggesting a mechanism by which nucleotides could control client protein binding and release.
•The HEALing Communities Study relies on data-driven decision-making by communities.•Community-tailored dashboards display opioid overdose death data and related measures.•Dashboards are co-created ...by researchers and community stakeholders.•Access to timely data can benefit other public health issues and health disparities.
With opioid misuse, opioid use disorder (OUD), and opioid overdose deaths persisting at epidemic levels in the U.S., the largest implementation study in addiction research—the HEALing Communities Study (HCS)—is evaluating the impact of the Communities That Heal (CTH) intervention on reducing opioid overdose deaths in 67 disproportionately affected communities from four states (i.e., “sites”). Community-tailored dashboards are central to the CTH intervention’s mandate to implement a community-engaged and data-driven process. These dashboards support a participating community’s decision-making for selection and monitoring of evidence-based practices to reduce opioid overdose deaths.
A community-tailored dashboard is a web-based set of interactive data visualizations of community-specific metrics. Metrics include opioid overdose deaths and other OUD-related measures, as well as drivers of change of these outcomes in a community. Each community-tailored dashboard is a product of a co-creation process between HCS researchers and stakeholders from each community. The four research sites used a varied set of technical approaches and solutions to support the scientific design and CTH intervention implementation. Ongoing evaluation of the dashboards involves quantitative and qualitative data on key aspects posited to shape dashboard use combined with website analytics.
The HCS presents an opportunity to advance how community-tailored dashboards can foster community-driven solutions to address the opioid epidemic. Lessons learned can be applied to inform interventions for public health concerns and issues that have disproportionate impact across communities and populations (e.g., racial/ethnic and sexual/gender minorities and other marginalized individuals).
ClinicalTrials.gov (NCT04111939)
PDF
