Extracellular Vesicles from Trypanosoma brucei Mediate Virulence Factor Transfer and Cause Host Anemia.

Intercellular communication between parasites and with host cells provides mechanisms for parasite development, immune evasion, and disease pathology. Bloodstream African trypanosomes produce membranous nanotubes that originate from the flagellar membrane and disassociate into free extracellular vesicles (EVs). Trypanosome EVs contain several flagellar proteins that contribute to virulence, and Trypanosoma brucei rhodesiense EVs contain the serum resistance-associated protein (SRA) necessary for human infectivity. T. b. rhodesiense EVs transfer SRA to non-human infectious trypanosomes, allowing evasion of human innate immunity. Trypanosome EVs can also fuse with mammalian erythrocytes, resulting in rapid erythrocyte clearance and anemia. These data indicate that trypanosome EVs are organelles mediating non-hereditary virulence factor transfer and causing host erythrocyte remodeling, inducing anemia.

Mitochondria in health, disease, and aging.

Mitochondria are well known as organelles responsible for the maintenance of cellular bioenergetics through the production of ATP. Although oxidative phosphorylation may be their most important function, mitochondria are also integral for the synthesis of metabolic precursors, calcium regulation, the production of reactive oxygen species, immune signaling, and apoptosis. Considering the breadth of their responsibilities, mitochondria are fundamental for cellular metabolism and homeostasis. Appreciating this significance, translational medicine has begun to investigate how mitochondrial dysfunction can represent a harbinger of disease. In this review, we provide a detailed overview of mitochondrial metabolism, cellular bioenergetics, mitochondrial dynamics, autophagy, mitochondrial damage-associated molecular patterns, mitochondria-mediated cell death pathways, and how mitochondrial dysfunction at any of these levels is associated with disease pathogenesis. Mitochondria-dependent pathways may thereby represent an attractive therapeutic target for ameliorating human disease.

Neoblast-like stem cells of Fasciola hepatica.

The common liver fluke (Fasciola hepatica) causes the disease fasciolosis, which results in considerable losses within the global agri-food industry. There is a shortfall in the drugs that are effective against both the adult and juvenile life stages within the mammalian host, such that new drug targets are needed. Over the last decade the stem cells of parasitic flatworms have emerged as reservoirs of putative novel targets due to their role in development and homeostasis, including at host-parasite interfaces. Here, we investigate and characterise the proliferating cells that underpin development in F. hepatica. We provide evidence that these cells are capable of self-renewal, differentiation, and are sensitive to ionising radiation- all attributes of neoblasts in other flatworms. Changes in cell proliferation were also noted during the early stages of in vitro juvenile growth/development (around four to seven days post excystment), which coincided with a marked reduction in the nuclear area of proliferating cells. Furthermore, we generated transcriptomes from worms following irradiation-based ablation of neoblasts, identifying 124 significantly downregulated transcripts, including known stem cell markers such as fgfrA and plk1. Sixty-eight of these had homologues associated with neoblast-like cells in Schistosoma mansoni. Finally, RNA interference mediated knockdown of histone h2b (a marker of proliferating cells), ablated neoblast-like cells and impaired worm development in vitro. In summary, this work demonstrates that the proliferating cells of F. hepatica are equivalent to neoblasts of other flatworm species and demonstrate that they may serve as attractive targets for novel anthelmintics.

Multi-omic comparative analysis of COVID-19 and bacterial sepsis-induced ARDS.

BACKGROUND: Acute respiratory distress syndrome (ARDS), a life-threatening condition characterized by hypoxemia and poor lung compliance, is associated with high mortality. ARDS induced by COVID-19 has similar clinical presentations and pathological manifestations as non-COVID-19 ARDS. However, COVID-19 ARDS is associated with a more protracted inflammatory respiratory failure compared to traditional ARDS. Therefore, a comprehensive molecular comparison of ARDS of different etiologies groups may pave the way for more specific clinical interventions. METHODS AND FINDINGS: In this study, we compared COVID-19 ARDS (n = 43) and bacterial sepsis-induced (non-COVID-19) ARDS (n = 24) using multi-omic plasma profiles covering 663 metabolites, 1,051 lipids, and 266 proteins. To address both between- and within- ARDS group variabilities we followed two approaches. First, we identified 706 molecules differently abundant between the two ARDS etiologies, revealing more than 40 biological processes differently regulated between the two groups. From these processes, we assembled a cascade of therapeutically relevant pathways downstream of sphingosine metabolism. The analysis suggests a possible overactivation of arginine metabolism involved in long-term sequelae of ARDS and highlights the potential of JAK inhibitors to improve outcomes in bacterial sepsis-induced ARDS. The second part of our study involved the comparison of the two ARDS groups with respect to clinical manifestations. Using a data-driven multi-omic network, we identified signatures of acute kidney injury (AKI) and thrombocytosis within each ARDS group. The AKI-associated network implicated mitochondrial dysregulation which might lead to post-ARDS renal-sequalae. The thrombocytosis-associated network hinted at a synergy between prothrombotic processes, namely IL-17, MAPK, TNF signaling pathways, and cell adhesion molecules. Thus, we speculate that combination therapy targeting two or more of these processes may ameliorate thrombocytosis-mediated hypercoagulation. CONCLUSION: We present a first comprehensive molecular characterization of differences between two ARDS etiologies-COVID-19 and bacterial sepsis. Further investigation into the identified pathways will lead to a better understanding of the pathophysiological processes, potentially enabling novel therapeutic interventions.

ADHD prescription patterns and medication adherence in children and adolescents during the COVID-19 pandemic in an urban academic setting.

BACKGROUND: COVID-19 impacted all students, especially those with attention deficit hyperactivity disorder (ADHD), putting them at risk for disruption to their medication regimen and school performance. Our study aimed to identify if ADHD medication regimens were disrupted through analyzing prescription refills and if telehealth management demonstrated a higher rate of adherence. METHODS: A total of 396 patients from the General Academic Pediatrics (GAP) clinic at Children's Hospital of The King's Daughters (CHKD) were included in the study. Patients were between the ages of 8-18 with a history of ADHD for three or more years that was medically managed with four or more prescription refills between January 2019 and May 2022. A retrospective chart review collected age, sex, race, refill schedule, appointment schedule, and number of telehealth appointments. Data analysis compared the variables and defined "pre-pandemic months" as January 2019 through March 2020 and "pandemic months" as April 2020 through June 2022. RESULTS: The total percentage of patients who had their ADHD medications during pre-pandemic months ranged from 40 to 66% versus 31-44% during pandemic months. Additionally, the total percentage of patients who had quarterly ADHD management appointments during pre-pandemic months ranged between 59 and 70% versus 33-50% during pandemic months. The number of months with ADHD prescription refills over the last three years was significantly higher among those who had both virtual and in-person visits than those who had just in-person visits, p < 0.001. Regarding race, Black patients had a lower number of medication refills compared to White patients when controlled for appointment type. They also had a lower number of total appointments, but there was not a significant difference in the number of virtual appointments. CONCLUSIONS: Since the start of the pandemic, ADHD patients have both refilled their prescriptions and returned to clinic less frequently. This data suggests a need to re-evaluate the ADHD symptoms of GAP patients periodically and return them to a more consistent medication regimen. Telehealth appointments are a potential solution to increase adherence. However, racial inequities found in this study need to be addressed.

'Border Country': health law in a devolved UK.

How are we to understand and research health law under devolution in the UK? Building on work in law and geography, we argue that the figure of the border is key to the production and implementation of devolved health law and the variety of forms that this takes. The utility of border thinking in this context is shown through a review of thematic areas, including infectious disease control, access to health care, and abortion, each instantiating a distinct bordering process. In each, we consider recent developments in policy and legislation, framed with reference to constitutional change, and the politics of devolution in the UK. Taking Wales as an exemplary site, we argue that health law produces borders in traditional and non-traditional places. It creates and blurs territories. It is equally constituted by pluralistic bordering practices. On the basis of this theoretically informed review, we conclude by proposing a cross-disciplinary legal, ethical, and socio-legal research agenda for future research.

Severe asthma ILC2s demonstrate enhanced proliferation that is modified by biologics.

BACKGROUND AND OBJECTIVE: Type 2 (T2) innate lymphoid cells (ILC2s) contribute to airway inflammation and disease in asthma. We hypothesize that ILC2s isolated from people with severe allergic and eosinophilic asthma would exhibit an enhanced T2 inflammatory activity that would be altered following treatment with mepolizumab and omalizumab. We compare peripheral blood (PB) isolated ILC2's proliferative capacity, IL-5 and IL-13 secretion and phenotype between healthy without asthma (HC), non-asthma allergic (NAA), mild asthma (MA) and severe allergic and eosinophilic asthma (SA) subjects. We then determined the impact of 6 months treatment with either mepolizumab or omalizumab on ILC2s physiology of SA subjects. METHODS: ILC2s were sorted and cultured in the presence of IL-2, IL-25, IL-33 and thymic stromal lymphopoietin (TSLP) for 14 days. ILC2s proliferation, phenotypes and functions were assessed using flowcytometry. The ILC2s response was then reassessed following clinically successful treatment of SA subjects with mepolizumab and omalizumab. RESULTS: SA ILC2s demonstrated increased proliferative capacity, TSLP receptor (TSLPR), GATA3 and NFATc1 protein expressions and increased IL-5 and IL-13 release. ILC2s were also capable of releasing IL-6 in response to stimulation. Mepolizumab treatment reduced ILC2s proliferative capacity and expression of TSLPR, GATA3 and NFATc1. Both mepolizumab and omalizumab were associated with reduced ILC2s release of IL-5 and IL-13, only mepolizumab reduced IL-6. CONCLUSION: ILC2s from severe allergic and eosinophilic asthma demonstrated an active phenotype typified by increased proliferation, TSLPR, GATA3 and NFATc1 expression and increased IL-5, IL-13 and IL-6 release. Mepolizumab reduced markers of ILC2s activation.

Asthma and landscape fire smoke: A Thoracic Society of Australia and New Zealand position statement.

Landscape fires are increasing in frequency and severity globally. In Australia, extreme bushfires cause a large and increasing health and socioeconomic burden for communities and governments. People with asthma are particularly vulnerable to the effects of landscape fire smoke (LFS) exposure. Here, we present a position statement from the Thoracic Society of Australia and New Zealand. Within this statement we provide a review of the impact of LFS on adults and children with asthma, highlighting the greater impact of LFS on vulnerable groups, particularly older people, pregnant women and Aboriginal and Torres Strait Islander peoples. We also highlight the development of asthma on the background of risk factors (smoking, occupation and atopy). Within this document we present advice for asthma management, smoke mitigation strategies and access to air quality information, that should be implemented during periods of LFS. We promote clinician awareness, and the implementation of public health messaging and preparation, especially for people with asthma.

Determination of climatologically suitable places in Türkiye for feedlot cattle production using the Comprehensive Climate Index model.

The purpose of this study was to determine climatologically suitable places to raise feedlot cattle in Türkiye. The Comprehensive Climate Index (CCI), a model that enables one to quantify beef cattle performance based on environmental conditions (temperature, relative humidity, wind speed, solar radiation) at any time in the year, was used to predict dry matter intake (DMI), average daily gain (ADG), and feed efficiency (FE) of feedlot cattle. Thirty years of daily average temperature, relative humidity, and wind speed values were obtained for 15 cities, namely, Antalya, Balikesir, Çorum, Diyarbakir, Edirne, Elazig, Erzincan, Erzurum, Eskisehir, Isparta, Izmir, Kayseri, Konya, Sivas, and Van. Measured daily solar radiation values were not available and values were calculated based on a formula that takes hemisphere, latitude, and day of the year into account. Since mostly dairy breed calves are placed into a feedlot in Türkiye, the Holstein option in the CCI model was chosen to calculate the maintenance energy requirement. Based on previous feedlot feeding studies conducted in Türkiye, it was assumed that calves would be placed on feed at 250 kg and be marketed at 520 kg, that the diet would have 2600 kcal/kg metabolic energy, and that DMI would be 2.31% of the body weight. Results indicate that cattle raised in Antalya (the hottest place) and Erzurum (the coldest place) had the lowest and highest DMI, respectively (P<0.05). Summer months depressed the DMI of cattle in hotter cities and winter months increased the DMI of cattle in colder cities (P<0.05). Feedlot cattle raised in hotter and colder regions of Türkiye had lower ADG than other places having a more temperate climate (P<0.05). In general, cattle raised in a hotter climate had better FE than those raised in a cold climate (P<0.05).

End-of-life intravenous chemotherapy administration patterns in the treatment of Queensland lung and pancreas cancer patients: a 10-year retrospective analysis.

BACKGROUND: End-of-life (EOL) chemotherapy administration rates for solid tumours are 12-20% and are associated with a reduced quality of life, increased hospitalisation and incidence of death within an acute care facility. AIM: We sought to determine the rate of EOL chemotherapy in government and private hospitals and determine the impact on hospitalisations and location of death in lung and pancreatic cancer patients. METHODS: Data were obtained from the Queensland Oncology Repository between 2005 and 2014. Lung (n = 16 501) and pancreatic cancer (n = 4144) deaths were analysed. EOL chemotherapy was determined to be within 30 days of death. Demographics, location of treatment and death are reported. RESULTS: Chemotherapy was administered to 6518 (40%) lung cancer and 1694 (41%) pancreatic cancer patients. A total of 1474 (9%) and 477 (12%) patients, respectively, received EOL chemotherapy. EOL chemotherapy was more common in males and those with distant metastatic disease, while less likely in the elderly and those with a lower socioeconomic status. EOL chemotherapy was more prevalent in large hospitals and was more common in private compared with government hospitals for pancreatic cancer (30 vs 26%; P < 0.001), while it was similar for lung cancer (24 vs 22%; P = 0.115). Death after EOL chemotherapy compared with all cancer deaths was more common in an acute care facility (lung cancer: 60 vs 37%; P < 0.001; pancreatic cancer: 53 vs 36%; P < 0.001). CONCLUSIONS: EOL chemotherapy rates were similar to Australian yet marginally lower than international rates, with variation dependent on the size and type of facility and increased the rate of deaths within an acute care facility.

COVID- 19 and human right to food: lived experiences of the urban poor in Kenya with the impacts of government's response measures, a participatory qualitative study.

BACKGROUND: Globally, governments put in place measures to curb the spread of COVID-19. Information on the effects of these measures on the urban poor is limited. This study aimed to explore the lived experiences of the urban poor in Kenya in the context of government's COVID-19 response measures and its impact on the human right to food. METHODS: A qualitative study was conducted in two informal settlements in Nairobi between January and March 2021. Analysis draws on eight focus group discussions, eight in-depth interviews, 12 key informant interviews, two photovoice sessions and three digital storytelling sessions. Phenomenology was applied to understand an individual's lived experiences with the human right to food during COVID - 19. Thematic analysis was performed using NVIVO software. RESULTS: The human right to food was affected in various ways. Many people lost their livelihoods, affecting affordability of food, due to response measures such as social distancing, curfew, and lockdown. The food supply chain was disrupted causing limited availability and access to affordable, safe, adequate, and nutritious food. Consequently, hunger and an increased consumption of low-quality food was reported. Social protection measures were instituted. However, these were inadequate and marred by irregularities. Some households resorted to scavenging food from dumpsites, skipping meals, sex-work, urban-rural migration and depending on food donations to survive. On the positive side, some households resorted to progressive measures such as urban farming and food sharing in the community. Generally, the response measures could have been more sensitive to the human rights of the urban poor. CONCLUSIONS: The government's COVID-19 restrictive measures exacerbated the already existing vulnerability of the urban poor to food insecurity and violated their human right to food. Future response measures should be executed in ways that respect the human right to food and protect marginalized people from resultant vulnerabilities.

Attributable mortality of acute respiratory distress syndrome: a systematic review, meta-analysis and survival analysis using targeted minimum loss-based estimation.

BACKGROUND: Although acute respiratory distress syndrome (ARDS) is associated with high mortality, its direct causal link with death is unclear. Clarifying this link is important to justify costly research on prevention of ARDS. OBJECTIVE: To estimate the attributable mortality, if any, of ARDS. DESIGN: First, we performed a systematic review and meta-analysis of observational studies reporting mortality of critically ill patients with and without ARDS matched for underlying risk factor. Next, we conducted a survival analysis of prospectively collected patient-level data from subjects enrolled in three intensive care unit (ICU) cohorts to estimate the attributable mortality of critically ill septic patients with and without ARDS using a novel causal inference method. RESULTS: In the meta-analysis, 44 studies (47 cohorts) involving 56 081 critically ill patients were included. Mortality was higher in patients with versus without ARDS (risk ratio 2.48, 95% CI 1.86 to 3.30; p<0.001) with a numerically stronger association between ARDS and mortality in trauma than sepsis. In the survival analysis of three ICU cohorts enrolling 1203 critically ill patients, 658 septic patients were included. After controlling for confounders, ARDS was found to increase the mortality rate by 15% (95% CI 3% to 26%; p=0.015). Significant increases in mortality were seen for severe (23%, 95% CI 3% to 44%; p=0.028) and moderate (16%, 95% CI 2% to 31%; p=0.031), but not for mild ARDS. CONCLUSIONS: ARDS has a direct causal link with mortality. Our findings provide information about the extent to which continued funding of ARDS prevention trials has potential to impart survival benefit. PROSPERO REGISTRATION NUMBER: CRD42017078313.

Oral corticosteroids stewardship for asthma in adults and adolescents: A position paper from the Thoracic Society of Australia and New Zealand.

Oral corticosteroids (OCS) are frequently used for asthma treatment. This medication is highly effective for both acute and chronic diseases, but evidence indicates that indiscriminate OCS use is common, posing a risk of serious side effects and irreversible harm. There is now an urgent need to introduce OCS stewardship approaches, akin to successful initiatives that optimized appropriate antibiotic usage. The aim of this TSANZ (Thoracic Society of Australia and New Zealand) position paper is to review current knowledge pertaining to OCS use in asthma and then delineate principles of OCS stewardship. Recent evidence indicates overuse and over-reliance on OCS for asthma and that doses >1000 mg prednisolone-equivalent cumulatively are likely to have serious side effects and adverse outcomes. Patient perspectives emphasize the detrimental impacts of OCS-related side effects such as weight gain, insomnia, mood disturbances and skin changes. Improvements in asthma control and prevention of exacerbations can be achieved by improved inhaler technique, adherence to therapy, asthma education, smoking cessation, multidisciplinary review, optimized medications and other strategies. Recently, add-on therapies including novel biological agents and macrolide antibiotics have demonstrated reductions in OCS requirements. Harm reduction may also be achieved through identification and mitigation of predictable adverse effects. OCS stewardship should entail greater awareness of appropriate indications for OCS prescription, risk-benefits of OCS medications, side effects, effective add-on therapies and multidisciplinary review. If implemented, OCS stewardship can ensure that clinicians and patients with asthma are aware that OCS should not be used lightly, while providing reassurance that asthma can be controlled in most people without frequent use of OCS.

Rapid Transition of a PICU Space and Staff to Adult Coronavirus Disease 2019 ICU Care.

OBJECTIVES: We describe the process by which a PICU and a PICU care team were incorporated into a hospital-wide ICU care model during the coronavirus disease 2019 pandemic. DESIGN: A descriptive, retrospective report from a single-center PICU. SETTING: Twenty-three bed, quaternary PICU, within an 862-bed hospital. PATIENTS: Critically ill adults, with coronavirus disease 2019-related disease. INTERVENTIONS: ICU care provided by pediatric intensivists with training and support from medical intensivists. MEASUREMENTS AND MAIN RESULTS: Within the context of the institution's comprehensive effort to centralize and systematize care for adults with severe coronavirus disease 2019 disease, the PICU was transitioned to an adult coronavirus disease 2019 critical care unit. Nurses and physicians underwent just-in-time training over 3 days and 2 weeks, respectively. Medical ICU physicians and nurses provided oversight for care and designated hospital-based teams were available for procedures and common adult emergencies. Over a 7-week period, the PICU cared for 60 adults with coronavirus disease 2019-related critical illness. Fifty-three required intubation and mechanical ventilation for a median of 18 days. Eighteen required renal replacement therapy and 17 died. CONCLUSIONS: During the current and potentially in future pandemics, where critical care resources are limited, pediatric intensivists and staff can be readily utilized to meaningfully contribute to the care of critically ill adults.

Mepolizumab effectiveness and identification of super-responders in severe asthma.

Severe asthma is a high-burden disease. Real-world data on mepolizumab in patients with severe eosinophilic asthma is needed to assess whether the data from randomised controlled trials are applicable in a broader population.The Australian Mepolizumab Registry (AMR) was established with an aim to assess the use, effectiveness and safety of mepolizumab for severe eosinophilic asthma in Australia.Patients (n=309) with severe eosinophilic asthma (median age 60 years, 58% female) commenced mepolizumab. They had poor symptom control (median Asthma Control Questionnaire (ACQ)-5 score of 3.4), frequent exacerbations (median three courses of oral corticosteroids (OCS) in the previous 12 months), and 47% required daily OCS. Median baseline peripheral blood eosinophil level was 590 cells·µL-1 Comorbidities were common: allergic rhinitis 63%, gastro-oesophageal reflux disease 52%, obesity 46%, nasal polyps 34%.Mepolizumab treatment reduced exacerbations requiring OCS compared with the previous year (annualised rate ratio 0.34 (95% CI 0.29-0.41); p<0.001) and hospitalisations (rate ratio 0.46 (95% CI 0.33-0.63); p<0.001). Treatment improved symptom control (median ACQ-5 reduced by 2.0 at 6 months), quality of life and lung function. Higher blood eosinophil levels (p=0.003) and later age of asthma onset (p=0.028) predicted a better ACQ-5 response to mepolizumab, whilst being male (p=0.031) or having body mass index ≥30 (p=0.043) predicted a lesser response. Super-responders (upper 25% of ACQ-5 responders, n=61, 24%) had a higher T2 disease burden and fewer comorbidities at baseline.Mepolizumab therapy effectively reduces the significant and long-standing disease burden faced by patients with severe eosinophilic asthma in a real-world setting.

Law and Rhetoric: Critical Possibilities.

What contribution can rhetoric make to socio-legal studies? Though now a byword for deception and spin, rhetoric was long identified with the very substance of law and politics. Latterly radical scholars have foregrounded an understanding of law as rhetoric in their polemics against legal formalism, but it needs to be complemented by a critical perspective which goes beyond simple revivalism, taking account of rhetoric's own blind spots, inquiring into the means by which some speakers and listeners are privileged and others excluded or silenced. The critical potential of legal rhetoric is tested here through a review of the developing law on mental capacity and the best interests of people with disabilities in England and Wales. Much of what is at stake there is properly grasped in terms of a politics of speech: who is addressed, who can speak, who must speak, and how are they represented in judicial and media discourse.

Plasma mitochondrial DNA and metabolomic alterations in severe critical illness.

BACKGROUND: Cell-free plasma mitochondrial DNA (mtDNA) levels are associated with endothelial dysfunction and differential outcomes in critical illness. A substantial alteration in metabolic homeostasis is commonly observed in severe critical illness. We hypothesized that metabolic profiles significantly differ between critically ill patients relative to their level of plasma mtDNA. METHODS: We performed a metabolomic study with biorepository plasma samples collected from 73 adults with systemic inflammatory response syndrome or sepsis at a single academic medical center. Patients were treated in a 20-bed medical ICU between 2008 and 2010. To identify key metabolites and metabolic pathways related to plasma NADH dehydrogenase 1 (ND1) mtDNA levels in critical illness, we first generated metabolomic data using gas and liquid chromatography-mass spectroscopy. We performed fold change analysis and volcano plot visualization based on false discovery rate-adjusted p values to evaluate the distribution of individual metabolite concentrations relative to ND1 mtDNA levels. We followed this by performing orthogonal partial least squares discriminant analysis to identify individual metabolites that discriminated ND1 mtDNA groups. We then interrogated the entire metabolomic profile using pathway overrepresentation analysis to identify groups of metabolite pathways that were different relative to ND1 mtDNA levels. RESULTS: Metabolomic profiles significantly differed in critically ill patients with ND1 mtDNA levels ≥ 3200 copies/µl plasma relative to those with an ND1 mtDNA level < 3200 copies/µl plasma. Several analytical strategies showed that patients with ND1 mtDNA levels ≥ 3200 copies/µl plasma had significant decreases in glycerophosphocholines and increases in short-chain acylcarnitines. CONCLUSIONS: Differential metabolic profiles during critical illness are associated with cell-free plasma ND1 mtDNA levels that are indicative of cell damage. Elevated plasma ND1 mtDNA levels are associated with decreases in glycerophosphocholines and increases in short-chain acylcarnitines that reflect phospholipid metabolism dysregulation and decreased mitochondrial function, respectively.

Mitochondrial DNA in Sepsis.

PURPOSE OF REVIEW: Our understanding of critical illness is transforming as we develop a better understanding of the impact pathogen-associated molecular patterns and damage-associated molecular patterns (DAMPs) have on the pathogenesis of disease. Of the known DAMPs, there is a growing interest in mitochondrial DNA (mtDNA) as a DAMP capable of propagating the inflammatory response seen in sepsis and other conditions. In this review, we describe the varying mechanisms by which mtDNA is translocated from mitochondria into cytosol and the extracellular space where it can illicit an inflammatory response. In addition, we present some of the most recent clinical studies to examine mtDNA in critical illness. RECENT FINDINGS: Basic science research provides convincing data that mtDNA can influence the immune system through toll-like receptor 9 and inflammasomes. Clinical trials provide evidence that mtDNA is elevated in critically ill patients and is associated with mortality. SUMMARY: Although mtDNA is a DAMP shown to be elevated in numerous conditions, the clinical ramifications of this finding remain elusive. Further work is needed to determine if mtDNA can be utilized as a biomarker of disease severity or mortality.