Systematic Analysis of Mobile Genetic Elements Mediating ß-Lactamase Gene Amplification in Noncarbapenemase-Producing Carbapenem-Resistant Enterobacterales Bloodstream Infections.

Noncarbapenemase-producing carbapenem-resistant Enterobacterales (non-CP-CRE) are increasingly recognized as important contributors to prevalent carbapenem-resistant Enterobacterales (CRE) infections. However, there is limited understanding of mechanisms underlying non-CP-CRE causing invasive disease. Long- and short-read whole-genome sequencing was used to elucidate carbapenem nonsusceptibility determinants in Enterobacterales bloodstream isolates at MD Anderson Cancer Center in Houston, Texas. We investigated carbapenem nonsusceptible Enterobacterales (CNSE) mechanisms (i.e., isolates with carbapenem intermediate resistance phenotypes or greater) through a combination of phylogenetic analysis, antimicrobial resistance gene detection/copy number quantification, porin assessment, and mobile genetic element (MGE) characterization. Most CNSE isolates sequenced were non-CP-CRE (41/79; 51.9%), whereas 25.3% (20/79) were Enterobacterales with intermediate susceptibility to carbapenems (CIE), and 22.8% (18/79) were carbapenemase-producing Enterobacterales (CPE). Statistically significant copy number variants (CNVs) of extended-spectrum ß-lactamase (ESBL) genes (Wilcoxon Test; P-value < 0.001) were present in both non-CP-CR E. coli (median CNV = 2.6×; n = 17) and K. pneumoniae (median CNV = 3.2×, n = 17). All non-CP-CR E. coli and K. pneumoniae had predicted reduced expression of at least one outer membrane porin gene (i.e., ompC/ompF or ompK36/ompK35). Completely resolved CNSE genomes revealed that IS26 and ISEcp1 structures harboring blaCTX-M variants along with other antimicrobial resistance elements were associated with gene amplification, occurring in mostly IncFIB/IncFII plasmid contexts. MGE-mediated ß-lactamase gene amplifications resulted in either tandem arrays, primarily mediated by IS26 translocatable units, or segmental duplication, typically due to ISEcp1 transposition units. Non-CP-CRE strains were the most common cause of CRE bacteremia with carbapenem nonsusceptibility driven by concurrent porin loss and MGE-mediated amplification of blaCTX-M genes. IMPORTANCE Carbapenem-resistant Enterobacterales (CRE) are considered urgent antimicrobial resistance (AMR) threats. The vast majority of CRE research has focused on carbapenemase-producing Enterobacterales (CPE) even though noncarbapenemase-producing CRE (non-CP-CRE) comprise 50% or more of isolates in some surveillance studies. Thus, carbapenem resistance mechanisms in non-CP-CRE remain poorly characterized. To address this problem, we applied a combination of short- and long-read sequencing technologies to a cohort of CRE bacteremia isolates and used these data to unravel complex mobile genetic element structures mediating ß-lactamase gene amplification. By generating complete genomes of 65 carbapenem nonsusceptible Enterobacterales (CNSE) covering a genetically diverse array of isolates, our findings both generate novel insights into how non-CP-CRE overcome carbapenem treatments and provide researchers scaffolds for characterization of their own non-CP-CRE isolates. Improved recognition of mechanisms driving development of non-CP-CRE could assist with design and implementation of future strategies to mitigate the impact of these increasingly recognized AMR pathogens.

An international survey of clinicians regarding their management of venous thromboembolism following the initial 3-6 months of anticoagulation.

After an initial treatment period for venous thromboembolism (VTE), indefinite anticoagulation may be considered, depending upon individual risks. The aim of the study was to determine if there is consensus amongst clinicians that manage VTE regarding which patients require 3-6 months versus indefinite anticoagulation. The importance of VTE site and severity in decision making was also evaluated. An international survey of clinicians involved in VTE management was undertaken. Respondents were asked about long-term treatment of six patients that had completed 3-6 months initial anticoagulation. These included four cases of VTE not associated with a major reversible risk factor and two control cases; one unprovoked VTE and one VTE associated with a major reversible risk factor. For consensus, there was a pre-defined equivalence boundary whereby at least 70% of clinicians had to decide either to stop or consider indefinite anticoagulation for each case. 351 responses were collected. In the control cases, there was a ≥ 95% consensus on long-term management (stop versus indefinite anticoagulation). In three of the four test cases, there was no consensus about duration of anticoagulation. In case 3, 78% (99% confidence interval 73-84%) would stop anticoagulation after 3-6 months. When analysed by grade or specialty of doctor, a lack of consensus remained. Opinion on whether site or severity of VTE influenced decision making was variable. For patients with unprovoked VTE or VTE associated with a major transient risk factor there is treatment consensus. For the remainder, there is a lack consensus regarding the need for indefinite anticoagulation.

Cost-effectiveness analysis of a randomized clinical trial of early versus deferred endovenous ablation of superficial venous reflux in patients with venous ulceration.

BACKGROUND: Treatment of superficial venous reflux in addition to compression therapy accelerates venous leg ulcer healing and reduces ulcer recurrence. The aim of this study was to evaluate the costs and cost-effectiveness of early versus delayed endovenous treatment of patients with venous leg ulcers. METHODS: This was a within-trial cost-utility analysis with a 1-year time horizon using data from the EVRA (Early Venous Reflux Ablation) trial. The study compared early versus deferred endovenous ablation for superficial venous truncal reflux in patients with a venous leg ulcer. The outcome measure was the cost per quality-adjusted life-year (QALY) over 1 year. Sensitivity analyses were conducted with alternative methods of handling missing data, alternative preference weights for health-related quality of life, and per protocol. RESULTS: After early intervention, the mean(s.e.m.) cost was higher (difference in cost per patient £163(318) (€184(358))) and early intervention was associated with more QALYs at 1 year (mean(s.e.m.) difference 0·041(0·017)). The incremental cost-effectiveness ratio (ICER) was £3976 (€4482) per QALY. There was an 89 per cent probability that early venous intervention is cost-effective at a threshold of £20 000 (€22 546)/QALY. Sensitivity analyses produced similar results, confirming that early treatment of superficial reflux is highly likely to be cost-effective. CONCLUSION: Early treatment of superficial reflux is highly likely to be cost-effective in patients with venous leg ulcers over 1 year. Registration number: ISRCTN02335796 (http://www.isrctn.com).

Cost-effectiveness of treatments for superficial venous reflux in patients with chronic venous ulceration.

BACKGROUND: Venous leg ulcers impair quality of life significantly, with substantial costs to health services. The aim of this study was to estimate the cost-effectiveness of interventional procedures alongside compression therapy versus compression therapy alone for the treatment of chronic venous leg ulceration. METHODS: A Markov decision analytical model was developed. The main outcome measures were quality-adjusted life-years (QALYs) and lifetime costs per patient, from the perspective of the UK National Health Service at 2015 prices. Resource use included the initial procedures, compression therapy, primary care and outpatient consultations. The interventional procedures included superficial venous surgery, endothermal ablation and ultrasound-guided foam sclerotherapy (UGFS). The study population was patients with a chronic venous ulcer who were eligible for either compression therapy or an interventional procedure. Data were obtained from systematic review and meta-analysis of RCTs. RESULTS: Surgery gained 0·112 (95 per cent c.i. -0·011 to 0·213) QALYs compared with compression therapy alone, with a difference in lifetime costs of €-1330 (-3570 to 1262). Given the expected savings in community care, the procedure would pay for itself within 4 years. There was insufficient evidence regarding endothermal ablation and UGFS to draw conclusions. DISCUSSION: This modelling study found surgery to be more effective and less costly than compression therapy alone. Further RCT evidence is required for both endothermal ablation and UGFS.

Tumor inhibitory effects of intravesical Ganoderma lucidum instillation in the syngeneic orthotopic MB49/C57 bladder cancer mice model.

ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum (GL) has been traditionally used in oriental medicine as superior health tonic, and there are numerous scientific evidences of its antitumorigenic activities. AIM OF THE STUDY: To evaluate the intravesical chemopreventive effects of ethanol extract of GL (GLe) on bladder cancer. MATERIALS AND METHODS: Intravesical therapy is defined as the direct instillation of a liquid drug into bladder through a catheter. Bacille Calmette-Guerin(BCG) solution is applied intravesically as a conventional immunotherapy for preventing recurrence of bladder cancer. By adopting the MB49/C57 bladder cancer mice model, an overall 60 MB49-implanted mice were randomized into 3 groups and treated according to 3 treatment arms, including GLe, BCG and PBS. Additionally, wild-type mice without MB49 cell inoculation and treated with PBS were used as the negative control group. Testing agents were instilled intravesically for 2 h and repeated after one week for evaluating the effects on preventing the tumor formation and growth. The treated-mice were closely monitored for major adverse effects. RESULTS: GLe demonstrated more potent cytotoxic effects than BCG on MB49 cells, although both in dose-dependent manner. In the MB49-implanted mice, 80 µg/ml GLe was shown to delay the tumor formation by one week, whereas the averaged tumor volume measured at endpoint was 3.6-fold and 4.6-fold smaller than that of the BCG or PBS, respectively. However, no significant effects were observed on body weight and hematuria. CONCLUSION: Current findings in mice suggested intravesical GLe therapy as an effective and safe chemopreventive strategy for inhibiting bladder tumor formation.

Truncal varicose vein diameter and patient-reported outcome measures.

BACKGROUND: Varicose veins and chronic venous disease are common, and some funding bodies ration treatment based on a minimum diameter of the incompetent truncal vein. This study assessed the effect of maximum vein diameter on clinical status and patient symptoms. METHODS: A prospective observational cohort study of patients presenting with symptomatic varicose veins to a tertiary referral public hospital vascular clinic between January 2011 and July 2012. Patients underwent standardized assessment with venous duplex ultrasonography, and completed questionnaires assessing quality of life (QoL) and symptoms (Aberdeen Varicose Vein Questionnaire, EuroQol Five Domain QoL assessment and EuroQol visual analogue scale). Clinical scores (Venous Clinical Severity Score (VCSS) and Clinical Etiologic Anatomic Pathophysiologic (CEAP) class) were also calculated. Regression analysis was used to investigate the relationship between QoL, symptoms and vein diameter. RESULTS: Some 330 patients were assessed before surgery. The median maximum vein diameter was 7·0 (i.q.r. 5·3-9·2) mm overall, 7·9 (6·0-9·8) mm for great saphenous vein and 6·0 (5·2-8·9) mm for small saphenous vein. In linear regression analysis, vein diameter was shown to have a significant association with VCSS (P = 0·041). For every 1-mm increase in vein diameter, there was a 2·75-fold increase in risk of being in CEAP class C4 compared with C2. No other QoL or symptom measures were related to vein diameter. CONCLUSION: Incompetent truncal vein diameter was associated with increasing VCSS, but not a variety of other varicose vein disease-specific and generic patient-reported outcome measures.

Graduated Compression Stockings as an Adjunct to Low Dose Low Molecular Weight Heparin in Venous Thromboembolism Prevention in Surgery: A Multicentre Randomised Controlled Trial.

BACKGROUND: The evidence base upon which current global venous thromboembolism (VTE) prevention recommendations have been made is not optimal. The cost of purchasing and applying graduated compression stockings (GCS) in surgical patients is considerable and has been estimated at £63.1 million per year in England alone. OBJECTIVE: The aim was to determine whether low dose low molecular weight heparin (LMWH) alone is non-inferior to a combination of GCS and low dose LMWH for the prevention of VTE. METHODS: The randomised controlled Graduated compression as an Adjunct to Pharmacoprophylaxis in Surgery (GAPS) Trial (ISRCTN 13911492) will randomise adult elective surgical patients identified as being at moderate and high risk of VTE to receive either the current "standard" combined thromboprophylactic LMWH with GCS mechanical thromboprophylaxis, or thromboprophylactic LMWH pharmacoprophylaxis alone. To show non-inferiority (3.5% non-inferiority margin) for the primary endpoint of all VTE within 90 days, 2236 patients are required. Recruitment will be from seven UK centres. Secondary outcomes include quality of life, compliance with stockings and LMWH, overall mortality, and GCS or LMWH related complications (including bleeding). Recruitment commenced in April 2016 with the seven UK centres coming "on-line" in a staggered fashion. Recruitment will be over a total of 18 months. The GAPS trial is funded by the National Institute for Health Research Health Technology Assessment in the UK (14/140/61).

Early Results of Physician Modified Fenestrated Stent Grafts for the Treatment of Thoraco-abdominal Aortic Aneurysms.

OBJECTIVES: The aim was to determine whether physician modified stent grafts (PMSGs) are safe and effective for the treatment of high risk patients with thoraco-abdominal aortic aneurysms (TAAAs). DESIGN: This was a retrospective single institution study. MATERIAL: Consecutive patients with TAAA undergoing endovascular repair using a PMSG between January 2012 and June 2014 were evaluated. METHODS: Fenestrations to preserve branch vessels were created in TX2 thoracic (Cook Medical) stent grafts. Pre- intra- and post-operative data were recorded by means of a prospectively maintained database. RESULTS: Eleven high risk patients with TAAA (type I, n = 4; type III, n = 3; type IV, n = 3; type V, n = 1) underwent fenestrated endovascular repair using PMSGs. Indications were painful aneurysm (n = 5), >70 mm rapidly enlarging aneurysm (n = 4), saccular aneurysm (n = 1), and visceral patch false aneurysm after open repair of a type IV TAAA (n = 1). In four asymptomatic patients, an additional fenestration was created for temporary selective sac perfusion and occluded 2-4 weeks later. Median duration for stent graft modifications was 2 hours (range 1-3 hours). The median number of fenestrations was three (range 2-4). One patient died during the post-operative period from colonic ischemia, giving a 9% in hospital mortality rate. Four (36%) patients presented with moderate to severe complications. One (9%) patient presented with a paraparesis that resolved completely after spinal fluid drainage. Among surviving patients, four required early endovascular re-intervention for type III endoleak (n = 2), type Ia endoleak (n = 1), or target vessel cannulation failure (n = 1). The median follow up time was 6 months (range 3-20 months). During follow up, no other complications occurred and all target vessels remained patent. One patient presented with a persistent type II endoleak. CONCLUSION: PMSGs provided acceptable short-term results and may be a management option for the treatment of TAAA in selected high risk patients. Durability concerns need to be assessed in additional studies with long-term follow up.

Incidence and Outcomes of Severe Renal Impairment Following Ruptured Abdominal Aortic Aneurysm Repair.

INTRODUCTION: Acute kidney injury (AKI) following ruptured abdominal aortic aneurysm (rAAA) repair is common and multifactorial. A standard definition of AKI after endovascular repair (EVAR), the Aneurysm Renal Injury Score (ARISe), has been proposed to facilitate standardised reporting and thus improve understanding of this issue. METHODS: Data were collected retrospectively on AKI in a prospectively maintained database of all patients treated for rAAA in a single tertiary referral centre since the availability of routine out of hours emergency EVAR. The ARISe score was used to describe the degree of AKI and factors which correlated with poor renal outcomes were assessed. RESULTS: Two-hundred and five patients were treated between January 2006 and April 2014. Of these, 125 were treated with open repair (OSR) and 80 were treated with EVAR. Severe AKI (defined as ARISe score ≥3) occurred in 36% of patients. After correction for confounders, patients treated with OSR were significantly more likely to develop severe AKI (43% vs. 26%, p = .02). There was no significant difference in preoperative serum creatinine between groups, but increased preoperative serum creatinine was strongly associated with severe AKI postoperatively (p < .001). Age, sex, endograft type, and preoperative CT scanning were not associated with differences in renal outcomes. Clamp position above renal arteries was predictive of severe AKI in patients treated with OSR (p < .01). Patients suffering severe AKI had significantly higher mortality at 30 days and 12 months (28% vs. 5% and 44% vs. 13%, p < .001 for both comparisons). CONCLUSION: Severe AKI is common following successful repair of rAAA. In this large case series of high-risk patients, OSR was associated with significantly higher rates of severe AKI compared with EVAR, despite the increased dose of contrast involved in EVAR and the older age of these patients. In turn, severe AKI was associated with higher mortality rates.

Effect of frailty on short- and mid-term outcomes in vascular surgical patients.

BACKGROUND: Frailty is a multidimensional vulnerability resulting from age-associated decline. The impact of frailty on outcomes was assessed in a cohort of vascular surgical patients. METHODS: The study included patients aged over 65 years with length of hospital stay (LOS) greater than 2 days, who were admitted to a tertiary vascular unit over a single calendar year. Demographics, mode of admission, diagnosis, mortality, LOS and discharge destination were recorded, as well as a variety of frailty-specific characteristics. The impact of frailty on LOS, discharge destination, survival and readmission rate was assessed using multivariable regression techniques. The ability of the models to predict these outcomes was also assessed. RESULTS: In total, 413 patients of median age 77 years were followed for a median of 18 (range 12-24) months. The in-hospital, 3- and 12-month mortality rates were 3·6, 8·5 and 13·8 per cent respectively. Receiver operating characteristic (ROC) curve analysis revealed that frailty-based regression models were excellent predictors of 12-month mortality (area under the ROC curve (AUC) = 0·81), prolonged LOS (AUC = 0·79) and discharge to a care institution (AUC = 0·84). A simple additive frailty score using six key features retained strong predictive power for 12-month mortality (AUC = 0·83), discharge to a care institution (AUC = 0·78) and prolonged LOS (AUC = 0·74). This frailty score was also strongly associated with readmission rates (P < 0·001). CONCLUSION: Frailty in vascular surgery patients predicts a multiplicity of poorer outcomes. Optimal management should include identification of at-risk patients and treatment of modifiable risk factors.

A systematic review and meta-analysis on the role of varicosity treatment in the context of truncal vein ablation.

BACKGROUND: With the advent of endovenous truncal ablation under local anaesthetic for the treatment of varicose veins, the fate of varicosed tributaries has become controversial, with centres offering different timings of treatment, if offered at all. This study aims to review the literature assessing delayed and simultaneous varicosity treatment during truncal ablation. METHODS: Randomised trials and cohort studies concerning varicosity treatment timing were identified through a systematic literature search. Requirements for further treatment, quality of life and rate of venous thrombotic events were assessed for meta-analysis. RESULTS: Four studies were identified assessing need for further varicosity procedure, with no significant difference seen between simultaneous or delayed treatment (p = 0.339). Two studies assessed quality of life, with simultaneous treatment providing significantly improved outcomes at six weeks (p = 0.029) but not at 12 weeks (p = 0.283). Studies examining venous thrombotic events showed no difference in venous thromboembolism rate between simultaneous or delayed treatment approaches (p = 0.078). CONCLUSION: The evidence base regarding timing of varicosity treatment is sparse; however, it does show that simultaneous treatment of varicosities leads to early gains in quality of life, with a non-significant trend for fewer further procedures but more venous thrombotic events.

Nomogram for computing the value of similarity factor.

The objective of present work was to construct nomogram for obtaining a value of similarity factor (f2) by employing the values of number of observations (n) and sum of squared difference of percentage drug dissolved between reference (R) and test (T) products . The steps for rearrangement of equation of similarity factor are presented. The values of f2 were selected in the range of 45 to 100 for 4 to 12 observations (n) for computing the values of Linear regression analysis was performed between number of observations and . Perfect correlation was observed in each case. Nomogram was constructed and later it was validated by using drug dissolution data from literature and our laboratory. The use of nomogram is recommended during research and development work to investigate effect of formulation or process variables. The nomogram can also be used during change in manufacturing site or change in equipment. It is concluded that the steps for calculation of f2 can be truncated in the middle (i.e. at the step of calculation of factor and a decision of similarity/dissimilarity can be taken employing the nomogram.

Which treatments are cost-effective in the management of varicose veins?

In the current economic climate, the cost-effectiveness of health-care interventions is under great scrutiny. In this article, the evidence for cost-effectiveness of treatments for varicose veins is summarized. The majority of studies evaluating treatments for varicose veins have not assessed health economic outcomes, but have focused on clinical and anatomical measures. The cost-effectiveness of treating varicose veins (compared with conservative management) was demonstrated in the REACTIV trial. Other in-trial economic analyses suggested that endovenous interventions are likely to be cost-effective and a decision tree analysis demonstrated that the greatest cost-effectiveness may be present for procedures performed under local or tumescent anaesthesia in the office or outpatient setting. However, the treatment modality that offers the greatest cost-effectiveness remains unclear. In conclusion, endovenous treatment performed in the outpatient setting under local anaesthesia is likely to be the most cost-effective treatment strategy for varicose veins. Better quality health economic analyses are needed to refine this conclusion.

Post-thrombotic syndrome: a clinical review.

Up to half of patients with proximal deep vein thrombosis (DVT) will develop post-thrombotic syndrome (PTS) despite optimal anticoagulant therapy. PTS significantly impacts upon quality of life and has major health-economic implications. This narrative review describes the pathophysiology, risk factors, and diagnosis, prevention and treatment of PTS, to improve our understanding of the disease and guide treatment. Relevant articles were identified through systematic searches of the PubMed, EMBASE and Cochrane databases between 1966 and November 2011. Studies were included for detailed assessment if they met the following criteria: published in English, human study participants, study population aged > 18 years, and lower limb post-thrombotic syndrome. All non-systematic reviews and single patient case reports were excluded. Recurrent thrombosis, thrombus location and obesity are major risk factors, whereas the importance of gender and age remain uncertain. The diagnosis of PTS is based on clinical findings in patients with a known history of DVT. Several clinical scales have been described, with the Villalta Score gaining increasing popularity. Adequate anticoagulation and use of elastic compression stockings (ECS) following DVT can reduce the incidence of PTS. Catheter-directed thrombolysis and mechanical thrombectomy of acute DVT may preserve valvular function. Studies to date of these techniques are encouraging, and have reported improved hemodynamics and a reduced incidence of PTS. The management of established PTS is challenging. Compression therapy, aimed at reducing the underling venous hypertension, remains the mainstay of treatment. This is despite a paucity of high-quality evidence to support its use. Pharmacologic and surgical treatments have also been described, with a number of studies citing symptomatic improvement.