Even a single positive blood culture may matter - A case of prosthetic valve infective endocarditis caused by Corynebacterium kroppenstedtii.

Corynebacterium is a skin commensal bacterium that can contaminate blood cultures. It is however also a rare cause of infective endocarditis (IE). Here we report a case of Corynebacterium kroppenstedtii aortic prosthesis IE in a 76-year-old man where only a single blood culture bottle was positive initially. C. kroppenstedtii is a very rare cause of IE, only reported two times previously. The diagnosis in our case was confirmed by repeated blood culture positivity and eventually by detection of DNA from C. kroppenstedtii on heart valves after valve exchange surgery. At surgery an aortic root abscess was detected and the valve was replaced by a homograft. Recovery was complicated by antibiotic-induced nephrotoxicity and treatment was concluded with moxifloxacin in combination with rifampicin. Recovery was uneventful. This case demonstrates that growth in even a single blood culture bottle may be important in patients with prosthetic heart valves.

Complex regulation of mitochondrial signaling by human adenovirus minor capsid protein VI.

The controlled release of mitochondrial content into the cytosol has emerged as one of the key steps in mitochondrial signaling. In particular, the release of mitochondrial DNA (mtDNA) into the cytosol has been shown to activate interferon beta (IFN-ß) gene expression to execute the innate immune response. In this report, we show that human adenovirus type 5 (HAdV-C5) infection induces the release of mtDNA into the cytosol. The release of mtDNA is mediated by the viral minor capsid protein VI (pVI), which localizes to mitochondria. The presence of the mitochondrial membrane proteins Bak and Bax are needed for the mtDNA release, whereas the viral E1B-19K protein blocked pVI-mediated mtDNA release. Surprisingly, the pVI-mediated mtDNA release did not increase but inhibited the IFN-ß gene expression. Notably, the pVI expression caused mitochondrial leakage of the HSP60 protein. The latter prevented specific phosphorylation of the interferon regulatory factor 3 (IRF3) needed for IFN-ß gene expression. Overall, we assign a new mitochondria and IFN-ß signaling-modulating function to the HAdV-C5 minor capsid protein VI. IMPORTANCE: Human adenoviruses (HAdVs) are common pathogens causing various self-limiting diseases, including conjunctivitis and the common cold. HAdVs need to interfere with multiple cellular signaling pathways during the infection to gain control over the host cell. In this study, we identified human adenovirus type 5 (HAdV-C5) minor capsid protein VI as a factor modulating mitochondrial membrane integrity and mitochondrial signaling. We show that pVI-altered mitochondrial signaling impedes the cell's innate immune response, which may benefit HAdV growth. Overall, our study provides new detailed insights into the HAdV-mitochondria interactions and signaling. This knowledge is helpful when developing new anti-viral treatments against pathogenic HAdV infections and improving HAdV-based therapeutics.

Biomarkers of inflammation and coagulation after minimally invasive mitral valve surgery: a prospective comparison to conventional surgery.

OBJECTIVES: Minimally invasive cardiac surgery techniques are increasingly used but have longer cardiopulmonary bypass time, which may increase inflammatory response and negatively affect coagulation. Our aim was to compare biomarkers of inflammation and coagulation as well as transfusion rates after minimally invasive mitral valve repair and mitral valve surgery using conventional sternotomy. DESIGN: A prospective non-randomized study was performed enrolling 71 patients undergoing mitral valve surgery (35 right mini-thoracotomy and 36 conventional sternotomy procedures). Blood samples were collected pre- and postoperatively to assess inflammatory response. Thromboelastometry (ROTEM) was performed to assess coagulation, and transfusion rates were monitored. RESULTS: The minimally invasive group had longer cardiopulmonary bypass times compared to the sternotomy group: 127 min ([115-146] vs 79 min [65-112], p < 0.001) and were cooled to a lower temperature during cardiopulmonary bypass, 34 °C vs 36 °C (p = 0.04). IL-6 was lower in the minimally invasive group compared to the conventional sternotomy group when measured at the end of the surgical procedure, (38 [23-69] vs 61[41-139], p = 0.008), but no differences were found at postoperative day 1 or postoperative day 3. The transfusion rate was lower in the minimally invasive group (14%) compared to full sternotomy (35%, p = 0.04) and the chest tube output was reduced, (395 ml [190-705] vs 570 ml [400-1040], p = 0.04). CONCLUSIONS: Our data showed that despite the longer use of extra corporal circulation during surgery, minimally invasive mitral valve repair is associated with reduced inflammatory response, lower rates of transfusion, and reduced chest tube output.

Retrograde cerebral perfusion reduces embolic and watershed lesions after acute type a aortic dissection repair with deep hypothermic circulatory arrest.

BACKGROUND: To assess whether retrograde cerebral perfusion reduces neurological injury and mortality in patients undergoing surgery for acute type A aortic dissection. METHODS: Single-center, retrospective, observational study including all patients undergoing acute type A aortic dissection repair with deep hypothermic circulatory arrest between January 1998 and December 2022 with or without the adjunct of retrograde cerebral perfusion. 515 patients were included: 257 patients with hypothermic circulatory arrest only and 258 patients with hypothermic circulatory arrest and retrograde cerebral perfusion. The primary endpoints were clinical neurological injury, embolic lesions, and watershed lesions. Multivariable logistic regression was performed to identify independent predictors of the primary outcomes. Survival analysis was performed using Kaplan-Meier estimates. RESULTS: Clinical neurological injury and embolic lesions were less frequent in patients with retrograde cerebral perfusion (20.2% vs. 28.4%, p = 0.041 and 13.7% vs. 23.4%, p = 0.010, respectively), but there was no significant difference in the occurrence of watershed lesions (3.0% vs. 6.1%, p = 0.156). However, after multivariable logistic regression, retrograde cerebral perfusion was associated with a significant reduction of clinical neurological injury (OR: 0.60; 95% CI 0.36-0.995, p = 0.049), embolic lesions (OR: 0.55; 95% CI 0.31-0.97, p = 0.041), and watershed lesions (OR: 0.25; 95%CI 0.07-0.80, p = 0.027). There was no significant difference in 30-day mortality (12.8% vs. 11.7%, p = ns) or long-term survival between groups. CONCLUSION: In this study, we showed that the addition of retrograde cerebral perfusion during hypothermic circulatory arrest in the setting of acute type A aortic dissection repair reduced the risk of clinical neurological injury, embolic lesions, and watershed lesions.

Mortality after non-surgically treated acute type A aortic dissection is higher than previously reported.

OBJECTIVES: It has been commonly accepted that untreated acute type A aortic dissection (ATAAD) results in an hourly mortality rate of 1-2% during the 1st 24 h after symptom onset. The data to support this statement rely solely on patients who have been denied surgical treatment after reaching surgical centres. The objective was to perform a total review of non-surgically treated (NST) ATAAD and provide contemporary mortality data. METHODS: This was a regional, retrospective, observational study. All patients receiving one of the following diagnoses: International Classification of Diseases (ICD)-9 4410, 4411, 4415, 4416 or ICD-10 I710, I711, I715, I718 in an area of 1.9 million inhabitants in Southern Sweden during a period of 23 years (January 1998 to November 2021) were retrospectively screened. The search was conducted using all available medical registries so that every patient diagnosed with ATAAD in our region was identified. The charts and imaging of each screened patient were subsequently reviewed to confirm or discard the diagnosis of ATAAD. RESULTS: Screening identified 2325 patients, of whom 184 NST ATAAD patients were included. The mortality of NST ATAAD was 47.3 ± 4.4%, 55.0 ± 4.4%, 76.7 ± 3.7% and 83.9 ± 4.3% at 24 h, 48 h, 14 days and 1 year, respectively. The hourly mortality rate during the 1st 24 h after symptom onset was 2.6%. CONCLUSIONS: This study observed higher mortality than has previously been reported. It emphasizes the need for timely diagnosis, swift management and emergent surgical treatment for patients suffering an acute type A aortic dissection.

Radiological properties of neurological injury following acute type A aortic dissection repair.

Objective: The study objective was to assess the radiological properties of acute type A aortic dissection-related neurological injuries and identify predictors of neurological injury. Methods: Our single-center, retrospective, observational study included all patients who underwent acute type A aortic dissection repair between January 1998 and December 2021. Multivariable analyses and Cox regression were performed to identify predictors of embolic lesions, watershed lesions, neurological injury, 30-day mortality, and late mortality. Results: A total of 538 patients were included. Of these, 120 patients (22.3%) experienced postoperative neurological injury; 74 patients (13.8%) had postoperative stroke, and 36 patients (6.8%) had postoperative coma. The 30-day mortality was 22.7% in the neurological injury group versus 5.8% in the no neurological injury group (P < .001). We identified several independent predictors of neurological injury. Cerebral malperfusion (odds ratio, 2.77; 95% confidence interval, 1.53-5.00), systemic hypotensive shock (odds ratio, 1.97; 95% confidence interval, 1.13-3.43), and aortic arch replacement (odds ratio, 3.08; 95% confidence interval, 1.17-8.08) predicted embolic lesions. Diabetes mellitus (odds ratio, 5.35; 95% confidence interval, 1.85-15.42), previous cardiac surgery (odds ratio, 8.62; 95% confidence interval, 1.47-50.43), duration of hypothermic circulatory arrest (odds ratio, 1.05; 95% confidence interval, 1.01-1.08), cardiopulmonary bypass time (odds ratio, 1.01; 95% confidence interval, 1.00-1.01), ascending aortic/arch cannulation (odds ratio, 5.68; 95% confidence interval, 1.88-17.12), and left ventricular cannulation (odds ratio, 17.81; 95% confidence interval, 1.69-188.01) predicted watershed lesions. Retrograde cerebral perfusion (odds ratio, 0.28; 95% confidence interval, 0.01-0.84) had a protective effect against watershed lesions. Conclusions: In this study, we demonstrated that the radiological features of neurological injury may be as important as clinical characteristics in understanding the pathophysiology and causality behind neurological injury related to acute type A aortic dissection repair.

The RNA-binding protein ZC3H11A interacts with the nuclear poly(A)-binding protein PABPN1 and alters polyadenylation of viral transcripts.

Nuclear mRNA metabolism is regulated by multiple proteins, which either directly bind to RNA or form multiprotein complexes. The RNA-binding protein ZC3H11A is involved in nuclear mRNA export, NF-κB signaling, and is essential during mouse embryo development. Furthermore, previous studies have shown that ZC3H11A is important for nuclear-replicating viruses. However, detailed biochemical characterization of the ZC3H11A protein has been lacking. In this study, we established the ZC3H11A protein interactome in human and mouse cells. We demonstrate that the nuclear poly(A)-binding protein PABPN1 interacts specifically with the ZC3H11A protein and controls ZC3H11A localization into nuclear speckles. We report that ZC3H11A specifically interacts with the human adenovirus type 5 (HAdV-5) capsid mRNA in a PABPN1-dependent manner. Notably, ZC3H11A uses the same zinc finger motifs to interact with PABPN1 and viral mRNA. Further, we demonstrate that the lack of ZC3H11A alters the polyadenylation of HAdV-5 capsid mRNA. Taken together, our results suggest that the ZC3H11A protein may act as a novel regulator of polyadenylation of nuclear mRNA.

Carbon dioxide flooding to reduce postoperative neurological injury following surgery for acute type A aortic dissection: a prospective, randomised, blinded, controlled clinical trial, CARTA study protocol - objectives and design.

INTRODUCTION: Neurological complications after surgery for acute type A aortic dissection (ATAAD) increase patient morbidity and mortality. Carbon dioxide flooding is commonly used in open-heart surgery to reduce the risk of air embolism and neurological impairment, but it has not been evaluated in the setting of ATAAD surgery. This report describes the objectives and design of the CARTA trial, investigating whether carbon dioxide flooding reduces neurological injury following surgery for ATAAD. METHODS AND ANALYSIS: The CARTA trial is a single-centre, prospective, randomised, blinded, controlled clinical trial of ATAAD surgery with carbon dioxide flooding of the surgical field. Eighty consecutive patients undergoing repair of ATAAD, and who do not have previous neurological injuries or ongoing neurological symptoms, will be randomised (1:1) to either receive carbon dioxide flooding of the surgical field or not. Routine repair will be performed regardless of the intervention. The primary endpoints are size and number of ischaemic lesions on brain MRI performed after surgery. Secondary endpoints are clinical neurological deficit according to the National Institutes of Health Stroke Scale, level of consciousness using the Glasgow Coma Scale motor score, brain injury markers in blood after surgery, neurological function according to the modified Rankin Scale and postoperative recovery 3 months after surgery. ETHICS AND DISSEMINATION: Ethical approval has been granted by Swedish Ethical Review Agency for this study. Results will be disseminated through peer-reviewed media. TRIAL REGISTRATION NUMBER: NCT04962646.

S100B predicts neurological injury and 30-day mortality following surgery for acute type A aortic dissection: an observational cohort study.

BACKGROUND: Neurological injuries are frequent following Acute Type A Aortic Dissection (ATAAD) repair occurring in 4-30% of all patients. Our objective was to study whether S100B can predict neurological injury following ATAAD repair. METHODS: This was a single-center, retrospective, observational study. The study included all patients that underwent ATAAD repair at our institution between Jan 1998 and Dec 2021 and had recorded S100B-values. The primary outcome measure was neurological injury, defined as focal neurological deficit or coma diagnosed by clinical assessment with or without radiological confirmation and with a symptom duration of more than 24 h. Secondary outcome measure was 30-day mortality. RESULTS: 538 patients underwent surgery during the study period and 393 patients, had recorded S100B-values. The patients had a mean age of 64.4 ± 11.1 years and 34% were female. Receiver operating characteristic curve for S100B 24 h postoperatively yielded area under the curve 0.687 (95% CI 0.615-0.759) and best Youden's index corresponded to S100B 0.225 which gave a sensitivity of 60% and specificity of 75%. Multivariable logistic regression identified S100B ≥ 0.23 µg/l at 24 h as an independent predictor for neurological injury (OR 4.71, 95% CI 2.59-8.57; p < 0.01) along with preoperative cerebral malperfusion (OR 4.23, 95% CI 2.03-8.84; p < 0.01) as well as an independent predictor for 30-day mortality (OR 4.57, 95% CI 1.18-11.70; p < 0.01). CONCLUSIONS: We demonstrated that S100B, 24 h after surgery is a strong independent predictor for neurological injury and 30-day mortality after ATAAD repair. TRIAL REGISTRATION: As this was a retrospective observational study it was not registered.

Limited Distal Repair Results in Low Rates of Distal Events Following Surgery for Acute Type A Aortic Dissection.

To investigate mortality and reoperation rates following limited distal repair after acute type A aortic dissection (ATAAD) at a single medium volume institution. We analyzed all patients that underwent limited distal repair (ascending aortic or hemiarch replacement) following ATAAD between January 1998 and April 2020 at our institution. During the study period, 489 patients underwent ATAAD surgery, of which 457 (94%) underwent limited distal repair with a 30-day mortality of 12.9%. Among 30-day survivors, late follow-up was 97.7% complete with a mean follow-up of 6.0 ± 5.5 years. In all, 50 patients (11%) required a reoperation during the study period at a mean of 3.4 ± 3.4 years after initial repair, with a 30-day mortality of 12%. An aortic reoperation was required in 4.1 (2.0-6.1)%, 10.3 (7.1-13.6)%, 15.1 (10.9-19.4)%, and 18.0 (13.0-22.9)% of patients at 1, 5, 10, and 15 years. A distal reoperation was required in 3.0 (1.2-4.7)%, 8.0 (5.1-10.9)%, 10.3 (6.8-13.8)%, and 12.4 (8.2-16.5)% of patients and 4.4 (2.3-6.4)%, 10.4 (7.1-13.7)%, 13.9 (9.8-18.0)%, and 16.9 (12.0-21.9)% of patents had a distal event at 1, 5, 10, and 15 years, respectively. Limited distal repair with an ascending aortic or hemiarch replacement was associated with acceptable survival and rates of reoperations and distal events. Limited distal repair is a safe and feasible standard approach to ATAAD surgery at a medium-volume center.

A prospective, controlled study on the utility of rotational thromboelastometry in surgery for acute type A aortic dissection.

To evaluate the hemostatic system with ROTEM in patients undergoing surgery for acute type aortic dissection (ATAAD) using elective aortic procedures as controls. This was a prospective, controlled, observational study. The study was performed at a tertiary referral center and university hospital. Twenty-three patients with ATAAD were compared to 20 control patients undergoing elective surgery of the ascending aorta or the aortic root. ROTEM (INTEM, EXTEM, HEPTEM and FIBTEM) was tested at 6 points in time before, during and after surgery for ATAAD or elective aortic surgery. The ATAAD group had an activated coagulation coming into the surgical theatre. The two groups showed activation of both major coagulation pathways during surgery, but the ATAAD group consistently had larger deficiencies. Reversal of the coagulopathy was successful, although none of the groups reached elective baseline until postoperative day 1. ROTEM did not detect low levels of clotting factors at heparin reversal nor low levels of platelets. This study demonstrated that ATAAD is associated with a coagulopathic state. Surgery causes additional damage to the hemostatic system in ATAAD patients as well as in patients undergoing elective surgery of the ascending aorta or the aortic root. ROTEM does not adequately catch the full coagulopathy in ATAAD. A transfusion protocol in ATAAD should be specifically created to target this complex coagulopathic state and ROTEM does not negate the need for routine laboratory tests.

The effect of postoperative anticoagulation on false lumen patency after surgery for acute type A aortic dissection.

BACKGROUND: Patent false lumen has been shown to have a negative impact on prognosis after surgery for acute type A aortic dissection (ATAAD). We aimed to assess the effect of postoperative anticoagulation on false lumen patency and clinical outcomes in relation to false lumen status. METHODS: Postoperative computed tomographies of 156 patients undergoing ATAAD DeBakey type I surgery were retrospectively evaluated for false lumen patency. The patients were divided into groups determined by anticoagulation treatment at discharge. Uni- and multivariable logistic regression was used for analysing the effect of anticoagulation on the false lumen, and Kaplan-Meier estimates were used to assess the association of a patent false lumen with the incidence of reoperation and long-term survival. RESULTS: A patent false lumen was present in 81% of the patients. Postoperative anticoagulants were not associated with a patent false lumen (p = 0.48) in univariable analysis. In multivariable analysis, both hemiarch replacement (OR 0.15, CI95% 0.05-0.49, p = 0.001) and the use of betablockers had a protective effect (OR 0.29, CI95% 0.10-0.85, p = 0.023). The Kaplan-Meier estimates for survival and the composite endpoint of survival and freedom from distal reintervention indicated no difference in outcome between patients in regard to anticoagulation treatment (survival p = 0.43, composite p = 0.82) or false lumen status (survival p = 0.21, composite p = 0.09). CONCLUSION: This study could not show negative effects from the postoperative use of anticoagulants on false lumen status, nor that false lumen patency was associated with poorer prognosis. A hemiarch procedure was shown to be associated with reduced risk of false lumen patency.

Impact of ABO blood group on bleeding complications after surgery for acute type A aortic dissection.

Excessive bleeding is a serious complication associated with impaired survival after surgery for acute type A aortic dissection (ATAAD). Different ABO blood groups are associated with variable levels of circulating von Willebrand factor and therefore potentially altered risks of surgical haemorrhage. The current study aimed to assess the impact of blood group on bleeding complications after ATAAD surgery. This was a retrospective cohort study including 336 patients surgically treated for ATAAD between January 2004 and January 2019. Patients with blood group O were compared with non-O patients. In total, 152 blood group O patients were compared with 184 non-O patients. There were no differences in rates of massive bleeding (27.0 vs. 25.5%, P = 0.767) or re-exploration for bleeding (16.4 vs. 13.0%, P = 0.379) in blood group O and non-O patients, respectively. Median chest tube output 12 h after surgery was 520 ml (350-815 ml) in blood group O and 490 ml (278-703 ml) in non-O patients (P = 0.229). Blood group O patients received more fibrinogen concentrate (6.1 ±â€Š4.0 vs. 4.9 ±â€Š3.3 g, P = 0.023) but administered units of packed red blood cells [5 (2-8) vs. 4 (2-9) U, P = 0.736], platelets [4 (2-4) vs. 3 (2-5) U, P = 0.521] or plasma [4 (1-7) vs. 4 (0-7) U, P = 0.562] were similar. This study could not demonstrate any association between blood group and bleeding after surgery for ATAAD. It cannot be ruled out that potential differences were levelled out by blood group O patients receiving significantly more fibrinogen concentrate.

The role of gelsolin domain 3 in familial amyloidosis (Finnish type).

In the disease familial amyloidosis, Finnish type (FAF), also known as AGel amyloidosis (AGel), the mechanism by which point mutations in the calcium-regulated actin-severing protein gelsolin lead to furin cleavage is not understood in the intact protein. Here, we provide a structural and biochemical characterization of the FAF variants. X-ray crystallography structures of the FAF mutant gelsolins demonstrate that the mutations do not significantly disrupt the calcium-free conformations of gelsolin. Small-angle X-ray-scattering (SAXS) studies indicate that the FAF calcium-binding site mutants are slower to activate, whereas G167R is as efficient as the wild type. Actin-regulating studies of the gelsolins at the furin cleavage pH (6.5) show that the mutant gelsolins are functional, suggesting that they also adopt relatively normal active conformations. Deletion of gelsolin domains leads to sensitization to furin cleavage, and nanobody-binding protects against furin cleavage. These data indicate instability in the second domain of gelsolin (G2), since loss or gain of G2-stabilizing interactions impacts the efficiency of cleavage by furin. To demonstrate this principle, we engineered non-FAF mutations in G3 that disrupt the G2-G3 interface in the calcium-activated structure. These mutants led to increased furin cleavage. We carried out molecular dynamics (MD) simulations on the FAF and non-FAF mutant G2-G3 fragments of gelsolin. All mutants showed an increase in the distance between the center of masses of the 2 domains (G2 and G3). Since G3 covers the furin cleavage site on G2 in calcium-activated gelsolin, this suggests that destabilization of this interface is a critical step in cleavage.

The role of von Willebrand factor in acute type A aortic dissection and aortic surgery.

INTRODUCTION: Massive bleeding is a serious complication associated with impaired survival after surgery for acute type A aortic dissection (ATAAD). There are no previous reports evaluating the effect of ATAAD and associated surgery on von Willebrand factor (VWF). The aim of the present study was to analyze VWF activity (VWF:GPIbM) and thus the potential of Factor (F) VIII/VWF concentrate as a treatment for refractory bleeding in surgery for acute type A aortic dissection. MATERIAL AND METHODS: We prospectively compared serial measurements of VWF:GPIbM in 25 patients with ATAAD to 20 control patients undergoing elective surgery of the ascending aorta or the aortic root. In 10 of the ATAAD patients, high molecular weight multimer distribution was measured. RESULTS: Preoperatively, ATAAD patients demonstrated significantly higher VWF:GPIbM (1.58 (1.40-2.05) kIU/L vs 1.25 (1.02-1.42) kIU/L, p = 0.003). In the ATAAD group, VWF:GPIbM significantly decreased to 1.24 (0.98-1.44) kIU/L at lowest core temperature (T0 vs T1 p < 0.001), but remained unchanged in the elective group (1.25 (1.04-1.43) kIU/L, T0 vs T1 p < 0.625). Neither aortic dissection nor hypothermia caused any changes to the proportion of high molecular weight multimers when compared to control patients. Both groups demonstrated supernormal VWF:GPIbM on the first and fifth day after surgery. CONCLUSIONS: This report showed that patients with acute aortic dissection had increased levels of VWF:GPIbM before surgery that decreased slightly during surgery. Our study could not provide evidence that would encourage administration of FVIII/VWF concentrate for major bleeding in patients undergoing surgery for ATAAD as well as elective aortic procedures.

The Coagulopathy of Acute Type A Aortic Dissection: A Prospective, Observational Study.

OBJECTIVE: To evaluate the hemostatic system in patients undergoing surgery for acute type A aortic dissection (ATAAD) compared with those undergoing elective aortic procedures. DESIGN: This was a prospective, observational study. SETTING: The study was performed at a single university hospital. PARTICIPANTS: Twenty-five patients with ATAAD were compared with 20 control patients undergoing elective surgery of the ascending aorta or the aortic root. INTERVENTIONS: No interventions were performed. MEASUREMENTS AND MAIN RESULTS: Platelet count and levels of fibrinogen, D-dimer, prothrombin time/international normalized ratio, activated partial thromboplastin time, and antithrombin were analyzed perioperatively and compared between the 2 groups. Patients with ATAAD had lower preoperative levels of platelets (188 [156-217] × 109/L v 221 [196-240] × 109/L; p = 0.018), fibrinogen (1.9 [1.6-2.4] g/L v 2.8 [2.2-3.0] g/L; p = 0.003), and antithrombin (0.81 [0.73-0.94] kIU/L v 0.96 [0.92-1.00] kIU/L; p = 0.003) and significantly higher levels of D-dimer (2.9 [1.7-9.7] mg/L v 0.1 [0.1-0.2] mg/L; p < 0.001) and prothrombin time/international normalized ratio (1.15 [1.1-1.2] v 1.0 [0.93-1.0]; p = 0.001). Surgery caused significant changes of the coagulation system in both groups. Intraoperative bleeding volumes were larger in the ATAAD group (2,407 [1,804-3,209] mL v 1,212 [917-1,920] mL; p < 0.001), and patients undergoing ATAAD surgery received significantly more transfusions of red blood cells (2.5 [0.25-4.75] U v 0 [0-2.75] U; p = 0.022), platelets (4 [3.25-6] U v 2 [2-4] U; p = 0.002), and plasma (2 [0-4] U v 0 [0-0] U; p = 0.004) compared with the elective group. CONCLUSIONS: This study demonstrates that ATAAD is associated with a coagulopathic state. Surgery causes additional damage to the hemostatic system in ATAAD patients, but also in patients undergoing elective surgery of the ascending aorta or the aortic root.

Perioperative Hyperlactemia Is a Poor Predictor of Outcome in Patients Undergoing Surgery for Acute Type-A Aortic Dissection.

OBJECTIVE: In patients presenting with acute type-A aortic dissection (aTAAD), lactic acid measurement is a frequently used analysis for diagnosis of acute ischemia, which may have a dismal prognosis. The aim of the current study was to determine the performance of perioperative arterial lactic acid measurements in predicting outcome in aTAAD patients. DESIGN: Retrospective, observational study. SETTING: Cardiothoracic surgery unit at a tertiary-level hospital. PARTICIPANTS: The study involved 285 consecutive patients undergoing surgery for aTAAD. INTERVENTIONS: Preoperative and postoperative lactic acid levels were measured and evaluated together with clinical data related to outcome, including in-hospital and 1-year mortality. MEASUREMENTS AND MAIN RESULTS: Altogether, 37 patients (13%) died during the index hospital admission, and survival was 84.4 ± 2.2 at 1 year. Preoperative cardiac malperfusion (odds ratio [OR] 3.1; 95% confidence interval [CI] 1.3-7.3) and cerebral malperfusion (OR 2.6; 95% CI 1.2-5.6) were associated significantly with poorer 1-year survival. The area under the curve (AUC) for in-hospital and 1-year mortality in relation to preoperative lactic acid levels was 0.684 and 0.673, respectively, corresponding to a lactic acid cut-off for in-hospital mortality of 2.75 mmol/L (sensitivity 56%; specificity 72%) and a cut-off for 1-year mortality of 2.85 mmol/L (sensitivity 48%; specificity 74%). The AUC for in-hospital and 1-year mortality in relation to lactic acid levels measured postoperatively on arrival at the intensive care unit was 0.582 and 0.498, respectively. CONCLUSION: Although hyperlactemia in aTAAD indicates an increased risk of postoperative mortality, the sole use of lactic acid levels as a tool for accurate assessment of postoperative mortality is inadvisable due to its poor discriminatory performance.

The evolution of Sex-linked barring alleles in chickens involves both regulatory and coding changes in CDKN2A.

Sex-linked barring is a fascinating plumage pattern in chickens recently shown to be associated with two non-coding and two missense mutations affecting the ARF transcript at the CDKN2A tumor suppressor locus. It however remained a mystery whether all four mutations are indeed causative and how they contribute to the barring phenotype. Here, we show that Sex-linked barring is genetically heterogeneous, and that the mutations form three functionally different variant alleles. The B0 allele carries only the two non-coding changes and is associated with the most dilute barring pattern, whereas the B1 and B2 alleles carry both the two non-coding changes and one each of the two missense mutations causing the Sex-linked barring and Sex-linked dilution phenotypes, respectively. The data are consistent with evolution of alleles where the non-coding changes occurred first followed by the two missense mutations that resulted in a phenotype more appealing to humans. We show that one or both of the non-coding changes are cis-regulatory mutations causing a higher CDKN2A expression, whereas the missense mutations reduce the ability of ARF to interact with MDM2. Caspase assays for all genotypes revealed no apoptotic events and our results are consistent with a recent study indicating that the loss of melanocyte progenitors in Sex-linked barring in chicken is caused by premature differentiation and not apoptosis. Our results show that CDKN2A is a major locus driving the differentiation of avian melanocytes in a temporal and spatial manner.

Erythropoietin and protection of renal function in cardiac surgery (the EPRICS Trial).

BACKGROUND: To date, there are no known methods for preventing acute kidney injury after cardiac surgery. Increasing evidence suggests that erythropoietin has renal antiapoptotic and tissue protective effects. However, recent human studies have shown conflicting results. The authors aimed to study the effect of a single high-dose erythropoietin preoperatively on renal function after coronary artery bypass grafting in patients with preoperative impaired renal function. METHODS: This single-center, randomized, double-blind, placebo-controlled study included 75 patients scheduled for coronary artery bypass grafting with preexisting renal impairment estimated glomerular filtration rate based on p-cystatin C (<60 and >15 ml/min). The patients either received a single high-dose erythropoietin (400 IU/kg) or placebo preoperatively. The primary endpoint was renal protection evaluated by p-cystatin C at the third postoperative day compared to the preoperative values. Incidence of acute kidney injury and other renal biomarker changes were among secondary endpoints. RESULTS: There was no statistically significant difference on the third postoperative day for relative p-cystatin C level changes from baseline between the groups, 131 ± 31% (mean ± SD) for the study group and 125 ± 24% for the control group (P = 0.31; 95% CI, -0.6 to 20% for the difference). There were no statistically significant differences in other renal biomarkers or measures between the groups (p-neutrophil gelatinase-associated lipocalin, p-creatinine, p-urea, and estimated glomerular filtration rate). There were no other differences in outcome variables between the groups. CONCLUSION: Intravenous administration of a single high-dose (400 IU/kg) erythropoietin did not have a renal protective effect on patients with reduced kidney function undergoing coronary artery bypass surgery.

Microtubule-like properties of the bacterial actin homolog ParM-R1.

In preparation for mammalian cell division, microtubules repeatedly probe the cytoplasm to capture chromosomes and assemble the mitotic spindle. Critical features of this microtubule system are the formation of radial arrays centered at the centrosomes and dynamic instability, leading to persistent cycles of polymerization and depolymerization. Here, we show that actin homolog, ParM-R1 that drives segregation of the R1 multidrug resistance plasmid from Escherichia coli, can also self-organize in vitro into asters, which resemble astral microtubules. ParM-R1 asters grow from centrosome-like structures consisting of interconnected nodes related by a pseudo 8-fold symmetry. In addition, we show that ParM-R1 is able to perform persistent microtubule-like oscillations of assembly and disassembly. In vitro, a whole population of ParM-R1 filaments is synchronized between phases of growth and shrinkage, leading to prolonged synchronous oscillations even at physiological ParM-R1 concentrations. These results imply that the selection pressure to reliably segregate DNA during cell division has led to common mechanisms within diverse segregation machineries.