Development of Patient Safety Measures to Identify Inappropriate Diagnosis of Common Infections.

BACKGROUND: Inappropriate diagnosis of infections results in antibiotic overuse and may delay diagnosis of underlying conditions. Here we describe the development and characteristics of 2 safety measures of inappropriate diagnosis of urinary tract infection (UTI) and community-acquired pneumonia (CAP), the most common inpatient infections on general medicine services. METHODS: Measures were developed from guidelines and literature and adapted based on data from patients hospitalized with UTI and CAP in 49 Michigan hospitals and feedback from end-users, a technical expert panel (TEP), and a patient focus group. Each measure was assessed for reliability, validity, feasibility, and usability. RESULTS: Two measures, now endorsed by the National Quality Forum (NQF), were developed. Measure reliability (derived from 24 483 patients) was excellent (0.90 for UTI; 0.91 for CAP). Both measures had strong validity demonstrated through (a) face validity by hospital users, the TEPs, and patient focus group, (b) implicit case review (ĸ 0.72 for UTI; ĸ 0.72 for CAP), and (c) rare case misclassification (4% for UTI; 0% for CAP) due to data errors (<2% for UTI; 6.3% for CAP). Measure implementation through hospital peer comparison in Michigan hospitals (2017 to 2020) demonstrated significant decreases in inappropriate diagnosis of UTI and CAP (37% and 32%, respectively, P < .001), supporting usability. CONCLUSIONS: We developed highly reliable, valid, and usable measures of inappropriate diagnosis of UTI and CAP for hospitalized patients. Hospitals seeking to improve diagnostic safety, antibiotic use, and patient care should consider using these measures to reduce inappropriate diagnosis of CAP and UTI.

Removal from the wild endangers the once widespread long-tailed macaque.

In 2022, long-tailed macaques (Macaca fascicularis), a once ubiquitous primate species, was elevated to Endangered on the International Union for Conservation of Nature (IUCN) Red List of Threatened Species. In 2023, recognizing that the long-tailed macaque is threatened by multiple factors: (1) declining native habitats across Southeast Asia; (2) overutilization for scientific, commercial, and recreational purposes; (3) inadequate regulatory mechanisms; and (4) culling due to human-macaque conflicts, a petition for rulemaking was submitted to the United States Fish and Wildlife Service to add the species to the US Endangered Species Act, the nation's most effective law to protect at risk species. The long-tailed macaque remains unprotected across much of its geographical range despite the documented continual decline of the species and related sub-species and the recent IUCN reassessment. This commentary presents a review of the factors that have contributed to the dramatic decline of this keystone species and makes a case for raising the level of protection they receive.

Resilience of swine nasal microbiota to influenza A virus challenge in a longitudinal study.

Influenza A virus (IAV) is an important contributing pathogen of porcine respiratory disease complex (PRDC) infections. Evidence in humans has shown that IAV can disturb the nasal microbiota and increase host susceptibility to bacterial secondary infections. Few, small-scale studies have examined the impact of IAV infection on the swine nasal microbiota. To better understand the effects of IAV infection on the nasal microbiota and its potential indirect impacts on the respiratory health of the host, a larger, longitudinal study was undertaken to characterize the diversity and community composition of the nasal microbiota of pigs challenged with an H3N2 IAV. The microbiome of challenged pigs was compared with non-challenged animals over a 6-week period using 16S rRNA gene sequencing and analysis workflows to characterize the microbiota. Minimal changes to microbial diversity and community structure were seen between the IAV infected and control animals the first 10 days post-IAV infection. However, on days 14 and 21, the microbial populations were significantly different between the two groups. Compared to the control, there were several genera showing significant increases in abundance in the IAV group during acute infection, such as Actinobacillus and Streptococcus. The results here highlight areas for future investigation, including the implications of these changes post-infection on host susceptibility to secondary bacterial respiratory infections.

Experimental characterization of a shape optimized acoustic lens: Application to compact speakerphone design.

This work presents the shape optimization and subsequent experimental validation of an acoustic lens with application to a compact loudspeaker, such as found in commercial speakerphones. The shape optimization framework is based on a combined lumped parameter and boundary element method model using free form deformation geometry parameterization. To test the optimized design, the loudspeaker lens is three-dimensionally printed and experimentally characterized under anechoic conditions on a finite baffle with respect to its off-axis frequency response. The overall tendencies of the frequency responses agree well between measurement and simulations within the optimization frequency range and at low frequencies. The optimization process is applied to a model including acoustic lumped parameter approximations. The shortcomings of the assumptions made in the model are revealed by laser Doppler vibrometer measurements of the loudspeaker driver and modelling of the mechanical vibrations of the lens.

Ocean acidification alters the nutritional value of Antarctic diatoms.

Primary production in the Southern Ocean is dominated by diatom-rich phytoplankton assemblages, whose individual physiological characteristics and community composition are strongly shaped by the environment, yet knowledge on how diatoms allocate cellular energy in response to ocean acidification (OA) is limited. Understanding such changes in allocation is integral to determining the nutritional quality of diatoms and the subsequent impacts on the trophic transfer of energy and nutrients. Using synchrotron-based Fourier transform infrared microspectroscopy, we analysed the macromolecular content of selected individual diatom taxa from a natural Antarctic phytoplankton community exposed to a gradient of fCO2 levels (288-1263 µatm). Strong species-specific differences in macromolecular partitioning were observed under OA. Large taxa showed preferential energy allocation towards proteins, while smaller taxa increased both lipid and protein stores at high fCO2 . If these changes are representative of future Antarctic diatom physiology, we may expect a shift away from lipid-rich large diatoms towards a community dominated by smaller taxa, but with higher lipid and protein stores than their present-day contemporaries, a response that could have cascading effects on food web dynamics in the Antarctic marine ecosystem.

Trait dimensions in bacteria and archaea compared to vascular plants.

Bacteria and archaea have very different ecology compared to plants. One similarity, though, is that much discussion of their ecological strategies has invoked concepts such as oligotrophy or stress tolerance. For plants, so-called 'trait ecology'-strategy description reframed along measurable trait dimensions-has made global syntheses possible. Among widely measured trait dimensions for bacteria and archaea three main axes are evident. Maximum growth rate in association with rRNA operon copy number expresses a rate-yield trade-off that is analogous to the acquisitive-conservative spectrum in plants, though underpinned by different trade-offs. Genome size in association with signal transduction expresses versatility. Cell size has influence on diffusive uptake and on relative wall costs. These trait dimensions, and potentially others, offer promise for interpreting ecology. At the same time, there are very substantial differences from plant trait ecology. Traits and their underpinning trade-offs are different. Also, bacteria and archaea use a variety of different substrates. Bacterial strategies can be viewed both through the facet of substrate-use pathways, and also through the facet of quantitative traits such as maximum growth rate. Preliminary evidence shows the quantitative traits vary widely within substrate-use pathways. This indicates they convey information complementary to substrate use.

Phenotypic trait variability as an indication of adaptive capacity in a cosmopolitan marine diatom.

Determining the adaptive capacity of marine phytoplankton is important in predicting changes in phytoplankton responses to ocean warming. Phytoplankton may consist of high levels of standing phenotypic and genetic variability, the basis of rapid evolution; however, few studies have quantified trait variability within and amongst closely related diatom species. Using 35 clonal cultures of the ubiquitous marine diatom Leptocylindrus isolated from six locations, spanning 2000 km of the south-eastern Australian coastline, we found evidence of significant intraspecific morphological and metabolic trait variability, which for 8 of 9 traits (growth rate, biovolume, C:N, silica deposition, silica incorporation rate, chl-a, and photosynthetic efficiency under dark adapted, growth irradiance, and high-light adaptation) were greater within a species than between species. Moreover, only two traits revealed a latitudinal trend with strains isolated from lower latitudes showing significantly higher silicification rates and protein:lipid content compared to their higher latitude counterparts. These data mirror recent studies on diatom intraspecific genetic diversity, which has found comparable levels of genetic diversity at a single site to those thousands of kilometres apart, and provide evidence of a functional role of diatom diversity that will allow for rapid adaptation via ecological selection on standing variation in response to changing conditions.

Achieving a flat, wideband frequency response of a loudspeaker unit by numerical optimization with requirements on its directivity.

This paper demonstrates how significant improvement in frequency response and directivity of a loudspeaker may be obtained by optimizing the local properties of the materials for the diaphragm and surround. Performance is investigated as the considered frequency range and off-axis requirements are progressively expanded. The results are generated by optimizing the values and layout of stiffness, mass, and damping of both the speaker diaphragm and surround. This is accomplished using a density and gradient-based optimization technique in conjunction with a fully coupled finite element model of the loudspeaker and the surrounding acoustic domain. The targeted frequency range is from 600 Hz up to 10 kHz and the range for the directivity is from 0° to 30°. The results show that a completely flat on-axis response is achievable even for very broad frequency ranges and that a reasonably flat response over a wide directivity can be obtained as well. The results presented in this research assume that complete design and production freedom are available.

Azotides as Modular Peptide-Based Ligands for Asymmetric Lewis Acid Catalysis.

Synthesis of azotides and evaluation of these as ligands for enantioselective Lewis acid catalysis is reported. The ligands were readily prepared from the chiral pool of amino acids and perform well in the cobalt(II)-catalyzed formation of asymmetric hetero Diels-Alder adducts. A rational for the observed enantioselectivity and conversion rate supported by computational calculations is provided.

Orally Absorbed Cyclic Peptides.

Peptides and proteins are not orally bioavailable in mammals, although a few peptides are intestinally absorbed in small amounts. Polypeptides are generally too large and polar to passively diffuse through lipid membranes, while most known active transport mechanisms facilitate cell uptake of only very small peptides. Systematic evaluations of peptides with molecular weights above 500 Da are needed to identify parameters that influence oral bioavailability. Here we describe 125 cyclic peptides containing four to thirty-seven amino acids that are orally absorbed by mammals. Cyclization minimizes degradation in the gut, blood, and tissues by removing cleavable N- and C-termini and by shielding components from metabolic enzymes. Cyclization also folds peptides into bioactive conformations that determine exposure of polar atoms to solvation by water and lipids and therefore can influence oral bioavailability. Key chemical properties thought to influence oral absorption and bioavailability are analyzed, including molecular weight, octanol-water partitioning, hydrogen bond donors/acceptors, rotatable bonds, and polar surface area. The cyclic peptides violated to different degrees all of the limits traditionally considered to be important for oral bioavailability of drug-like small molecules, although fewer hydrogen bond donors and reduced flexibility generally favored oral absorption.

Seagrass rhizosphere microenvironment alters plant-associated microbial community composition.

The seagrass rhizosphere harbors dynamic microenvironments, where plant-driven gradients of O2 and dissolved organic carbon form microhabitats that select for distinct microbial communities. To examine how seagrass-mediated alterations of rhizosphere geochemistry affect microbial communities at the microscale level, we applied 16S rRNA amplicon sequencing of artificial sediments surrounding the meristematic tissues of the seagrass Zostera muelleri together with microsensor measurements of the chemical conditions at the basal leaf meristem (BLM). Radial O2 loss (ROL) from the BLM led to ∼ 300 µm thick oxic microzones, wherein pronounced decreases in H2 S and pH occurred. Significantly higher relative abundances of sulphate-reducing bacteria were observed around the meristematic tissues compared to the bulk sediment, especially around the root apical meristems (RAM; ∼ 57% of sequences). Within oxic microniches, elevated abundances of sulphide-oxidizing bacteria were observed compared to the bulk sediment and around the RAM. However, sulphide oxidisers within the oxic microzone did not enhance sediment detoxification, as rates of H2 S re-oxidation here were similar to those observed in a pre-sterilized root/rhizome environment. Our results provide novel insights into how chemical and microbiological processes in the seagrass rhizosphere modulate plant-microbe interactions potentially affecting seagrass health.

A multi-trait systems approach reveals a response cascade to bleaching in corals.

BACKGROUND: Climate change causes the breakdown of the symbiotic relationships between reef-building corals and their photosynthetic symbionts (genus Symbiodinium), with thermal anomalies in 2015-2016 triggering the most widespread mass coral bleaching on record and unprecedented mortality on the Great Barrier Reef. Targeted studies using specific coral stress indicators have highlighted the complexity of the physiological processes occurring during thermal stress, but have been unable to provide a clear mechanistic understanding of coral bleaching. RESULTS: Here, we present an extensive multi-trait-based study in which we compare the thermal stress responses of two phylogenetically distinct and widely distributed coral species, Acropora millepora and Stylophora pistillata, integrating 14 individual stress indicators over time across a simulated thermal anomaly. We found that key stress responses were conserved across both taxa, with the loss of symbionts and the activation of antioxidant mechanisms occurring well before collapse of the physiological parameters, including gross oxygen production and chlorophyll a. Our study also revealed species-specific traits, including differences in the timing of antioxidant regulation, as well as drastic differences in the production of the sulfur compound dimethylsulfoniopropionate during bleaching. Indeed, the concentration of this antioxidant increased two-fold in A. millepora after the corals started to bleach, while it decreased 70% in S. pistillata. CONCLUSIONS: We identify a well-defined cascading response to thermal stress, demarking clear pathophysiological reactions conserved across the two species, which might be central to fully understanding the mechanisms triggering thermally induced coral bleaching. These results highlight that bleaching is a conserved mechanism, but specific adaptations linked to the coral's antioxidant capacity drive differences in the sensitivity and thus tolerance of each coral species to thermal stress.

Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients.

Enhancing the oral bioavailability of peptide drug leads is a major challenge in drug design. As such, methods to address this challenge are highly sought after by the pharmaceutical industry. Here, we propose a strategy to identify appropriate amides for N-methylation using temperature coefficients measured by NMR to identify exposed amides in cyclic peptides. N-methylation effectively caps these amides, modifying the overall solvation properties of the peptides and making them more membrane permeable. The approach for identifying sites for N-methylation is a rapid alternative to the elucidation of 3D structures of peptide drug leads, which has been a commonly used structure-guided approach in the past. Five leucine-rich peptide scaffolds are reported with selectively designed N-methylated derivatives. In vitro membrane permeability was assessed by parallel artificial membrane permeability assay and Caco-2 assay. The most promising N-methylated peptide was then tested in vivo. Here we report a novel peptide (15), which displayed an oral bioavailability of 33% in a rat model, thus validating the design approach. We show that this approach can also be used to explain the notable increase in oral bioavailability of a somatostatin analog.

Dimethylsulfoniopropionate, superoxide dismutase and glutathione as stress response indicators in three corals under short-term hyposalinity stress.

Corals are among the most active producers of dimethylsulfoniopropionate (DMSP), a key molecule in marine sulfur cycling, yet the specific physiological role of DMSP in corals remains elusive. Here, we examine the oxidative stress response of three coral species (Acropora millepora, Stylophora pistillata and Pocillopora damicornis) and explore the antioxidant role of DMSP and its breakdown products under short-term hyposalinity stress. Symbiont photosynthetic activity declined with hyposalinity exposure in all three reef-building corals. This corresponded with the upregulation of superoxide dismutase and glutathione in the animal host of all three species. For the symbiont component, there were differences in antioxidant regulation, demonstrating differential responses to oxidative stress between the Symbiodinium subclades. Of the three coral species investigated, only A. millepora provided any evidence of the role of DMSP in the oxidative stress response. Our study reveals variability in antioxidant regulation in corals and highlights the influence life-history traits, and the subcladal differences can have on coral physiology. Our data expand on the emerging understanding of the role of DMSP in coral stress regulation and emphasizes the importance of exploring both the host and symbiont responses for defining the threshold of the coral holobiont to hyposalinity stress.

Microenvironment and phylogenetic diversity of Prochloron inhabiting the surface of crustose didemnid ascidians.

The cyanobacterium Prochloron didemni is primarily found in symbiotic relationships with various marine hosts such as ascidians and sponges. Prochloron remains to be successfully cultivated outside of its host, which reflects a lack of knowledge of its unique ecophysiological requirements. We investigated the microenvironment and diversity of Prochloron inhabiting the upper, exposed surface of didemnid ascidians, providing the first insights into this microhabitat. The pH and O2 concentration in this Prochloron biofilm changes dynamically with irradiance, where photosynthetic activity measurements showed low light adaptation (Ek ∼ 80 ± 7 µmol photons m(-2) s(-1)) but high light tolerance. Surface Prochloron cells exhibited a different fine structure to Prochloron cells from cloacal cavities in other ascidians, the principle difference being a central area of many vacuoles dissected by single thylakoids in the surface Prochloron. Cyanobacterial 16S rDNA pyro-sequencing of the biofilm community on four ascidians resulted in 433 operational taxonomic units (OTUs) where on average -85% (65-99%) of all sequence reads, represented by 136 OTUs, were identified as Prochloron via blast search. All of the major Prochloron-OTUs clustered into independent, highly supported phylotypes separate from sequences reported for internal Prochloron, suggesting a hitherto unexplored genetic variability among Prochloron colonizing the outer surface of didemnids.

Flexibility versus Rigidity for Orally Bioavailable Cyclic Hexapeptides.

Cyclic peptides and macrocycles have the potential to be membrane permeable and orally bioavailable, despite often not complying with the "rule of five" used in medicinal chemistry to guide the discovery of oral drugs. Here we compare solvent-dependent three-dimensional structures of three cyclic hexapeptides containing d-amino acids, prolines, and intramolecular hydrogen bonds. Conformational rigidity rather than flexibility resulted in higher membrane permeability, metabolic stability and oral bioavailability, consistent with less polar surface exposure to solvent and a reduced entropy penalty for transition between polar and nonpolar environments.

Oxic microshield and local pH enhancement protects Zostera muelleri from sediment derived hydrogen sulphide.

Seagrass is constantly challenged with transporting sufficient O2 from above- to belowground tissue via aerenchyma in order to maintain aerobic metabolism and provide protection against phytotoxins. Electrochemical microsensors were used in combination with a custom-made experimental chamber to analyse the belowground biogeochemical microenvironment of Zostera muelleri under changing environmental conditions. Measurements revealed high radial O2 release of up to 500 nmol O2 cm(-2) h(-1) from the base of the leaf sheath, maintaining a c. 300-µm-wide plant-mediated oxic microzone and thus protecting the vital meristematic regions of the rhizome from reduced phytotoxic metabolites such as hydrogen sulphide (H2S). H2S intrusion was prevented through passive diffusion of O2 to belowground tissue from leaf photosynthesis in light, as well as from the surrounding water column into the flow-exposed plant parts during darkness. Under water column hypoxia, high belowground H2S concentrations at the tissue surface correlated with the inability to sustain the protecting oxic microshield around the meristematic regions of the rhizome. We also found increased pH levels in the immediate rhizosphere of Z. muelleri, which may contribute to further detoxification of H2S through shifts in the chemical speciation of sulphide. Zostera muelleri can modify the geochemical conditions in its immediate rhizosphere, thereby reducing its exposure to H2S.

Improving on nature: making a cyclic heptapeptide orally bioavailable.

The use of peptides in medicine is limited by low membrane permeability, metabolic instability, high clearance, and negligible oral bioavailability. The prediction of oral bioavailability of drugs relies on physicochemical properties that favor passive permeability and oxidative metabolic stability, but these may not be useful for peptides. Here we investigate effects of heterocyclic constraints, intramolecular hydrogen bonds, and side chains on the oral bioavailability of cyclic heptapeptides. NMR-derived structures, amide H-D exchange rates, and temperature-dependent chemical shifts showed that the combination of rigidification, stronger hydrogen bonds, and solvent shielding by branched side chains enhances the oral bioavailability of cyclic heptapeptides in rats without the need for N-methylation.

Seasonal environmental transitions and metabolic plasticity in a sea-ice alga from an individual cell perspective.

Sea-ice microalgae are a key source of energy and nutrient supply to polar marine food webs, particularly during spring, prior to open-water phytoplankton blooms. The nutritional quality of microalgae as a food source depends on their biomolecular (lipid:protein:carbohydrate) composition. In this study, we used synchrotron-based Fourier transform infra-red microspectroscopy (s-FTIR) to measure the biomolecular content of a dominant sea-ice taxa, Nitzschia frigida, from natural land-fast ice communities throughout the Arctic spring season. Repeated sampling over six weeks from an inner (relatively stable) and an outer (relatively dynamic) fjord site revealed high intra-specific variability in biomolecular content, elucidating the plasticity of N. frigida to adjust to the dynamic sea ice and water conditions. Environmental triggers indicating the end of productivity in the ice and onset of ice melt, including nitrogen limitation and increased water temperature, drove an increase in lipid and fatty acids stores, and a decline in protein and carbohydrate content. In the context of climate change and the predicted Atlantification of the Arctic, dynamic mixing and abrupt warmer water advection could truncate these important end-of-season environmental shifts, causing the algae to be released from the ice prior to adequate lipid storage, influencing carbon transfer through the polar marine system.

Biomolecular profiles of Arctic sea-ice diatoms highlight the role of under-ice light in cellular energy allocation.

Arctic sea-ice diatoms fuel polar marine food webs as they emerge from winter darkness into spring. Through their photosynthetic activity they manufacture the nutrients and energy that underpin secondary production. Sea-ice diatom abundance and biomolecular composition vary in space and time. With climate change causing short-term extremes and long-term shifts in environmental conditions, understanding how and in what way diatoms adjust biomolecular stores with environmental perturbation is important to gain insight into future ecosystem energy production and nutrient transfer. Using synchrotron-based Fourier transform infrared microspectroscopy, we examined the biomolecular composition of five dominant sea-ice diatom taxa from landfast ice communities covering a range of under-ice light conditions during spring, in Svalbard, Norway. In all five taxa, we saw a doubling of lipid and fatty acid content when light transmitted to the ice-water interface was >5% but <15% (85%-95% attenuation through snow and ice). We determined a threshold around 15% light transmittance after which biomolecular synthesis plateaued, likely because of photoinhibitory effects, except for Navicula spp., which continued to accumulate lipids. Increasing under-ice light availability led to increased energy allocation towards carbohydrates, but this was secondary to lipid synthesis, whereas protein content remained stable. It is predicted that under-ice light availability will change in the Arctic, increasing because of sea-ice thinning and potentially decreasing with higher snowfall. Our findings show that the nutritional content of sea-ice diatoms is taxon-specific and linked to these changes, highlighting potential implications for future energy and nutrient supply for the polar marine food web.