Rationale and design of the colchicine for the prevention of perioperative atrial fibrillation in patients undergoing major noncardiac thoracic surgery (COP-AF) trial.

BACKGROUND: Perioperative atrial fibrillation (AF) and myocardial injury after noncardiac surgery (MINS) are common complications after noncardiac surgery. Inflammation has been implicated in the pathogenesis of both disorders. The COP-AF trial tests the hypothesis that colchicine reduces the incidence of perioperative AF and MINS in patients undergoing major noncardiac thoracic surgery. METHODS AND RESULTS: The 'COlchicine for the Prevention of Perioperative Atrial Fibrillation' (COP-AF) trial is an international, blinded, randomized trial that compares colchicine to placebo in patients aged at least 55 years and undergoing major noncardiac thoracic surgery with general anesthesia. Exclusion criteria include a history of AF and a contraindication to colchicine (eg, severe renal dysfunction). Oral colchicine at a dose of 0.5 mg or matching placebo is given within 4 hours before surgery. Thereafter, patients receive colchicine 0.5 mg or placebo twice daily for a total of 10 days. The 2 independent co-primary outcomes are clinically important perioperative AF (including atrial flutter) and MINS during 14 days of follow-up. The main safety outcomes are sepsis or infection and non-infectious diarrhea. We aim to enroll 3,200 patients from approximately 40 sites across 11 countries to have at least 80% power for the independent evaluation of the 2 co-primary outcomes. The COP-AF main results are expected in 2023. CONCLUSIONS: COP-AF is a large randomized and blinded trial designed to determine whether colchicine reduces the risk of perioperative AF or MINS in patients who have major noncardiac thoracic surgery.

Tranexamic acid and rosuvastatin in patients at risk of cardiovascular events after noncardiac surgery: a pilot of the POISE-3 randomized controlled trial.

BACKGROUND: Surgical bleeding is associated with postoperative cardiovascular complications. The efficacy and safety of tranexamic acid (TXA) in noncardiac surgery are still uncertain. Statins may prevent perioperative cardiovascular complications. We conducted a pilot to assess the feasibility of a perioperative trial of TXA and rosuvastatin. METHODS: Using a factorial design, we randomized patients at cardiovascular risk undergoing noncardiac surgery to intravenous TXA (1 g at the start and end of surgery) or placebo, and oral rosuvastatin (40 mg before and 20 mg daily for 30 days after surgery) or placebo. Feasibility outcomes included recruitment rates, follow-up, and compliance to interventions. Clinical outcomes were secondarily explored. RESULTS: After 3 months, we changed the design to a partial factorial due to the difficult recruitment of statin-naive patients. Over 6 months, 100 patients were randomized in the TXA trial (49 TXA, 51 placebo), 34 in the rosuvastatin trial (18 rosuvastatin, 16 placebo). Ninety-two percent (95% CI 80-98) of TXA and 86% (95% CI 74-94) of TXA-placebo patients received the 2 study doses. Thirty-three percent (95% CI 13-59) of rosuvastatin patients and 37% (95% CI 15-65) of rosuvastatin-placebo patients discontinued the study drug. A major cardiovascular complication occurred at 30 days in 1 TXA and 6 TXA-placebo patients, and 1 rosuvastatin and no rosuvastatin-placebo patients. CONCLUSIONS: Our pilot study supports the feasibility of a perioperative TXA trial in noncardiac surgery. Feasibility of a perioperative rosuvastatin trial is uncertain because of a high prevalence of statin use in the target population and concerns about compliance. TRIAL REGISTRATION: ClinicalTrials.govNCT02546648.

Neuroprotection Following Concussion: The Potential Role for Cannabidiol.

Cannabidiol (CBD) has been generating increasing interest in medicine due to its therapeutic properties and an apparent lack of negative side effects. Research has suggested that high dosages of CBD can be taken acutely and chronically with little to no risk. This review focuses on the neuroprotective effects of a CBD, with an emphasis on its implications for recovering from a mild traumatic brain injury (TBI) or concussion. CBD has been shown to influence the endocannabinoid system, both by affecting cannabinoid receptors and other receptors involved in the endocannabinoid system such as vanilloid receptor 1, adenosine receptors, and 5-hydroxytryptamine via cannabinoid receptor-independent mechanisms. Concussions can result in many physiological consequences, potentially resulting in post-concussion syndrome. While impairments in cerebrovascular and cardiovascular physiology following concussion have been shown, there is unfortunately still no single treatment available to enhance recovery. CBD has been shown to influence the blood brain barrier, brain-derived neurotrophic factors, cognitive capacity, the cerebrovasculature, cardiovascular physiology, and neurogenesis, all of which have been shown to be altered by concussion. CBD can therefore potentially provide treatment to enhance neuroprotection by reducing inflammation, regulating cerebral blood flow, enhancing neurogenesis, and protecting the brain against reactive oxygen species. Double-blind randomized controlled trials are still required to validate the use of CBD as medication following mild TBIs, such as concussion.

Effects of accelerated versus standard care surgery on the risk of acute kidney injury in patients with a hip fracture: a substudy protocol of the hip fracture Accelerated surgical TreaTment And Care tracK (HIP ATTACK) international randomised controlled trial.

INTRODUCTION: Inflammation, dehydration, hypotension and bleeding may all contribute to the development of acute kidney injury (AKI). Accelerated surgery after a hip fracture can decrease the exposure time to such contributors and may reduce the risk of AKI. METHODS AND ANALYSIS: Hip fracture Accelerated surgical TreaTment And Care tracK (HIP ATTACK) is a multicentre, international, parallel-group randomised controlled trial (RCT). Patients who suffer a hip fracture are randomly allocated to either accelerated medical assessment and surgical repair with a goal of surgery within 6 hours of diagnosis or standard care where a repair typically occurs 24 to 48 hours after diagnosis. The primary outcome of this substudy is the development of AKI within 7 days of randomisation. We anticipate at least 1998 patients will participate in this substudy. ETHICS AND DISSEMINATION: We obtained ethics approval for additional serum creatinine recordings in consecutive patients enrolled at 70 participating centres. All patients provide consent before randomisation. We anticipate reporting substudy results by 2021. TRIAL REGISTRATION NUMBER: NCT02027896; Pre-results.

Rationale and design of the HIP fracture Accelerated surgical TreaTment And Care tracK (HIP ATTACK) Trial: a protocol for an international randomised controlled trial evaluating early surgery for hip fracture patients.

INTRODUCTION: Annually, millions of adults suffer hip fractures. The mortality rate post a hip fracture is 7%-10% at 30 days and 10%-20% at 90 days. Observational data suggest that early surgery can improve these outcomes in hip fracture patients. We designed a clinical trial-HIP fracture Accelerated surgical TreaTment And Care tracK (HIP ATTACK) to determine the effect of accelerated surgery compared with standard care on the 90-day risk of all-cause mortality and major perioperative complications. METHODS AND ANALYSIS: HIP ATTACK is a multicentre, international, parallel group randomised controlled trial (RCT) that will include patients ≥45 years of age and diagnosed with a hip fracture from a low-energy mechanism requiring surgery. Patients are randomised to accelerated medical assessment and surgical repair (goal within 6 h) or standard care. The co-primary outcomes are (1) all-cause mortality and (2) a composite of major perioperative complications (ie, mortality and non-fatal myocardial infarction, pulmonary embolism, pneumonia, sepsis, stroke, and life-threatening and major bleeding) at 90 days after randomisation. All patients will be followed up for a period of 1 year. We will enrol 3000 patients. ETHICS AND DISSEMINATION: All centres had ethics approval before randomising patients. Written informed consent is required for all patients before randomisation. HIP ATTACK is the first large international trial designed to examine whether accelerated surgery can improve outcomes in patients with a hip fracture. The dissemination plan includes publishing the results in a policy-influencing journal, conference presentations, engagement of influential medical organisations, and providing public awareness through multimedia resources. TRIAL REGISTRATION NUMBER: NCT02027896; Pre-results.

A Novel Approach for Total Nasal Reconstruction.

A 61-year-old woman who lost her nose, upper lip, and most of her midface bony structures because of cancer 20 years previously underwent advanced surgical reconstruction. This patient previously underwent multiple reconstructive surgeries that failed to satisfactorily restore her nose. Therefore, a multistage reconstruction was performed to recreate a complete nose and increase her upper lip length. Because of a lack of sufficient facial bone and nasal supporting structures, the reconstruction was extremely challenging. Virtual surgical planning technology was used to create a customized titanium nasal plate. The patient's nose was successfully reconstructed using the nasal plate, costal cartilage, and a paramedian forehead flap. The patient is highly satisfied with the cosmetic and functional results and has had marked psychosocial improvement since the reconstruction.

Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): an international, randomised, placebo-controlled trial.

BACKGROUND: Myocardial injury after non-cardiac surgery (MINS) increases the risk of cardiovascular events and deaths, which anticoagulation therapy could prevent. Dabigatran prevents perioperative venous thromboembolism, but whether this drug can prevent a broader range of vascular complications in patients with MINS is unknown. The MANAGE trial assessed the potential of dabigatran to prevent major vascular complications among such patients. METHODS: In this international, randomised, placebo-controlled trial, we recruited patients from 84 hospitals in 19 countries. Eligible patients were aged at least 45 years, had undergone non-cardiac surgery, and were within 35 days of MINS. Patients were randomly assigned (1:1) to receive dabigatran 110 mg orally twice daily or matched placebo for a maximum of 2 years or until termination of the trial and, using a partial 2-by-2 factorial design, patients not taking a proton-pump inhibitor were also randomly assigned (1:1) to omeprazole 20 mg once daily, for which results will be reported elsewhere, or matched placebo to measure its effect on major upper gastrointestinal complications. Research personnel randomised patients through a central 24 h computerised randomisation system using block randomisation, stratified by centre. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary efficacy outcome was the occurrence of a major vascular complication, a composite of vascular mortality and non-fatal myocardial infarction, non-haemorrhagic stroke, peripheral arterial thrombosis, amputation, and symptomatic venous thromboembolism. The primary safety outcome was a composite of life-threatening, major, and critical organ bleeding. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01661101. FINDINGS: Between Jan 10, 2013, and July 17, 2017, we randomly assigned 1754 patients to receive dabigatran (n=877) or placebo (n=877); 556 patients were also randomised in the omeprazole partial factorial component. Study drug was permanently discontinued in 401 (46%) of 877 patients allocated to dabigatran and 380 (43%) of 877 patients allocated to placebo. The composite primary efficacy outcome occurred in fewer patients randomised to dabigatran than placebo (97 [11%] of 877 patients assigned to dabigatran vs 133 [15%] of 877 patients assigned to placebo; hazard ratio [HR] 0·72, 95% CI 0·55-0·93; p=0·0115). The primary safety composite outcome occurred in 29 patients (3%) randomised to dabigatran and 31 patients (4%) randomised to placebo (HR 0·92, 95% CI 0·55-1·53; p=0·76). INTERPRETATION: Among patients who had MINS, dabigatran 110 mg twice daily lowered the risk of major vascular complications, with no significant increase in major bleeding. Patients with MINS have a poor prognosis; dabigatran 110 mg twice daily has the potential to help many of the 8 million adults globally who have MINS to reduce their risk of a major vascular complication [corrected]. FUNDING: Boehringer Ingelheim and Canadian Institutes of Health Research.

Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis.

BACKGROUND: Supplemental oxygen is often administered liberally to acutely ill adults, but the credibility of the evidence for this practice is unclear. We systematically reviewed the efficacy and safety of liberal versus conservative oxygen therapy in acutely ill adults. METHODS: In the Improving Oxygen Therapy in Acute-illness (IOTA) systematic review and meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, HealthSTAR, LILACS, PapersFirst, and the WHO International Clinical Trials Registry from inception to Oct 25, 2017, for randomised controlled trials comparing liberal and conservative oxygen therapy in acutely ill adults (aged ≥18 years). Studies limited to patients with chronic respiratory diseases or psychiatric disease, patients on extracorporeal life support, or patients treated with hyperbaric oxygen therapy or elective surgery were excluded. We screened studies and extracted summary estimates independently and in duplicate. We also extracted individual patient-level data from survival curves. The main outcomes were mortality (in-hospital, at 30 days, and at longest follow-up) and morbidity (disability at longest follow-up, risk of hospital-acquired pneumonia, any hospital-acquired infection, and length of hospital stay) assessed by random-effects meta-analyses. We assessed quality of evidence using the grading of recommendations assessment, development, and evaluation approach. This study is registered with PROSPERO, number CRD42017065697. FINDINGS: 25 randomised controlled trials enrolled 16 037 patients with sepsis, critical illness, stroke, trauma, myocardial infarction, or cardiac arrest, and patients who had emergency surgery. Compared with a conservative oxygen strategy, a liberal oxygen strategy (median baseline saturation of peripheral oxygen [SpO2] across trials, 96% [range 94-99%, IQR 96-98]) increased mortality in-hospital (relative risk [RR] 1·21, 95% CI 1·03-1·43, I2=0%, high quality), at 30 days (RR 1·14, 95% CI 1·01-1·29, I2=0%, high quality), and at longest follow-up (RR 1·10, 95% CI 1·00-1·20, I2=0%, high quality). Morbidity outcomes were similar between groups. Findings were robust to trial sequential, subgroup, and sensitivity analyses. INTERPRETATION: In acutely ill adults, high-quality evidence shows that liberal oxygen therapy increases mortality without improving other patient-important outcomes. Supplemental oxygen might become unfavourable above an SpO2 range of 94-96%. These results support the conservative administration of oxygen therapy. FUNDING: None.

Design of a Randomized Placebo-Controlled Trial to Assess Dabigatran and Omeprazole in Patients with Myocardial Injury after Noncardiac Surgery (MANAGE).

BACKGROUND: Worldwide approximately 200 million adults undergo major surgery annually, of whom 8 million are estimated to suffer a myocardial injury after noncardiac surgery (MINS). There is currently no trial data informing the management of MINS. Antithrombotic agents such as direct oral anticoagulants might prevent major vascular complications in patients with MINS. METHODS: The Management of Myocardial Injury After Noncardiac Surgery (MANAGE) trial is a large international blinded randomized controlled trial of dabigatran vs placebo in patients who suffered MINS. We used a partial factorial design to also determine the effect of omeprazole vs placebo in reducing upper gastrointestinal bleeding and complications. Both study drugs were initiated in eligible patients within 35 days of suffering MINS and continued for a maximum of 2 years. The primary outcome is a composite of major vascular complications for the dabigatran trial and a composite of upper gastrointestinal complications for the omeprazole trial. We present the rationale and design of the trial and baseline characteristics of enrolled patients. RESULTS: The trial randomized 1754 patients between January 2013 and July 2017. Patients' mean age was 69.9 years, 51.1% were male, 14.3% had a history of peripheral artery disease, 6.6% had a history of stroke or transient ischemic attack, 12.9% had a previous myocardial infarction, and 26.0% had diabetes. The diagnosis of MINS was on the basis of an isolated ischemic troponin elevation in 80.4% of participants. CONCLUSION: MANAGE is the first randomized controlled trial to evaluate a potential treatment of patients who suffered MINS.

The effect of colchicine administration on postoperative pleural effusion following lung resection: a randomized blinded placebo-controlled feasibility pilot study.

OBJECTIVES: This substudy of the colchicine for prevention of perioperative atrial fibrillation (COP-AF) pilot trial seeks to assess the effect of colchicine administration on the volume of postoperative pleural drainage, duration of chest tube in situ and length of stay following lung resection. METHODS: Between April 2014 and April 2015, 100 patients undergoing lung resection at 2 tertiary care centres participated in a pilot blinded randomized trial comparing perioperative twice daily 0.6 mg of colchicine orally (n = 49) or placebo (n = 51) twice daily for 10 days. The primary outcome was total pleural drainage volume, which was recorded in 8-h intervals for the first 2 postoperative days per standardized protocol. RESULTS: Only 1 patient did not complete the trial. The mean volume of pleural drainage at 40-h mark postoperation was significantly less in the colchicine group (550.9 ml) compared with the placebo group (741.3 ml, P = 0.039). Compared with the placebo group, the colchicine group showed significantly less mean pleural drainage on postoperative Day 2 (583.8 vs 763.3 ml, P = 0.039) and beyond. There were no differences in mean time to chest tube removal (6.8 days for the colchicine group vs 5.9 days for the placebo group, P = 0.585) and mean hospital length of stay (7.4 vs 6.9 days, P = 0.641). CONCLUSIONS: Oral colchicine is potentially effective in diminishing the amount of pleural drainage following lung resection and can be considered in patients at high risk of large postoperative pleural effusion. A full-scale, prospective placebo-controlled randomized trial is needed to assess the clinical significance of perioperative colchicine administration following oncological lung resection.

Colchicine for Prevention of Perioperative Atrial Fibrillation in patients undergoing lung resection surgery: a pilot randomized controlled study.

OBJECTIVES: We carried out a pilot randomized controlled study to determine the feasibility of a large trial evaluating the impact of colchicine versus placebo on postoperative atrial fibrillation or atrial flutter (POAF) among patients undergoing lung resection surgery. METHODS: Patients ≥55 years of age undergoing lung resection surgery were randomly assigned to receive colchicine 0.6 mg or placebo starting a few hours before surgery. Postoperatively, patients received colchicine 0.6 mg or placebo twice daily for an additional 9 days. Our feasibility outcomes included the period of time required to recruit 100 patients, the completeness of follow-up and compliance with the study drug. The primary efficacy outcome was POAF within 30 days of randomization. RESULTS: One hundred patients were randomized (49 to colchicine and 51 to placebo) over a period of 12 months at 2 centres in Canada. All patients completed the 30-day follow-up. The mean staff time required to recruit and to follow-up each patient was 165 min. In all, 71% of patients completed the study drug course without interruption. Patient refusal to continuing taking the study drug was the main reason for permanent drug discontinuation. New POAF occurred in 5 (10.2%) patients in the colchicine group and 7 (13.7%) patients in the placebo group (adjusted hazard ratio 0.69, 95% confidence interval 0.20-2.34). CONCLUSIONS: These results show the feasibility of a trial evaluating Colchicine for the prevention of perioperative Atrial Fibrillation in patients undergoing lung resection surgery. This pilot study will serve as the foundation for the large multicentre COP-AF trial.

Alcohol Misuse Link to POEMS Syndrome in a Patient.

Previously called Crow-Fukase syndrome, POEMS syndrome is characterized by poly-neuropathy, osteo-sclerotic myeloma, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes. Extremely elevated levels of serum vascular endothelial growth factor (VEGF) are characteristic of the syndrome. Chronic hepatitis B (HBV) and C (HCV) infections can also be present in POEMS. The pathogenesis of the syndrome is not well understood. The link between chronic alcohol consumption and this malignant condition has not been reported until now. In addition, no previous study has evaluated the influence of cytokine and chemokines or viruses in the severity and evolution of POEMS. OBJECTIVES: (1) to describe a heavy-alcohol user, who was diagnosed with POEMS; (2) to demonstrate the utility of quantitative measurement of serum levels of VEGF in the diagnosis of POEMS and the monitoring of therapeutic interventions; (3) to demonstrate that overproduction of pro-inflammatory cytokines is a characteristic of POEMS. METHODS: We describe a case of a POEMS patient presenting HCV and who is a heavy drinker; we compare the serum levels of cytokines and chemokines between the POEMS patient with 80 patients with HCV, 12 healthy controls, and 80 individuals with alcoholic liver disease (ALD). We quantified (ELISA pg/mL) the levels of VEGF, Interferon gamma (IFN-γ), Tumor Necrosis Factor alpha (TNF-α), Regulated-upon-Activation Normal-T-cell-Expressed and presumably-Secreted (RANTES), and Nuclear Factor kappa-B (NFκB). RESULTS: In POEMS patients, VEGF levels were elevated versus control or other diseases, TNFα levels were higher versus control, but lower when compared with HCV or ALD patients. VEGF levels in POEMS patients decreased with therapeutic intervention. CONCLUSIONS: Chronic alcohol misuse can be a strong risk factor to rare malignancies such as POEMS syndrome. Extreme elevation of VEGF levels is diagnostic for POEMS syndrome, and should be followed to assess response to therapy. In addition, other comorbidities should be considered individually to ensure personalized therapeutic intervention.

Risk Factors for Severe Complications of Operative Mandibular Fractures.

PURPOSE: The purpose of the present study was to identify the risk factors for major complications developing during the operative treatment of mandibular fractures. PATIENTS AND METHODS: We conducted a retrospective medical record review of patients who had undergone open reduction, internal fixation of mandibular fractures from August 1, 2012 to December 31, 2014 at a large, urban teaching hospital and level 1 trauma center. The outcome variable of interest was major complications, defined as the occurrence of any one of the following events: hospital readmission, return to the operating room, and a prolonged, unexpected postoperative stay. Multiple demographic, social, medical, injury-related, and treatment-related variables were recorded during the medical record review. The relationships between these variables and our outcome variable were analyzed using univariate and multivariable logistic regression analyses. RESULTS: A total of 317 patients met the inclusion criteria. The hospital readmission rate was 7.2%, the reoperation rate was 9.5%, and the rate of unplanned, prolonged admission was 0.6%, for a total major complication rate of 11.4%. Eight variables reached statistical significance in their association with the occurrence of major complications. These were the presence of medical comorbidities, a diagnosis of depression, a diagnosis of a psychiatric disorder, incarceration, interpersonal violence as a mechanism of injury, the presence of a left angle fracture, the removal of a tooth in the line of fracture, and patient noncompliance. On multivariable analysis, patient noncompliance, depression, the presence of a left angle fracture, and the removal of a tooth in the line of fracture continued to have statistically significant associations with the occurrence of major complications. CONCLUSIONS: The identification of risk factors for the development of complications in mandibular trauma is a primary concern for surgeons in the modern healthcare system. The present study identified a number of variables significantly associated with an increased risk of the occurrence of major complications, and special consideration should be given to patients with these risk factors.

Barriers to goals of care discussions with seriously ill hospitalized patients and their families: a multicenter survey of clinicians.

IMPORTANCE: Seriously ill hospitalized patients have identified communication and decision making about goals of care as high priorities for quality improvement in end-of-life care. Interventions to improve care are more likely to succeed if tailored to existing barriers. OBJECTIVE: To determine, from the perspective of hospital-based clinicians, (1) barriers impeding communication and decision making about goals of care with seriously ill hospitalized patients and their families and (2) their own willingness and the acceptability for other clinicians to engage in this process. DESIGN, SETTING, AND PARTICIPANTS: Multicenter survey of medical teaching units of nurses, internal medicine residents, and staff physicians from participating units at 13 university-based hospitals from 5 Canadian provinces. MAIN OUTCOMES AND MEASURES: Importance of 21 barriers to goals of care discussions rated on a 7-point scale (1 = extremely unimportant; 7 = extremely important). RESULTS: Between September 2012 and March 2013, questionnaires were returned by 1256 of 1617 eligible clinicians, for an overall response rate of 77.7% (512 of 646 nurses [79.3%], 484 of 634 residents [76.3%], 260 of 337 staff physicians [77.2%]). The following family member-related and patient-related factors were consistently identified by all 3 clinician groups as the most important barriers to goals of care discussions: family members' or patients' difficulty accepting a poor prognosis (mean [SD] score, 5.8 [1.2] and 5.6 [1.3], respectively), family members' or patients' difficulty understanding the limitations and complications of life-sustaining treatments (5.8 [1.2] for both groups), disagreement among family members about goals of care (5.8 [1.2]), and patients' incapacity to make goals of care decisions (5.6 [1.2]). Clinicians perceived their own skills and system factors as less important barriers. Participants viewed it as acceptable for all clinician groups to engage in goals of care discussions-including a role for advance practice nurses, nurses, and social workers to initiate goals of care discussions and be a decision coach. CONCLUSIONS AND RELEVANCE: Hospital-based clinicians perceive family member-related and patient-related factors as the most important barriers to goals of care discussions. All health care professionals were viewed as playing important roles in addressing goals of care. These findings can inform the design of future interventions to improve communication and decision making about goals of care.

Role of the carboxy terminus of SecA in iron acquisition, protein translocation, and virulence of the bacterial pathogen Acinetobacter baumannii.

Acinetobacter baumannii is a Gram-negative opportunistic nosocomial pathogen that causes pneumonia and soft tissue and systemic infections. Screening of a transposon insertion library of A. baumannii ATCC 19606T resulted in the identification of the 2010 derivative, which, although capable of growing well in iron-rich media, failed to prosper under iron chelation. Genetic, molecular, and functional assays showed that 2010's iron utilization-deficient phenotype is due to an insertion within the 3' end of secA, which results in the production of a C-terminally truncated derivative of SecA. SecA plays a critical role in protein translocation through the SecYEG membrane channel. Accordingly, the secA mutation resulted in undetectable amounts of the ferric acinetobactin outer membrane receptor protein BauA while not affecting the production of other acinetobactin membrane protein transport components, such as BauB and BauE, or the secretion of acinetobactin by 2010 cells cultured in the presence of subinhibitory concentrations of the synthetic iron chelator 2,2'-dipyridyl. Outer membrane proteins involved in nutrient transport, adherence, and biofilm formation were also reduced in 2010. The SecA truncation also increased production of 30 different proteins, including proteins involved in adaptation/tolerance responses. Although some of these protein changes could negatively affect the pathobiology of the 2010 derivative, its virulence defect is mainly due to its inability to acquire iron via the acinetobactin-mediated system. These results together indicate that although the C terminus of the A. baumannii ATCC 19606T SecA is not essential for viability, it plays a critical role in the production and translocation of different proteins and virulence.

A hybrid CFHR3-1 gene causes familial C3 glomerulopathy.

Controlled activation of the complement system, a key component of innate immunity, enables destruction of pathogens with minimal damage to host tissue. Complement factor H (CFH), which inhibits complement activation, and five CFH-related proteins (CFHR1-5) compose a family of structurally related molecules. Combined deletion of CFHR3 and CFHR1 is common and confers a protective effect in IgA nephropathy. Here, we report an autosomal dominant complement-mediated GN associated with abnormal increases in copy number across the CFHR3 and CFHR1 loci. In addition to normal copies of these genes, affected individuals carry a unique hybrid CFHR3-1 gene. In addition to identifying an association between these genetic observations and complement-mediated kidney disease, these results provide insight into the protective role of the combined deletion of CFHR3 and CFHR1 in IgA nephropathy.

Renal artery stenosis is not associated with the development of acute renal failure following coronary artery bypass grafting.

BACKGROUND: Acute renal failure (ARF) is a frequent complication of coronary artery bypass grafting (CABG) surgery and is strongly associated with perioperative morbidity and mortality. We hypothesized that renal artery stenosis (RAS), causing occult renal ischemia, may be an important factor contributing to development of ARF after CABG surgery. METHODS: Preoperative and intraoperative data on 798 consecutive adult patients undergoing CABG surgery with cardiopulmonary bypass from February 1, 1995 to February 1, 1997 (who had also undergone an abdominal aortogram for the evaluation of RAS) were recorded and entered into a computerized database. The development of ARF was defined as a rise in serum creatinine of 1 mg/dL (88.4 micromol/L) above baseline postoperatively. The association between the presence of renal artery stenosis together with preoperative and intraoperative variables and the development of ARF was assessed by multivariate logistic regression. RESULTS: A total of 798 patients underwent isolated coronary bypass grafting, of which 18.7% demonstrated 50% or more RAS. ARF developed in 82 patients (10.2%), of which three (0.3%) required dialysis support. The mortality for patients who developed ARF was 14% (OR 15, P=0.0001) compared to 0.2% among those who did not develop ARF. The presence of renal artery stenosis of any severity ranging from unilateral 50% RAS to bilateral 95% RAS was not associated with the subsequent development of ARF. CONCLUSIONS: The development of ARF following CABG surgery is associated with high mortality. The presence of RAS does not appear to increase the risk for developing ARF.

Familial membranoproliferative glomerulonephritis type III.

BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) is a relatively uncommon cause of progressive renal disease characterized by immune complex deposition resulting in mesangial proliferation and endocapillary inflammation with capillary wall thickening and double contour formation. Although a familial linkage has been reported in MPGN type II disease and less often in type I disease, a familial linkage in type III disease has not been reported previously. METHODS: We identified a family in which MPGN type III developed in a living-related donor 12 years later and recurred in the renal allograft of his son, whose primary disease was MPGN type III. We screened the members of the extended family, looking for evidence of hematuria and proteinuria. Renal biopsy specimens exhibited the findings of subendothelial deposits, subepithelial deposits, and complex glomerular basement membrane changes with C3 but not IgG seen on immunofluorescence. RESULTS: Screening identified eight affected family members (six biopsy proven) over three generations. The condition is inherited in an apparent autosomal dominant fashion. CONCLUSION: This is the first description of familial MPGN type III. We hope that by studying the disease in this family group, we may learn more about the pathogenesis of the condition.