Cavitation in soft matter

Cavitation is the sudden, unstable expansion of a void or bubble within a liquid or solid subjected to a negative hydrostatic stress. Cavitation rheology is a field emerging from the development of a suite of materials characterization, damage quantification, and therapeutic techniques that exploit the physical principles of cavitation. Cavitation rheology is inherently complex and broad in scope with wide-ranging applications in the biology, chemistry, materials, and mechanics communities. This perspective aims to drive collaboration among these communities and guide discussion by defining a common core of high-priority goals while highlighting emerging opportunities in the field of cavitation rheology. A brief overview of the mechanics and dynamics of cavitation in soft matter is presented. This overview is followed by a discussion of the overarching goals of cavitation rheology and an overview of common experimental techniques. The larger unmet needs and challenges of cavitation in soft matter are then presented alongside specific opportunities for researchers from different disciplines to contribute to the field

Cross-Platform Mechanical Characterization of Lung Tissue

Published data on the mechanical strength and elasticity of lung tissue is widely variable, primarily due to differences in how testing was conducted across individual studies. This makes it extremely difficult to find a benchmark modulus of lung tissue when designing synthetic extracellular matrices (ECMs). To address this issue, we tested tissues from various areas of the lung using multiple characterization techniques, including micro-indentation, small amplitude oscillatory shear (SAOS), uniaxial tension, and cavitation rheology. We report the sample preparation required and data obtainable across these unique but complimentary methods to quantify the modulus of lung tissue. We highlight cavitation rheology as a new method, which can measure the modulus of intact tissue with precise spatial control, and reports a modulus on the length scale of typical tissue heterogeneities. Shear rheology, uniaxial, and indentation testing require heavy sample manipulation and destruction; however, cavitation rheology can be performed in situ across nearly all areas of the lung with minimal preparation. The Young’s modulus of bulk lung tissue using micro-indentation (1.4±0.4 kPa), SAOS (3.3±0.5 kPa), uniaxial testing (3.4±0.4 kPa), and cavitation rheology (6.1±1.6 kPa) were within the same order of magnitude, with higher values consistently reported from cavitation, likely due to our ability to keep the tissue intact. Although cavitation rheology does not capture the non-linear strains revealed by uniaxial testing and SAOS, it provides an opportunity to measure mechanical characteristics of lung tissue on a microscale level on intact tissues. Overall, our study demonstrates that each technique has independent benefits, and each technique revealed unique mechanical features of lung tissue that can contribute to a deeper understanding of lung tissue mechanics

Evaluation of Typhoid Conjugate Vaccine Effectiveness in Ghana (TyVEGHA) Using a Cluster-Randomized Controlled Phase IV Trial: Trial Design and Population Baseline Characteristics.

Typhoid fever remains a significant health problem in sub-Saharan Africa, with incidence rates of >100 cases per 100,000 person-years of observation. Despite the prequalification of safe and effective typhoid conjugate vaccines (TCV), some uncertainties remain around future demand. Real-life effectiveness data, which inform public health programs on the impact of TCVs in reducing typhoid-related mortality and morbidity, from an African setting may help encourage the introduction of TCVs in high-burden settings. Here, we describe a cluster-randomized trial to investigate population-level protection of TYPBAR-TCV®, a Vi-polysaccharide conjugated to a tetanus-toxoid protein carrier (Vi-TT) against blood-culture-confirmed typhoid fever, and the synthesis of health economic evidence to inform policy decisions. A total of 80 geographically distinct clusters are delineated within the Agogo district of the Asante Akim region in Ghana. Clusters are randomized to the intervention arm receiving Vi-TT or a control arm receiving the meningococcal A conjugate vaccine. The primary study endpoint is the total protection of Vi-TT against blood-culture-confirmed typhoid fever. Total, direct, and indirect protection are measured as secondary outcomes. Blood-culture-based enhanced surveillance enables the estimation of incidence rates in the intervention and control clusters. Evaluation of the real-world impact of TCVs and evidence synthesis improve the uptake of prequalified/licensed safe and effective typhoid vaccines in public health programs of high burden settings. This trial is registered at the Pan African Clinical Trial Registry, accessible at Pan African Clinical Trials Registry (ID: PACTR202011804563392)

Evaluation of Typhoid Conjugate Vaccine Effectiveness in Ghana (TyVEGHA) Using a Cluster-Randomized Controlled Phase IV Trial: Trial Design and Population Baseline Characteristics.

Typhoid fever remains a significant health problem in sub-Saharan Africa, with incidence rates of >100 cases per 100,000 person-years of observation. Despite the prequalification of safe and effective typhoid conjugate vaccines (TCV), some uncertainties remain around future demand. Real-life effectiveness data, which inform public health programs on the impact of TCVs in reducing typhoid-related mortality and morbidity, from an African setting may help encourage the introduction of TCVs in high-burden settings. Here, we describe a cluster-randomized trial to investigate population-level protection of TYPBAR-TCV®, a Vi-polysaccharide conjugated to a tetanus-toxoid protein carrier (Vi-TT) against blood-culture-confirmed typhoid fever, and the synthesis of health economic evidence to inform policy decisions. A total of 80 geographically distinct clusters are delineated within the Agogo district of the Asante Akim region in Ghana. Clusters are randomized to the intervention arm receiving Vi-TT or a control arm receiving the meningococcal A conjugate vaccine. The primary study endpoint is the total protection of Vi-TT against blood-culture-confirmed typhoid fever. Total, direct, and indirect protection are measured as secondary outcomes. Blood-culture-based enhanced surveillance enables the estimation of incidence rates in the intervention and control clusters. Evaluation of the real-world impact of TCVs and evidence synthesis improve the uptake of prequalified/licensed safe and effective typhoid vaccines in public health programs of high burden settings. This trial is registered at the Pan African Clinical Trial Registry, accessible at Pan African Clinical Trials Registry (ID: PACTR202011804563392)

The genomic epidemiology of multi-drug resistant invasive non-typhoidal Salmonella in selected sub-Saharan African countries

Funder: Swedish International Development Cooperation Agency (SIDA)Funder: Government of Republic of KoreaFunder: US Centers for Disease Control and PreventionBackground: Invasive non-typhoidal Salmonella (iNTS) is one of the leading causes of bacteraemia in sub-Saharan Africa. We aimed to provide a better understanding of the genetic characteristics and transmission patterns associated with multi-drug resistant (MDR) iNTS serovars across the continent. Methods: A total of 166 iNTS isolates collected from a multi-centre surveillance in 10 African countries (2010–2014) and a fever study in Ghana (2007–2009) were genome sequenced to investigate the geographical distribution, antimicrobial genetic determinants and population structure of iNTS serotypes–genotypes. Phylogenetic analyses were conducted in the context of the existing genomic frameworks for various iNTS serovars. Population-based incidence of MDR-iNTS disease was estimated in each study site. Results: Salmonella Typhimurium sequence-type (ST) 313 and Salmonella Enteritidis ST11 were predominant, and both exhibited high frequencies of MDR; Salmonella Dublin ST10 was identified in West Africa only. Mutations in the gyrA gene (fluoroquinolone resistance) were identified in S. Enteritidis and S. Typhimurium in Ghana; an ST313 isolate carrying blaCTX-M-15 was found in Kenya. International transmission of MDR ST313 (lineage II) and MDR ST11 (West African clade) was observed between Ghana and neighbouring West African countries. The incidence of MDR-iNTS disease exceeded 100/100 000 person-years-of-observation in children aged <5 years in several West African countries. Conclusions: We identified the circulation of multiple MDR iNTS serovar STs in the sampled sub-Saharan African countries. Investment in the development and deployment of iNTS vaccines coupled with intensified antimicrobial resistance surveillance are essential to limit the impact of these pathogens in Africa

Global diversity and antimicrobial resistance of typhoid fever pathogens : insights from a meta-analysis of 13,000 Salmonella Typhi genomes

DATA AVAILABILITY : All data analysed during this study are publicly accessible. Raw Illumina sequence reads have been submitted to the European Nucleotide Archive (ENA), and individual sequence accession numbers are listed in Supplementary file 2. The full set of n=13,000 genome assemblies generated for this study are available for download from FigShare: https://doi.org/10.26180/21431883. All assemblies of suitable quality (n=12,849) are included as public data in the online platform Pathogenwatch (https://pathogen.watch). The data are organised into collections, which each comprise a neighbour-joining phylogeny annotated with metadata, genotype, AMR determinants, and a linked map. Each contributing study has its own collection, browsable at https://pathogen.watch/collections/all?organismId= 90370. In addition, we have provided three large collections, each representing roughly a third of the total dataset presented in this study: Typhi 4.3.1.1 (https://pathogen.watch/collection/ 2b7mp173dd57-clade-4311), Typhi lineage 4 (excluding 4.3.1.1) (https://pathogen.watch/collection/ wgn6bp1c8bh6-clade-4-excluding-4311), and Typhi lineages 0-3 (https://pathogen.watch/collection/ 9o4bpn0418n3-clades-0-1-2-and-3). In addition, users can browse the full set of Typhi genomes in Pathogenwatch and select subsets of interest (e.g. by country, genotype, and/or resistance) to generate a collection including neighbour-joining tree for interactive exploration.SUPPLEMENTARY FILES : Available at https://elifesciences.org/articles/85867/figures#content. SUPPLEMENTARY FILE 1. Details of local ethical approvals provided for studies that were unpublished at the time of contributing data to this consortium project. Most data are now published, and the citations for the original studies are provided here. National surveillance programs in Chile (Maes et al., 2022), Colombia (Guevara et al., 2021), France, New Zealand, and Nigeria (Ikhimiukor et al., 2022b) were exempt from local ethical approvals as these countries allow sharing of non-identifiable pathogen sequence data for surveillance purposes. The US CDC Internal Review Board confirmed their approval was not required for use in this project (#NCEZID-ARLT- 10/ 20/21-fa687). SUPPLEMENTARY FILE 2. Line list of 13,000 genomes included in the study. SUPPLEMENTARY FILE 3. Source information recorded for genomes included in the study. ^Indicates cases included in the definition of ‘assumed acute illness’. SUPPLEMENTARY FILE 4. Summary of genomes by country. SUPPLEMENTARY FILE 5. Genotype frequencies per region (N, %, 95% confidence interval; annual and aggregated, 2010–2020). SUPPLEMENTARY FILE 6. Genotype frequencies per country (N, %, 95% confidence interval; annual and aggregated, 2010–2020). SUPPLEMENTARY FILE 7. Antimicrobial resistance (AMR) frequencies per region (N, %, 95% confidence interval; aggregated 2010–2020). SUPPLEMENTARY FILE 8. Antimicrobial resistance (AMR) frequencies per country (N, %, 95% confidence interval; annual and aggregated, 2010–2020). SUPPLEMENTARY FILE 9. Laboratory code master list. Three letter laboratory codes assigned by the consortium.BACKGROUND : The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). METHODS : This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. RESULTS : Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal ‘sentinel’ surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. CONCLUSIONS : The consortium’s aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies.Fellowships from the European Union (funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council.https://elifesciences.org/am2024Medical MicrobiologySDG-03:Good heatlh and well-bein

QUANTIFYING BRAIN MECHANICS AND RESPONSE TO CAVITATION- INDUCED MILD TRAUMATIC BRAIN INJURY

Cavitation, or the formation and collapse of bubbles, is an important phenomenon to study in soft tissues since cavitation is a damage mechanism implicated in both concussive and blast-associated traumatic brain injury (TBI). More than 1.7 million people suffer from TBI in the U.S. every year, and 5.3 million suffer from TBI-related disabilities. Brain mechanics play an essential role in the propagation of cavitation-related damage in vivo, but the heterogeneous, complex nature of brain tissues makes it particularly difficult to characterize. I use cavitation to quantify brain mechanics and measure cavitation-related tissue and cellular damage in mild TBI. I use needle-induced cavitation (NIC) to create a single bubble in ex vivo mouse brain at specific locations and measure the pressure associated with a cavitation event, which is used to calculate a localized modulus. Local and distant cavitation damage indicates that cavitation sometimes expands through fracture along interfaces between regions. I use my experimental NIC fracture data with hydraulic fracture models to estimate brain tissue fracture energy, which has never been measured in intact brain tissue and will aid in understanding how cavitation damage propagates through brain. There is a lack of TBI models that relate injury forces to macroscale tissue damage and brain function at the cellular level. We use NIC as a mild TBI model in the hippocampus to measure the impact of injury on synaptic signaling and astrocyte specific extracellular matrix remodeling. Using patch-clamp electrophysiology, we demonstrate that injury in the hippocampus temporarily decreases synaptic activity in a cannabinoid 1 receptor-dependent manner. Further, we show that NIC induces an increase in astrocyte activation and upregulation of astrocyte secreted extracellular matrix proteins associated with neural repair 72 hours after injury. NIC provides a valuable tool to study real time neuronal response to small- scale injuries and understand how mild TBI impacts neural function at the cellular level in the seconds, minutes, and days following injury. This research lays the groundwork to unravel cellular mechanisms post-TBI to develop treatments that promote neural repair in response to brain injury and prevent neurodegeneration for concussion and blast wave victims

Cavitation Induced Fracture of Intact Brain Tissue

Nonpenetrating traumatic brain injuries (TBI) are linked to cavitation. The structural organization of the brain makes it particularly susceptible to tears and fractures from these cavitation events, but limitations in existing characterization methods make it difficult to understand the relationship between fracture and cavitation in this tissue. More broadly, fracture energy is an important, yet often overlooked, mechanical property of all soft tissues. We combined needle-induced cavitation (NIC) with hydraulic fracture models to induce and quantify fracture in intact brains at precise locations. We report here the first measurements of the fracture energy of intact brain tissue that range from 1.5 to 8.9 J/m2, depending on the location in the brain and the model applied. We observed that fracture consistently occurs along interfaces between regions of brain tissue, which allow cavitation-related damage to propagate several millimeters away from the initial injury site. Quantifying the forces necessary to fracture brain and other soft tissues is critical for understanding how impact and blast waves damage tissue in vivo and has implications for the design of protective gear and tissue engineering

Whole genome sequence analysis of Salmonella Typhi provides evidence of phylogenetic linkage between cases of typhoid fever in Santiago, Chile in the 1980s and 2010-2016.

Typhoid fever epidemiology was investigated rigorously in Santiago, Chile during the 1980s, when Salmonella enterica serovar Typhi (S. Typhi) caused seasonal, hyperendemic disease. Targeted interventions reduced the annual typhoid incidence rates from 128-220 cases/105 population occurring between 1977-1984 to <8 cases/105 from 1992 onwards. As such, Santiago represents a contemporary example of the epidemiologic transition of an industrialized city from amplified hyperendemic typhoid fever to a period when typhoid is no longer endemic. We used whole genome sequencing (WGS) and phylogenetic analysis to compare the genotypes of S. Typhi cultured from acute cases of typhoid fever occurring in Santiago during the hyperendemic period of the 1980s (n = 74) versus the nonendemic 2010s (n = 80) when typhoid fever was rare. The genotype distribution between "historical" (1980s) isolates and "modern" (2011-2016) isolates was similar, with genotypes 3.5 and 2 comprising the majority of isolations, and 73/80 (91.3%) of modern isolates matching a genotype detected in the 1980s. Additionally, phylogenomically 'ancient' genotypes 1.1 and 1.2.1, uncommon in the global collections, were also detected in both eras, with a notable rise amongst the modern isolates. Thus, genotypes of S. Typhi causing acute illness in the modern nonendemic era match the genotypes circulating during the hyperendemic 1980s. The persistence of historical genotypes may be explained by chronic typhoid carriers originally infected during or before the 1980s