Real-world experience of immune checkpoint inhibitors in patients with solid tumours in the Top End of the Northern Territory, Australia from 2016 to 2021: a retrospective observational cohort study.

BACKGROUND: Use of immune checkpoint inhibitors is growing, but clinical trial data may not apply to Indigenous patients or patients living in remote areas. AIMS: To provide real-world incidence of immune-related adverse events (irAE) in the Top End of the Northern Territory and compare incidence between demographic subgroups. METHODS: This retrospective, observational, cohort study collected data from electronic records of patients living in the Top End with solid organ cancer treated with immunotherapy between January 2016 and December 2021. The primary outcome was cumulative incidence of any-grade and severe irAE. Secondary outcomes were overall survival, treatment duration and reason for treatment discontinuation. RESULTS: Two hundred and twenty-six patients received immunotherapy. Forty-eight (21%) lived in a remote or very remote area, and 36 (16%) were Indigenous. Cumulative incidence of any-grade irAE was 54% (122/226 patients); incidence of severe irAE was 26% (59/226 patients). Rates were similar between Indigenous and non-Indigenous patients of any-grade (42% vs 56%, P = 0.11) and severe (11% vs 18%, P = 0.29) irAE. However, Indigenous patients had shorter treatment duration, more frequently discontinued treatment due to patient preference and appeared to have shorter median overall survival than non-Indigenous patients (17.1 vs 30.4 months; hazard ratio (HR) = 1.5, 95% confidence interval (CI) = 0.92-2.66). There was no difference in mortality between remote and urban patients (median overall survival 27.5 vs 30.2 months; HR = 1.1, 95% CI = 0.7-1.7). CONCLUSIONS: Rates of irAE in our cohort are comparable to those in the published literature. There was no significant difference in any-grade or severe irAE incidence observed between Indigenous and non-Indigenous patients.

The quaternary question: Determining allostery in spastin through dynamics classification learning and bioinformatics.

The nanomachine from the ATPases associated with various cellular activities superfamily, called spastin, severs microtubules during cellular processes. To characterize the functionally important allostery in spastin, we employed methods from evolutionary information, to graph-based networks, to machine learning applied to atomistic molecular dynamics simulations of spastin in its monomeric and the functional hexameric forms, in the presence or absence of ligands. Feature selection, using machine learning approaches, for transitions between spastin states recognizes all the regions that have been proposed as allosteric or functional in the literature. The analysis of the composition of the Markov State Model macrostates in the spastin monomer, and the analysis of the direction of change in the top machine learning features for the transitions, indicate that the monomer favors the binding of ATP, which primes the regions involved in the formation of the inter-protomer interfaces for binding to other protomer(s). Allosteric path analysis of graph networks, built based on the cross-correlations between residues in simulations, shows that perturbations to a hub specific for the pre-hydrolysis hexamer propagate throughout the structure by passing through two obligatory regions: the ATP binding pocket, and pore loop 3, which connects the substrate binding site to the ATP binding site. Our findings support a model where the changes in the terminal protomers due to the binding of ligands play an active role in the force generation in spastin. The secondary structures in spastin, which are found to be highly degenerative within the network paths, are also critical for feature transitions of the classification models, which can guide the design of allosteric effectors to enhance or block allosteric signaling.

Designing stable binary endohedral fullerene lattices.

Nanoparticle lattices and endohedral fullerenes have both been identified as potential building blocks for future electronic, magnetic and optical devices; here it is proposed that it could be possible to combine those concepts and design stable nanoparticle lattices composed from binary collections of endohedral fullerenes. The inclusion of an atom, for example Ca or F, within a fullerene cage is known to be accompanied by a redistribution of surface charge, whereby the cage can acquire either a negative (Ca) or positive (F) charge. From calculations involving a combination of van der Waals and many-body electrostatic interactions, it is predicted that certain binary combinations, for example a metal (A) and a halogen (B), could result in the formation of stable nanoparticle lattices with the familiar AB and AB2 stoichiometries. Much of the stability is due to Coulomb interactions, however, charge-induced and van der Waals interactions, which always enhance stability, are found to extend the range of charge on a cage over which lattices are stable. Some lattice types are shown to be three or four times more stable than an equivalent neutral C60 structure. An extension of the calculations to the fabrication of structures involving endohedral C84 is also discussed.

"She is courageous because she does not care what people think about her ": attitudes toward adolescent contraception use among Rwandan family planning providers and adult female modern contraceptive users.

INTRODUCTION: In Rwanda, only 20% of sexually active unmarried young women use family planning as compared to 64% of married women. Adolescence is an important time of growth and development that often includes the initiation of sexual activity. Sexually active adolescents need support in accessing contraceptive services to prevent negative health outcomes. In sub-Saharan Africa, the adolescent population represents a large share of the total population and that proportion is predicted to expand over time. Adolescent contraceptive needs have largely been unmet, and with growing numbers, there is increased potential for negative health sequelae. Due to the low use of contraception by adolescents in Rwanda, and the growing population of adolescents, this study aims to explore the perspectives of family planning providers and adult modern contraceptive users on adolescent contraceptive use. Inclusion of adult community members in the study is a unique contribution, as research on adolescent contraceptive use in sub-Saharan Africa relies primarily on perspectives from adolescents and family planning providers. METHODS: This qualitative study in 2018 utilized 32 in-depth interviews with modern contraceptive users and eight focus group discussions with family planning providers. Respondents were from Musanze and Nyamasheke districts in Rwanda, the districts with the highest and lowest modern contraceptive use among married women, respectively. Coding was conducted in Atlas.ti. RESULTS: Stigma regarding premarital sex results in barriers to adolescent access to contraceptive services. Family planning providers do provide services to adolescents; however, they often recommend secondary abstinence, offer a limited method selection, and accentuate risks associated with sexual activity and contraceptive use. Providers support adolescent clients by emphasizing the need for privacy, confidentiality, and expedient services, particularly through youth corners, which are spaces within health facilities designed to meet youth needs specifically. Modern contraceptive-using adult female community members advocate for youth access to contraception, however mothers have mixed comfort discussing sexual health with their own youth. CONCLUSION: To destigmatize premarital sexual activity, government efforts to initiate communication about this topic must occur at national and community levels with the goal of continued conversation within the family. The government should also train family planning providers and all health personnel interacting with youth on adolescent-friendly health services. Dialogue between community members and family planning providers about adolescent access to contraceptive services could also reduce barriers for adolescents due to community members' generally supportive views on adolescent contraceptive use. Efforts to engage adolescent caregivers in how to talk to youth about sex could also contribute to expanded use.

In Rwanda, youth who are having sex use family planning less than married women. This study involved asking family planning providers and adults what they think about youth using family planning. Data for this study was collected in 2018, and included 32 interviews with adult family planning users and eight group discussions with family planning providers in two areas of Rwanda. The findings show that Rwandans believe youth should not have sex before they are married. Family planning providers do provide youth with services; however, they often push stopping sexual activity, offer a smaller selection of family planning methods, and exaggerate risks associated with sex and family planning use. Family planning providers support youth by honoring their need for privacy, keeping their secrets, and providing fast services so fewer people see them at the clinic. Providers like to help adolescents in youth corners, which are special spaces within health facilities just for youth. Importantly, adult women who use family planning want youth in their community to be able to use family planning, too. In order to respond to the issues raised, the Rwandan government can start conversations in villages and more broadly about the need for youth to have access to family planning. The government should also teach family planning providers and anyone who comes into contact with youth to offer helpful and friendly services. Setting up spaces for adults to talk with family planning providers about youth access to family planning could also contribute to fewer barriers to services for adolescents.

" the availability of contraceptives is everywhere.": coordinated and integrated public family planning service delivery in Rwanda.

BACKGROUND: Contraceptive use in Rwanda tripled since 2005. This study aims to understand the role of coordinated and integrated public family planning service delivery in achieving this increase in contraceptive use in Rwanda. METHODS: This qualitative study in 2018 included eight focus group discussions with family planning providers and 32 in-depth interviews with experienced family planning users. RESULTS: Results indicate a well-coordinated public family planning service delivery system with community health workers and nurses filling different and complementary roles in meeting family planning client needs at the local level. In addition, integration of family planning into other maternal and child health services is the norm. CONCLUSIONS: The coordination and integration of family planning across both providers and services may help explain the rapid increase in Rwanda's contraceptive use and has potential applications for enhancing family planning service delivery in other settings.

Family planning use increased from 17 to 53% in Rwanda in between 2005 and 2015. The purpose of this study is to understand the roles of two types of family planning workers in providing family planning services, how those providers work together to achieve the goal to provide public services, and how the Rwandan health system includes family planning services in a variety of other types of health services. To achieve the study purpose, 32 women with experience using modern methods of contraception were interviewed. In addition, 88 providers participated in eight group discussions to discuss these topics. The results from the interviews and group discussions showed that family planning services are easy to access for Rwandans­due to two types of family planning providers filling different roles to assist Rwandans start and keep using family planning methods. Family planning services are included in services for pregnant, delivering, and postpartum mothers­as well as services for infants and children. These are all times when those adults using the services would also be in need of family planning services. The family planning service delivery team approach­as well as including family planning services in mother's and children's health services likely helps explain the increase in family planning use in Rwanda. Other nations might learn from Rwanda's service delivery approach to family planning to also increase access to family planning for their citizens.

Family planning providers and contraceptive users in Rwanda employ strategies to prevent discontinuation.

BACKGROUND: In Rwanda, nearly a third of contraceptive users discontinue within the first year of use. Family planning programs often focus more on recruitment of new users as opposed to maintaining use among current users. A focus on sustaining users and minimizing discontinuation is imperative for long-term family planning program success. This study explores the efforts providers and contraceptive users in Rwanda employ to prevent one of the greatest challenges to family planning programs: contraceptive discontinuation. METHODS: This was a qualitative study conducted in Rwanda between February and July 2018. It included eight focus group discussions with 88 family planning providers and 32 in-depth interviews with experienced modern contraceptive users. Data were collected in two districts with the highest (Musanze) and lowest (Nyamasheke) rates of contraceptive use. Data were analyzed using thematic content approach. RESULTS: Family planning providers in this study used the following strategies to prevent discontinuation: counseling new users on the potential for side effects and switching, reminding clients about appointments for resupply, as well as supporting dissatisfied users by providing counseling, medicine for side effects, and discussing options for switching methods. Users, on the other hand, employed the following strategies to prevent discontinuation: having an understanding that experiences of side effects vary by individuals, supporting peers to sustain use, persisting with use despite experiences of side effects, and switching methods. CONCLUSIONS: The strategies used by family planning providers and users in Rwanda to prevent discontinuation suggest the possibility of long-term sustained use of contraception in the country. Harnessing and supporting such strategies could contribute to sustaining or improving further contraceptive use in the country.

" the way we welcome them is how we will lead them to love family planning.": family planning providers in Rwanda foster compassionate relationships with clients despite workplace challenges.

BACKGROUND: Rwanda has markedly increased the nation's contraceptive use in a short period of time, tripling contraceptive prevalence in just 5 years between 2005 and 2010. An integral aspect of family planning programs is the interactions between family planning providers and clients. This study aims to understand the client-provider relationship in the Rwandan family planning program and to also examine barriers to those relationships. METHODS: This qualitative study in Rwanda utilized convenience sampling to include eight focus group discussions with family planning providers, both family planning nurses and community health workers, as well as in-depth interviews with 32 experienced modern contraceptive users. Study participants were drawn from the two districts in Rwanda with the highest and lowest modern contraceptive rates, Musanze and Nyamasheke, respectively Data analysis was guided by the thematic content approach, Atlas.ti 8 was utilized for coding the transcripts and collating the coding results, and Microsoft Excel for analyzing the data within code. RESULTS: Data analysis revealed that, despite workplace related challenges - including inadequate staffing, training, and resources, relationships between providers and clients are strong. Family planning providers work hard to understand, learn from, and support clients in their initiation and sustained use of contraceptives. CONCLUSION: Given the existing context of purposeful efforts on the part of family planning providers to build relationships with their clients, if the current level of government support for family planning service provision is enhanced, Rwanda will likely sustain many current users of contraception and engage even more Rwandans in contraceptive services in the future.

An examination of the barriers to and benefits from collaborative couple contraceptive use in Rwanda.

BACKGROUND: Supportive male involvement is strongly correlated with contraceptive use. In Rwanda, where the contraceptive prevalence rate among married women increased from 17 to 52% from 2005 to 2010, and stagnated at 53% in 2015, understanding the role of male partners in collaborative couple contraceptive use can help inform programs designed to further increase the use of contraception in Rwanda. METHODS: This study utilized qualitative methods in 2018, specifically 32 in-depth interviewers with mostly current users of modern contraceptive methods and eight focus group discussions with family planning providers-both family planning nurses and community health workers (CHWs). Respondents were from Musanze and Nyamasheke Districts, the districts with the highest and lowest modern contraceptive use, respectively, to explore the role of couple collaboration in family planning use in Rwanda. Data were analyzed using the thematic content approach in Atlas.ti (8). RESULTS: Findings demonstrate that some men are opposed to use of male methods of contraception, and some are opposed to any contraceptive use, which can lead to covert use. Women and providers prefer collaborative couple contraceptive use-as a result, providers advocate for and encourage male partner participation in contraceptive use. Women are most often burdened with seeking out information, initiating discussions, and sharing information discovered about contraceptive use with partners. Decision-making about contraceptive use, once discussed, can be collaborative and motivated by financial considerations. When couple contraceptive use is collaborative, benefits range from marital harmony to husband's support of sustained use through reminders about appointments, joint counseling, and support in managing side effects. CONCLUSION: Family planning providers at the community and clinic levels encourage collaborative contraceptive use among couples and some Rwandan couples communicate well about family planning use. Despite the positives, women are expected to source family planning information, share that information with their male partners, seek out family planning services, and use family planning. If more Rwandan male partners accepted use, used male methods of contraception, and participated even more in the work it takes to use family planning, the potential for sustained, and even enhanced, contraceptive use in Rwanda could be realized.

In vitro reconstruction and analysis of evolutionary variation of the tomato acylsucrose metabolic network.

Plant glandular secreting trichomes are epidermal protuberances that produce structurally diverse specialized metabolites, including medically important compounds. Trichomes of many plants in the nightshade family (Solanaceae) produce O-acylsugars, and in cultivated and wild tomatoes these are mixtures of aliphatic esters of sucrose and glucose of varying structures and quantities documented to contribute to insect defense. We characterized the first two enzymes of acylsucrose biosynthesis in the cultivated tomato Solanum lycopersicum. These are type I/IV trichome-expressed BAHD acyltransferases encoded by Solyc12g006330--or S. lycopersicum acylsucrose acyltransferase 1 (Sl-ASAT1)--and Solyc04g012020 (Sl-ASAT2). These enzymes were used--in concert with two previously identified BAHD acyltransferases--to reconstruct the entire cultivated tomato acylsucrose biosynthetic pathway in vitro using sucrose and acyl-CoA substrates. Comparative genomics and biochemical analysis of ASAT enzymes were combined with in vitro mutagenesis to identify amino acids that influence CoA ester substrate specificity and contribute to differences in types of acylsucroses that accumulate in cultivated and wild tomato species. This work demonstrates the feasibility of the metabolic engineering of these insecticidal metabolites in plants and microbes.

The chemical, mechanical, and physical properties of 3D printed materials composed of TiO2-ABS nanocomposites.

To expand the chemical capabilities of 3D printed structures generated from commercial thermoplastic printers, we have produced and printed polymer filaments that contain inorganic nanoparticles. TiO2 was dispersed into acrylonitrile butadiene styrene (ABS) and extruded into filaments with 1.75 mm diameters. We produced filaments with TiO2 compositions of 1%, 5%, and 10% (kg/kg) and printed structures using a commercial 3D printer. Our experiments suggest that ABS undergoes minor degradation in the presence of TiO2 during the different processing steps. The measured mechanical properties (strain and Young's modulus) for all of the composites are similar to those of structures printed from the pure polymer. TiO2 incorporation at 1% negatively affects the stress at breaking point and the flexural stress. Structures produced from the 5 and 10% nanocomposites display a higher breaking point stress than those printed from the pure polymer. TiO2 within the printed matrix was able to quench the intrinsic fluorescence of the polymer. TiO2 was also able to photocatalyze the degradation of a rhodamine 6G in solution. These experiments display chemical reactivity in nanocomposites that are printed using commercial 3D printers, and we expect that our methodology will help to inform others who seek to incorporate catalytic nanoparticles in 3D printed structures.

The significance of multipole interactions for the stability of regular structures composed from charged particles.

Identifying the forces responsible for stabilising binary particle lattices is key to the controlled fabrication of many new materials. Experiments have shown that the presence of charge can be integral to the formation of ordered arrays; however, a complete analysis of the forces responsible has not included many of the significant lattice types that may form during fabrication. A theory of many-body electrostatic interactions has been applied to six lattice stoichiometries, AB, AB2, AB3, AB4, AB5 and AB6, to show that induced multipole interactions can make a very significant (>80 %) contribution to the total lattice energy of arrays of charged particles. Particle radii ratios which favour global minima in electrostatic energy are found to be the same or a close match to those observed by experiment. Although certain lattice types exhibit local energy minima, the calculations show that many-body rather than two-body interactions are ultimately responsible for the structures observed by experiment. For a lattice isostructural with CFe4, a particle size ratio not previously observed is found to be particularly stable due to many-body effects.

Avenanthramide and ß-Glucan Therapeutics Accelerate Wound Healing Via Distinct and Nonoverlapping Mechanisms.

Objective: Given the significant economic, health care, and personal burden of acute and chronic wounds, we investigated the dose dependent wound healing mechanisms of two Avena sativa derived compounds: avenanthramide (AVN) and ß-Glucan. Approach: We utilized a splinted excisional wound model that mimics human-like wound healing and performed subcutaneous AVN and ß-Glucan injections in 15-week-old C57BL/6 mice. Histologic and immunohistochemical analysis was performed on the explanted scar tissue to assess changes in collagen architecture and cellular responses. Results: AVN and ß-Glucan treatment provided therapeutic benefits at a 1% dose by weight in a phosphate-buffered saline vehicle, including accelerated healing time, beneficial cellular recruitment, and improved tissue architecture of healed scars. One percent AVN treatment promoted an extracellular matrix (ECM) architecture similar to unwounded skin, with shorter, more randomly aligned collagen fibers and reduced inflammatory cell presence in the healed tissue. One percent ß-Glucan treatment promoted a tissue architecture characterized by long, thick bundles of collagen with increased blood vessel density. Innovation: AVN and ß-Glucan have previously shown promise in promoting wound healing, although the therapeutic efficacies and mechanisms of these bioactive compounds remain incompletely understood. Furthermore, the healed ECM architecture of these wounds has not been characterized. Conclusions: AVN and ß-Glucan accelerated wound closure compared to controls through distinct mechanisms. AVN-treated scars displayed a more regenerative tissue architecture with reduced inflammatory cell recruitment, while ß-Glucan demonstrated increased angiogenesis with more highly aligned tissue architecture more indicative of fibrosis. A deeper understanding of the mechanisms driving healing in these two naturally derived therapeutics will be important for translation to human use.

Mapping the Vif-A3G interaction using peptide arrays: a basis for anti-HIV lead peptides.

Human apolipoprotein-B mRNA-editing catalytic polypeptide-like 3G (A3G) is a cytidine deaminase that restricts retroviruses, endogenous retro-elements and DNA viruses. A3G plays a key role in the anti-HIV-1 innate cellular immunity. The HIV-1 Vif protein counteracts A3G mainly by leading A3G towards the proteosomal machinery and by direct inhibition of its enzymatic activity. Both activities involve direct interaction between Vif and A3G. Disrupting the interaction between A3G and Vif may rescue A3G antiviral activity and inhibit HIV-1 propagation. Here, mapping the interaction sites between A3G and Vif by peptide array screening revealed distinct regions in Vif important for A3G binding, including the N-terminal domain (NTD), C-terminal domain (CTD) and residues 83-99. The Vif-binding sites in A3G included 12 different peptides that showed strong binding to either full-length Vif, Vif CTD or both. Sequence similarity was found between Vif-binding peptides from the A3G CTD and NTD. A3G peptides were synthesized and tested for their ability to counteract Vif action. A3G 211-225 inhibited HIV-1 replication in cell culture and impaired Vif dependent A3G degradation. In vivo co-localization of full-length Vif with A3G 211-225 was demonstrated by use of FRET. This peptide has the potential to serve as an anti-HIV-1 lead compound. Our results suggest a complex interaction between Vif and A3G that is mediated by discontinuous binding regions with different affinities.

Concurrent zero-dimensional and one-dimensional biomineralization of gold from a solution of Au3+ and bovine serum albumin.

A technique was developed for preparing a novel material that consists of gold nanoparticles trapped within a fiber of unfolded proteins. These fibers are made in an aqueous solution that contains HAuCl4 and the protein, bovine serum albumin (BSA). By changing the ratio of gold to BSA in solution, two different types of outcomes are observed. At lower gold to BSA ratios (30-120), a purple solution results after heating the mixture at 80 °C for 4 h. At higher gold to BSA ratios (130-170), a clear solution containing purple fibers results after heating the mixture at 80 °C for 4 h. UV-Vis spectroscopy and light scattering techniques show growth in nanocolloid size as gold to BSA ratio rises above 100. Data indicate that, for the higher gold to BSA ratios, the gold is sequestered within the solid material. The material mass, visible by eye, appears to be an aggregation of smaller individual fibers. Scanning electron microscopy and transmission electron microscopy indicate that these fibers are primarily one-dimensional aggregates, which can display some branching, and can be as narrow as 400 nm in size. The likely mechanism for the synthesis of the novel material is discussed.

The effect of marine algae-derived exosomes on breast cancer cells: Hypothesis on a new treatment for cancer.

Breast cancer is one of the most common cancers among women worldwide. Therefore, further research in this area remains necessary. In pursuit of cancer treatment, the use of aquatic and marine resources has been considered in recent years. Marine algae create a wide variety of metabolites with different biological activities, and their anticancer properties have been reported in several studies. With particles ranging in size between 30 and 100 nm in size, exosomes are a class of cell-released extracellular vesicles that contain DNA, RNA, and proteins. Nontoxic properties and lack of an immune response are critical considerations in the medical use of exosome nanoparticles. Studies have demonstrated that exosomes are used for cancer therapy and in several drug delivery trials; however, no study so far has been done on exosomes derived from marine algae. Research has shown that three-dimensional (3D) models of cancer are advantageous for studying drug effects. This hypothesis aims to design a 3D model of breast cancer in vitro and evaluate cell growth after treatment with a marine algae-derived exosome.

A Rare Case of Paratesticular Leiomyosarcoma.

Paratesticular leiomyosarcoma is a rare urologic cancer that arises from undifferentiated smooth muscles of the spermatic cord or epididymis. Few accounts of this cancer have been reported but previous reports have identified radiation and anabolic steroids as possible risk factors. We report a case of an 83-year-old man with a previous history of radiation therapy for prostate cancer, who presented with a painless left scrotal mass. Given the nonspecific presentation, a histopathological classification was warranted for a definitive diagnosis. The tumor was resected via simple orchiectomy and was diagnosed as a paratesticular grade III leiomyosarcoma without any further treatment. Patient had a follow-up CT scan of the abdomen and pelvis that was normal without metastasis. The patient's history of previous external beam radiation and now development of a secondary tumor sums to the few cases that have been previously reported with this association.

Mortality in the Emergency Department and the Effectiveness of Conventional Safety Event Reporting.

Background Patient mortality reviews identify care, system, and process deficiencies. Patient deaths undergo quarterly review in our academic emergency department (ED), whereas in other departments, mortality reviews are requested by the pronouncing physician within 24 hours. In the ED, individual physicians encounter barriers to 24-hour reviews, including feasibility, the perception of futility, re-exposure to traumatic events, and a high frequency of pre-hospital and non-preventable deaths. This quality review aimed to determine the preventable death rate, contributing factors to ED patient mortality, cases requiring further review, and the capture rate of individual case submissions into the patient safety reporting system. Methods A retrospective chart review was performed on all patient deaths occurring in our ED from July 2019 to February 2020. All patients 18 years or older who were pronounced dead in the ED during our data collection period were included. Patients declared deceased pre-hospital, on an inpatient floor, or in the operating room were excluded. Deaths were assessed for characteristics such as sex, presence of a pulse upon arrival, diagnostics and interventions performed, and whether the cause of death was traumatic or medical. Deaths were categorized on a 5-point Likert scale ranging from "not preventable" to "likely preventable." The presence or absence of contributing factors and the need for further review were recorded. Results Of the 166 reviewed cases, 87% (n=144) were non-preventable due to a terminal condition upon arrival, 12% (n=20) were non-preventable despite maximal efforts, 0.6% (n=1) were non-preventable despite a medical or systems error, and 0.6% (n=1) were possibly preventable due to a medical or systems error. No cases were definitively preventable. Only 1.2% (n=2) of cases required further safety review. In 55% (n=91) of cases, the patient arrived without a pulse. Medical deaths (60%, n=100) outnumbered traumatic deaths (39%, n=64). The most utilized diagnostic test was ultrasound (67%, n=111), and the most utilized intervention was advanced cardiac life support (59%, n=98). Conclusion There is a high prevalence of unpreventable deaths in the ED (99%, n=164). Only two cases (1.2%) were identified for further patient safety review. Standard safety event reporting practices correctly identified all possibly preventable ED deaths.

Cooperation between physiological defenses and immune resistance produces asymptomatic carriage of a lethal bacterial pathogen.

Animals evolved two defense strategies to survive infections. Antagonistic strategies include immune resistance mechanisms that operate to kill invading pathogens. Cooperative or physiological defenses mediate host adaptation to the infected state, limiting physiological damage and disease, without killing the pathogen, and have been shown to cause asymptomatic carriage and transmission of lethal pathogens. Here, we demonstrate that physiological defenses cooperate with the adaptive immune response to generate long-term asymptomatic carriage of the lethal enteric murine pathogen, Citrobacter rodentium. Asymptomatic carriage of genetically virulent C. rodentium provided immune resistance against subsequent infections. Immune protection was dependent on systemic antibody responses and pathogen virulence behavior rather than the recognition of specific virulent antigens. Last, we demonstrate that an avirulent strain of C. rodentium in the field has background mutations in genes that are important for LPS structure. Our work reveals insight into how asymptomatic infections can arise mechanistically with immune resistance, mediating exclusion of phenotypically virulent enteric pathogen to promote asymptomatic carriage.

DAB2IP Is a Bifunctional Tumor Suppressor That Regulates Wild-Type RAS and Inflammatory Cascades in KRAS Mutant Colon Cancer.

The DAB2IP tumor suppressor encodes a RAS GTPase-activating protein. Accordingly, DAB2IP has been shown to be mutated or suppressed in tumor types that typically lack RAS mutations. However, here we report that DAB2IP is mutated or selectively silenced in the vast majority of KRAS and BRAF mutant colorectal cancers. In this setting, DAB2IP loss promoted tumor development by activating wild-type H- and N-RAS proteins, which was surprisingly required to achieve robust activation of RAS effector pathways in KRAS-mutant tumors. DAB2IP loss also triggered production of inflammatory mediators and the recruitment of protumorigenic macrophages in vivo. Importantly, tumor growth was suppressed by depleting macrophages or inhibiting cytokine/inflammatory mediator expression with a JAK/TBK1 inhibitor. In human tumors, DAB2IP was lost at early stages of tumor development, and its depletion was associated with an enrichment of macrophage and inflammatory signatures. Together, these findings demonstrate that DAB2IP restrains the activation of the RAS pathway and inflammatory cascades in the colon and that its loss represents a common and unappreciated mechanism for amplifying these two critical oncogenic signals in colorectal cancer. SIGNIFICANCE: DAB2IP is lost in early-stage tumors, which amplifies RAS signaling, triggers inflammatory mediators, and recruits macrophages in KRAS-mutant colon cancers.