Objective Our objective was to execute a prospective cohort study to determine relationships between plasma mtDNA DAMP levels and the occurrence of systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), and mortality. Background Mitochondrial DNA damage-associated molecular patterns (DAMPs) accumulate in the circulation after severe injury. Observations in animal models demonstrate that mtDNA DAMPs contribute to organ dys-function; however, the link between plasma mtDNA DAMPs and outcome in severely injured human subjects has not been established. Methods DNA was isolated from plasma samples taken from severely injured patients at hospital days 0, 1, and 2. Real-time PCR was used to quantify selected ≈200 base pair sequences of mtDNA within the COX1, ND1, and ND6 genes, as well as from the D-Loop transcriptional regulatory region. MODS was defined as a Denver Multiple Organ Failure score of 4 or greater. Results MtDNA DAMPs were quantified as PCR threshold cycle number. Lower threshold cycles indicate increased mtDNA DAMP content. Patients with SIRS had significantly increased mtDNA DAMP levels in all 4 sequences examined (32.14 ± 0.90 vs 29.00 ± 1.15 for COX1, 31.90 ± 0.47 vs 30.16 ± 1.42 for ND1, 32.40 ± 0.61 vs 28.94 ± 1.13 for ND6, and 33.12 ± 0.83 vs 28.30 ± 1.14 for D-Loop). Patients who developed MODS also had elevated mtDNA DAMP levels compared with those who did not (32.57 ± 0.74 vs 27.12 ± 0.66 for COX1, 32.45 ± 0.65 vs 28.20 ± 0.73 for ND1, 32.52 ± 0.56 vs 27.60 ± 0.79 for ND6, and 32.85 ± 0.75 vs 27.86 ± 1.27 for D-Loop). Patients with above-median mtDNA DAMP levels had a significantly elevated relative risk for mortality. Four patients died secondary to severe MODS. Conclusions These findings comprise the first observational evidence that plasma mtDNA DAMPs is associated with the evolution of SIRS, MODS, and mortality in severely injured human subjects.

Lung ischemia-reperfusion (IR) injury contributes to post-transplant complications, including primary graft dysfunction. Decades of reports show that reactive oxygen species generated during lung IR contribute to pulmonary vascular endothelial barrier disruption and edema formation, but the specific target molecule(s) that "sense" injury-inducing oxidant stress to activate signaling pathways culminating in pathophysiologic changes have not been established. This review discusses evidence that mitochondrial DNA (mtDNA) may serve as a molecular sentinel wherein oxidative mtDNA damage functions as an upstream trigger for lung IR injury. First, the mitochondrial genome is considerably more sensitive than nuclear DNA to oxidant stress. Multiple studies suggest that oxidative mtDNA damage could be transduced to physiologic dysfunction by pathways that are either a direct consequence of mtDNA damage per se or involve formation of proinflammatory mtDNA damage-associated molecular patterns. Second, transgenic animals or cells overexpressing components of the base excision DNA repair pathway in mitochondria are resistant to oxidant stress-mediated pathophysiologic effects. Finally, published and preliminary studies show that pharmacologic enhancement of mtDNA repair or mtDNA damage-associated molecular pattern degradation suppresses reactive oxygen species-induced or IR injury in multiple organs, including preclinical models of lung procurement for transplant. Collectively, these findings point to the interesting prospect that pharmacologic enhancement of DNA repair during procurement or ex vivo lung perfusion may increase the availability of lungs for transplant and reduce the IR injury contributing to primary graft dysfunction.

OBJECTIVE: To investigate published cases of cervical ectopic pregnancy between 2000 and 2018 and compare management strategies and treatment success rates based on initial patient characteristics. METHODS: PubMed, EMBASE, and Web of Science were searched to capture peer-reviewed citations published between 2000 and 2018. Cases reporting either β-hCG level, crown–rump length, or gestational sac diameter for each individual patient were included. Data regarding the article information, patient characteristics, treatment used, and outcomes were collected. Initial success was defined as resolution of the cervical ectopic pregnancy with the predefined treatment plan. Initial failure was defined as the requirement of additional unplanned interventions due to the predefined treatment plan not being successful. End success was defined as resolution of the cervical ectopic pregnancy without hysterectomy. RESULTS: A total of 204 articles from 44 countries comprising 454 cases were reviewed. The initial β-hCG level ranged from 9 to 286,500, with a median of 14,773, and gestational age ranged from 4 to 18 weeks, with an average of 7 4/7 weeks (±2 0/7 weeks). In looking at initial success, compared with methotrexate alone, dilation, and curettage (odds ratio [OR] 2.26; 95% CI 2.64–10.45), dilation and curettage combined with uterine artery embolization (OR 4.85; 95% CI 2.06–11.44) and uterine artery embolization (OR 5.17; 95% CI 1.14–23.53) were more effective options. More than half of patients (50.2%) required multiple interventions, and 41 (9%) resulted in hysterectomy. CONCLUSIONS: Management of cervical ectopic pregnancies should be guided by patient stability, β-hCG level, size of pregnancy, and fetal cardiac activity but may benefit from a planned multimodal approach.