In vitro evaluation of using ceftazidime/avibactam against carbapenem-resistant Acinetobacter baumannii.

OBJECTIVE: Carbapenem-resistant Acinetobacter baumannii (CRAB) is a global concern as effective treatments are very limited. We previously used a modified susceptibility testing approach to predict growth suppression in carbapenem-resistant Enterobacterales, but there are uncertainties about the generalizability of the model. The objective of this study is to verify if a similar approach can be extended to CRAB. METHOD: A clinical isolate of CRAB resistant to ceftazidime/avibactam (CAZ/AVI, MIC=32/4 mg/L) was examined. CAZ susceptibility was determined using increasing concentrations of AVI (0-64 mg/L), and MIC reduction was characterized with a sigmoid inhibitory maximum effect (Emax) model. The effectiveness of CAZ/AVI was validated in a hollow fiber infection model (HFIM) over 72 hours, using simulated unbound serum / epithelial lining fluid (ELF) exposures of 2.5 g over 2 hours every 8 hours. Baseline inocula of approximately 5.5 log CFU/mL were examined. RESULTS: An AVI concentration-dependent reduction in CAZ MIC was observed (r2=0.99). Ceftazidime MIC was dramatically reduced from 512 mg/L (no AVI) to 32 mg/L (AVI=4 mg/L), and further to 8 mg/L (AVI=16 mg/L). Pharmacokinetic simulations were satisfactory in the HFIM (r2>0.96). Bacterial suppression was observed > 24 hours with the serum exposure, but not that from the ELF. CONCLUSION: Using multiple AVI concentrations within the clinically relevant range, our susceptibility testing approach could have better insights of treatment outcome for infections caused by CRAB. This could potentially lead to effective intervention(s) overlooked by conventional susceptibility testing method. This case highlights the importance of site-specific drug exposures on determining treatment outcome.

Health Related Quality of life Amongst Refugees: A meta Analysis of Studies Using the SF-36.

The health of refugees has been widely documented, as has the impact of a range of factors throughout the migration journey from being exposed to violence to the impacts of immigration detention. This study adds to our understanding of health-related quality of life amongst refugees and asylum seekers by evaluating health-related quality of life as measured by the Short-Form 36 (SF-36) Health Survey using meta-analysis. The aims of this study were to (1) provide a summary and overview of health-related quality of life (as measured by the SF-36), including the extent to which this varies and (2) explore the factors that influence health-related quality of life (as measured by the SF-36) amongst refugees and asylum seekers. A search was undertaken of MEDLINE, CINAHL, PSYCINFO and SCOPUS, returning 3965 results. Papers were included if they sampled refugees (or asylum seeker or those with refugee-like experiences) and used the SF-36 (or its variants) as an outcome measure. Mean scores and standard deviations were pooled using a random effects model. The pooled sample size was 18,418. The pooled mean scores for the SF-36 physical summary measures was 54.99 (95% CI 46.01-63.99), while the mental health summary measure was 52.39 (95% CI 43.35-61.43). The pooled mean scores for each of the sub-scales ranged from 49.6 (vitality) to 65.54 (physical functioning). High heterogeneity was found between both summary measures and all sub-scales. In comparison to SF-36 results from general populations in high and middle income countries, these results suggest that refugee quality of life is generally poorer. However, this varied substantially between studies. One issue that is not well clarified by this review are the factors that contributed to health-related quality of life.

Myocardial inflammation after elective percutaneous coronary intervention.

OBJECTIVE: It is well established that inflammation plays a central role in the sequelae of percutaneous coronary intervention (PCI). Most of the studies to date have focused on the inflammatory reaction affecting the vessel wall after angioplasty. However, there are data to suggest that the main foci of inflammation are in fact in the myocardium beyond the vessel wall. The main aim of our study was to investigate the myocardial inflammation after elective, uncomplicated angioplasty with cardiovascular magnetic resonance (CMR) enhanced by ultrasmall superparamagnetic particles of iron oxide (USPIO) and also blood biomarkers. This is the first study to report such findings after elective angioplasty. METHODS: We assessed patients undergoing elective angioplasty for stable angina with USPIO-enhanced CMR two weeks after the procedure and compared the results with those of healthy volunteers who constituted the control group. We excluded patients with previous myocardial infarction, previous PCI, or any significant inflammatory condition. All patients also underwent blood biomarker testing at baseline (pre-PCI), 4 h, and two weeks later. RESULTS: A total of five patients and three controls were scanned. There was a small absolute increase, although statistically insignificant, in R2∗ values in the PCI area compared with either remote myocardium from the same patient (PCI area [left anterior descending artery (LAD)] vs remote myocardium [circumflex area]: 19.3 ± 10.8 vs 9.2 ± 7.9, p = 0.1) or healthy myocardium from healthy volunteers (PCI area [LAD] vs healthy myocardium [LAD]: 19.3 ± 10.8 vs 12.2 ± 4.0, p = 0.2). PTX3 and IL-6 were the only biomarkers that changed significantly from baseline to 4 h and 2 weeks. Both biomarkers peaked at 4 h. CONCLUSION: We used USPIO-enhanced CMR for the first time to assess myocardial inflammation after elective, uncomplicated PCI. We have demonstrated a small numerical increase in inflammation, which was not statistically significant. This study opens the way for future studies to use this method as a means to target inflammation.

Transoceanic pathogen transfer in the age of sail and steam.

In the centuries following Christopher Columbus's 1492 voyage to the Americas, transoceanic travel opened unprecedented pathways in global pathogen circulation. Yet no biological transfer is a single, discrete event. We use mathematical modeling to quantify historical risk of shipborne pathogen introduction, exploring the respective contributions of journey time, ship size, population susceptibility, transmission intensity, density dependence, and pathogen biology. We contextualize our results using port arrivals data from San Francisco, 1850 to 1852, and from a selection of historically significant voyages, 1492 to 1918. We offer numerical estimates of introduction risk across historically realistic ranges of journey time and ship population size, and show that both steam travel and shipping regimes that involved frequent, large-scale movement of people substantially increased risk of transoceanic pathogen circulation.

Investigating the Feasibility and Performance of Hybrid Overmolded UHMWPE 3D-Printed PEEK Structural Composites for Orthopedic Implant Applications: A Pilot Study.

Ultra-high-molecular-weight polyethylene (UHMWPE) components for orthopedic implants have historically been integrated into metal backings by direct-compression molding (DCM). However, metal backings are costly, stiffer than cortical bone, and may be associated with medical imaging distortion and metal release. Hybrid-manufactured DCM UHMWPE overmolded additively manufactured polyetheretherketone (PEEK) structural components could offer an alternative solution, but are yet to be explored. In this study, five different porous topologies (grid, triangular, honeycomb, octahedral, and gyroid) and three surface feature sizes (low, medium, and high) were implemented into the top surface of digital cylindrical specimens prior to being 3D printed in PEEK and then overmolded with UHMWPE. Separation forces were recorded as 1.97-3.86 kN, therefore matching and bettering the historical industry values (2-3 kN) recorded for DCM UHMWPE metal components. Infill topology affected failure mechanism (Type 1 or 2) and obtained separation forces, with shapes having greater sidewall numbers (honeycomb-60%) and interconnectivity (gyroid-30%) through their builds, tolerating higher transmitted forces. Surface feature size also had an impact on applied load, whereby those with low infill-%s generally recorded lower levels of performance vs. medium and high infill strategies. These preliminary findings suggest that hybrid-manufactured structural composites could replace metal backings and produce orthopedic implants with high-performing polymer-polymer interfaces.

The importance of 'place' and its influence on rural and remote health and well-being in Australia.

AIMS: This article explores the crucial role of 'place' as an ecological, social and cultural determinant of health and well-being, with a focus on the benefits and challenges of living rurally and remotely in Australia. CONTEXT: The health system, including health promotion, can contribute actively to creating supportive environments and places that foster health and well-being among individuals residing in rural and remote locations. For First Nations peoples, living on Country, and caring for Country and its people, are core to Indigenous worldviews, and the promotion of Aboriginal and Torres Strait Islander health and well-being. Their forced removal from ancestral lands has been catastrophic. For all people, living in rural and remote areas can deliver an abundance of the elements that contribute to a 'liveable' community, including access to fresh air, green and blue space, agricultural employment, tight-knit communities, a sense of belonging and identity, and social capital. However, living remotely also can limit access to employment opportunities, clean water, affordable food, reliable transport, social infrastructure, social networks and preventive health services. 'Place' is a critical enabler of maintaining a healthy life. However, current trends have led to a reduction in local services and resources, and increased exposure to the impacts of climate change. APPROACH: This commentary suggests ideas and strategies through which people in rural and remote locations can strengthen the liveability, resilience and identity of their communities, and regain access to essential health care and health promotion services and resources. CONCLUSION: Recommended strategies include online access to education, employment and telehealth; flexible provision of social infrastructure; and meaningful and responsive university-health service partnerships.

Computationally-accelerated prediction of polyester-melamine coatings degradation to design sustainable organically-coated steels for outdoor applications.

This work implements computational chemistry as a screening tool to aid in the coating and resin formulation process. Conceptual Density Functional theory (DFT) reactivity descriptors like the global chemical hardness and the dual descriptor Fukui function identify the tendency of polyester-melamine coatings to undergo electrophilic and nucleophilic attack during weathering exposure. Coatings were subjected to natural and accelerated weathering tests, with periodic infrared spectroscopy, colour, and gloss measurements to assess for the degree of changes brought about through photodegradation. It was found that the number of attack sites in the atomistic models, when weighted as a function of the polyester : crosslinker ratio, effectively ranked the degradation of different coating systems upon weathering. This ranking matched the performance of the coatings subjected to both accelerated and natural weathering, showing affinity with naturally weathered samples, and matching in all areas. The results were shown to demonstrate significant correlation, being over R 2 = 0.8 for 7 of the 8 measured areas, and greater than R 2 = 0.9 for 6 compared areas. Comparison of computationally derived and experimentally acquired results showed that the performance of naturally weathered samples was matched across all areas by the computational rankings, showing superior correlation than that observed between natural and accelerated weathering tests. This indicates that the method utilised within this work provides a novel, cost-effective alternative to evaluate the projected performance of selected coatings, while enabling a computationally accelerated platform for more sustainable low-degradation coatings without the requirement of long-term weathering tests.

Man versus machine: cost and carbon emission savings of 4G-connected Artificial Intelligence technology for classifying species in camera trap images.

Timely and accurate detection and identification of species are crucial for monitoring wildlife for conservation and management. Technological advances, including connectivity of camera traps to mobile phone networks and artificial intelligence (AI) algorithms for automated species identification, can potentially improve the timeliness and accuracy of species detection and identification. Adoption of this new technology, however, is often seen as cost-prohibitive as it has been difficult to calculate the cost savings or qualitative benefits over the life of the program. We developed a decision tool to quantify potential cost savings associated with incorporating the use of mobile phone network connectivity and AI technologies into monitoring programs. Using a feral cat eradication program as a case study, we used our decision tool to quantify technology-related savings in costs and carbon emissions, and compared the accuracy of AI species identification to that of experienced human observers. Over the life of the program, AI technology yielded cost savings of $0.27 M and when coupled with mobile phone network connectivity, AI saved $2.15 M and 115,838 kg in carbon emissions, with AI algorithms outperforming human observers in both speed and accuracy. Our case study demonstrates how advanced technologies can improve accuracy and cost-effectiveness and improve monitoring program efficiencies.

The microbial composition of pancreatic ductal adenocarcinoma: A systematic review of 16S rRNA gene sequencing.

BACKGROUND: Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), continues to pose a significant clinical and scientific challenge. The most significant finding of recent years is that PDAC tumours harbour their specific microbiome, which differs amongst tumour entities and is distinct from healthy tissue. This review aims to evaluate and summarise all PDAC studies that have used the next-generation technique, 16S rRNA gene amplicon sequencing within each bodily compartment. As well as establishing a causal relationship between PDAC and the microbiome. MATERIALS AND METHODS: This systematic review was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. A comprehensive search strategy was designed, and 1727 studies were analysed. RESULTS: In total, 38 studies were selected for qualitative analysis and summarised significant PDAC bacterial signatures. Despite the growing amount of data provided, we are not able to state a universal 16S rRNA gene microbial signature that can be used for PDAC screening. This is most certainly due to the heterogeneity of the presentation of results, lack of available datasets and the intrinsic selection bias between studies. CONCLUSION: Several key studies have begun to shed light on causality and the influence the microbiome constituents and their produced metabolites could play in tumorigenesis and influencing outcomes. The challenge in this field is to shape the available microbial data into targetable signatures. Making sequenced data readily available is critical, coupled with the coordinated standardisation of data and the need for consensus guidelines in studies investigating the microbiome in PDAC.

Detection of Leptospira kirschneri in a short-beaked common dolphin (Delphinus delphis delphis) stranded off the coast of southern California, USA.

BACKGROUND: Pathogenic Leptospira species are globally important zoonotic pathogens capable of infecting a wide range of host species. In marine mammals, reports of Leptospira have predominantly been in pinnipeds, with isolated reports of infections in cetaceans. CASE PRESENTATION: On 28 June 2021, a 150.5 cm long female, short-beaked common dolphin (Delphinus delphis delphis) stranded alive on the coast of southern California and subsequently died. Gross necropsy revealed multifocal cortical pallor within the reniculi of the kidney, and lymphoplasmacytic tubulointerstitial nephritis was observed histologically. Immunohistochemistry confirmed Leptospira infection, and PCR followed by lfb1 gene amplicon sequencing suggested that the infecting organism was L.kirschneri. Leptospira DNA capture and enrichment allowed for whole-genome sequencing to be conducted. Phylogenetic analyses confirmed the causative agent was a previously undescribed, divergent lineage of L.kirschneri. CONCLUSIONS: We report the first detection of pathogenic Leptospira in a short-beaked common dolphin, and the first detection in any cetacean in the northeastern Pacific Ocean. Renal lesions were consistent with leptospirosis in other host species, including marine mammals, and were the most significant lesions detected overall, suggesting leptospirosis as the likely cause of death. We identified the cause of the infection as L.kirschneri, a species detected only once before in a marine mammal - a northern elephant seal (Mirounga angustirostris) of the northeastern Pacific. These findings raise questions about the mechanism of transmission, given the obligate marine lifestyle of cetaceans (in contrast to pinnipeds, which spend time on land) and the commonly accepted view that Leptospira are quickly killed by salt water. They also raise important questions regarding the source of infection, and whether it arose from transmission among marine mammals or from terrestrial-to-marine spillover. Moving forward, surveillance and sampling must be expanded to better understand the extent to which Leptospira infections occur in the marine ecosystem and possible epidemiological linkages between and among marine and terrestrial host species. Generating Leptospira genomes from different host species will yield crucial information about possible transmission links, and our study highlights the power of new techniques such as DNA enrichment to illuminate the complex ecology of this important zoonotic pathogen.

The FAM13A Long Isoform Regulates Cilia Movement and Co-ordination in Airway Mucociliary Transport.

SNPs in the FAM13A locus are amongst the most commonly reported risk alleles associated with chronic obstructive pulmonary disease (COPD) and other respiratory diseases, however the physiological role of FAM13A is unclear. In humans, two major protein isoforms are expressed at the FAM13A locus: 'long' and 'short', but their functions remain unknown, partly due to a lack of isoform conservation in mice. We performed in-depth characterisation of organotypic primary human airway epithelial cell subsets and show that multiciliated cells predominantly express the FAM13A long isoform containing a putative N-terminal Rho GTPase activating protein (RhoGAP) domain. Using purified proteins, we directly demonstrate RhoGAP activity of this domain. In Xenopus laevis, which conserve the long isoform, Fam13a-deficiency impaired cilia-dependent embryo motility. In human primary epithelial cells, long isoform deficiency did not affect multiciliogenesis but reduced cilia co-ordination in mucociliary transport assays. This is the first demonstration that FAM13A isoforms are differentially expressed within the airway epithelium, with implications for the assessment and interpretation of SNP effects on FAM13A expression levels. We also show that the long FAM13A isoform co-ordinates cilia-driven movement, suggesting that FAM13A risk alleles may affect susceptibility to respiratory diseases through deficiencies in mucociliary clearance. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Urban development pattern's influence on extreme rainfall occurrences.

Growing urban population and the distinct strategies to accommodate them lead to diverse urban development patterns worldwide. While local evidence suggests the presence of urban signatures in rainfall anomalies, there is limited understanding of how rainfall responds to divergent urban development patterns worldwide. Here we unveil a divergence in the exposure to extreme rainfall for 1790 inland cities globally, attributable to their respective urban development patterns. Cities that experience compact development tend to witness larger increases in extreme rainfall frequency over downtown than their rural surroundings, while the anomalies in extreme rainfall frequency diminish for cities with dispersed development. Convection-permitting simulations further suggest compact urban footprints lead to more pronounced urban-rural thermal contrasts and aerodynamic disturbances. This is directly responsible for the divergent rainfall responses to urban development patterns. Our analyses offer significant insights pertaining to the priorities and potential of city-level efforts to mitigate the emerging climate-related hazards, particularly for countries experiencing rapid urbanization.

PDB NextGen Archive: centralizing access to integrated annotations and enriched structural information by the Worldwide Protein Data Bank.

The Protein Data Bank (PDB) is the global repository for public-domain experimentally determined 3D biomolecular structural information. The archival nature of the PDB presents certain challenges pertaining to updating or adding associated annotations from trusted external biodata resources. While each Worldwide PDB (wwPDB) partner has made best efforts to provide up-to-date external annotations, accessing and integrating information from disparate wwPDB data centers can be an involved process. To address this issue, the wwPDB has established the PDB Next Generation (or NextGen) Archive, developed to centralize and streamline access to enriched structural annotations from wwPDB partners and trusted external sources. At present, the NextGen Archive provides mappings between experimentally determined 3D structures of proteins and UniProt amino acid sequences, domain annotations from Pfam, SCOP2 and CATH databases and intra-molecular connectivity information. Since launch, the PDB NextGen Archive has seen substantial user engagement with over 3.5 million data file downloads, ensuring researchers have access to accurate, up-to-date and easily accessible structural annotations. Database URL: http://www.wwpdb.org/ftp/pdb-nextgen-archive-site.

Biomaterials for immunomodulation in wound healing.

The substantial economic impact of non-healing wounds, scarring, and burns stemming from skin injuries is evident, resulting in a financial burden on both patients and the healthcare system. This review paper provides an overview of the skin's vital role in guarding against various environmental challenges as the body's largest protective organ and associated developments in biomaterials for wound healing. We first introduce the composition of skin tissue and the intricate processes of wound healing, with special attention to the crucial role of immunomodulation in both acute and chronic wounds. This highlights how the imbalance in the immune response, particularly in chronic wounds associated with underlying health conditions such as diabetes and immunosuppression, hinders normal healing stages. Then, this review distinguishes between traditional wound-healing strategies that create an optimal microenvironment and recent peptide-based biomaterials that modulate cellular processes and immune responses to facilitate wound closure. Additionally, we highlight the importance of considering the stages of wounds in the healing process. By integrating advanced materials engineering with an in-depth understanding of wound biology, this approach holds promise for reshaping the field of wound management and ultimately offering improved outcomes for patients with acute and chronic wounds.

Effects of Abaloparatide on Bone Mineral Density in Proximal Femoral Regions Corresponding to Arthroplasty Gruen Zones: A Study of Postmenopausal Women with Osteoporosis.

BACKGROUND: Low hip bone mineral density (BMD) in patients who undergo total hip arthroplasty (THA) increases the risk of periprosthetic fractures, implant instability, and other complications. Recently, emphasis has been placed on bone health optimization: treating low BMD prior to a planned orthopaedic implant procedure in an effort to normalize BMD and reduce the potential risk of future complications. Abaloparatide is a U.S. Food and Drug Administration-approved osteoanabolic agent for men and postmenopausal women with osteoporosis and a candidate drug for bone health optimization that, in addition to benefits at the spine, increases hip BMD and reduces nonvertebral fracture risk. We hypothesized that abaloparatide would improve BMD in proximal femoral regions surrounding a virtual THA stem. METHODS: This post hoc analysis obtained dual x-ray absorptiometry (DXA) hip scans from 500 randomly selected postmenopausal women with osteoporosis from the Phase-3 Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE, NCT01343004) study after 0, 6, and 18 months of abaloparatide (250 patients) or placebo (250 patients). Hip DXA scans underwent 3-dimensional (3D) modeling via 3D-Shaper, followed by virtual resection of the proximal femur and simulated placement of a tapered, flat-wedge hip stem that guided delineation of the Gruen zones that were fully (zones 1 and 7) or largely (zones 2 and 6) captured in the scanning region. Integral, cortical, and trabecular volumetric BMD, cortical thickness, and cortical surface BMD (the product of cortical volumetric BMD and cortical thickness) were determined for each zone. RESULTS: Compared with placebo, the abaloparatide group showed greater increases in integral volumetric BMD in all zones at months 6 and 18; cortical surface BMD in zones 1, 6, and 7 at month 6; cortical thickness, cortical volumetric BMD, and cortical surface BMD in all zones at month 18; and trabecular volumetric BMD in zones 1 and 7 at months 6 and 18. CONCLUSIONS: Abaloparatide increases BMD in proximal femoral regions that interact with and support femoral stems, suggesting that abaloparatide may have value for preoperative or potentially perioperative bone health optimization in patients with osteoporosis undergoing THA. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.