Search

In the AMPLIFY clinical trial, apixaban was non-inferior to warfarin plus subcutaneous enoxaparin bridge therapy in the treatment of acute venous thromboembolism (VTE) and was associated with significantly less bleeding. This study evaluated their comparative effectiveness and safety in routine clinical practice. A matched-cohort design and data from four U.S. private health care claims databases were employed. Study population comprised patients who initiated outpatient treatment with apixaban versus warfarin (plus parenteral anticoagulant bridge therapy) within 30 days of their initial VTE episode; apixaban and warfarin patients were matched on age, characteristics of VTE episode, study database and propensity score. Major bleeding, clinically relevant non-major (CRNM) bleeding and recurrent VTE during the 180-day (maximum) follow-up period were compared using shared frailty models. During mean follow-up of 143 days among apixaban patients ( n = 17,878) and 152 days among warfarin patients ( n = 17,878), incidence proportions for apixaban versus warfarin, respectively, were 1.7% versus 2.3% for major bleeding, 7.0% versus 9.4% for CRNM bleeding and 2.3% versus 2.9% for recurrent VTE. In shared frailty models, risks of major bleeding (hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.64–0.87), CRNM bleeding (HR = 0.77, 95% CI = 0.71–0.83) and recurrent VTE (HR = 0.80, 95% CI = 0.70–0.91) were lower for apixaban versus warfarin. In this large-scale evaluation of VTE patients receiving outpatient treatment with apixaban or warfarin in U.S. clinical practice, risks of major bleeding, CRNM bleeding and recurrent VTE were significantly lower among patients who received apixaban.

Objective: To conduct a systematic review of real-world (RWD) studies comparing the risk of major bleeding (MB) among patients with non-valvular atrial fibrillation (NVAF) on direct oral anticoagulants (DOACs) or warfarin. Methods: MEDLINE, Embase, NHS-EED, and EconLit were searched for RWD studies published between January 2003 and November 2016 comparing MB risk among DOACs and warfarin. Proceedings of clinical conferences from 2012 to 2016 were reviewed. Results: A total of 4218 citations were identified, 26 of which met eligibility criteria. Most studies were retrospective analyses of administrative claims databases and patient registries (n = 23 of 26); about half were based in the United States (n = 15). Apixaban showed a significantly lower risk of MB versus warfarin in all eight included studies. MB risk was either significantly lower (n = 9 of 16) or not significantly different (n = 7 of 16) between dabigatran and warfarin; there was no significant difference between rivaroxaban and warfarin in all seven included studies. The risk was significantly lower with apixaban versus rivaroxaban (n = 7 of 7) but not significantly different from dabigatran (n = 6 of 7). MB risk was significantly lower (n = 3 of 4) or not significantly different (n = 1 of 4) with dabigatran versus rivaroxaban. No evidence was identified for edoxaban. Conclusion: DOACs were associated with similar or lower risks of MB versus warfarin. A lower MB risk was consistently observed for apixaban, but less consistently for dabigatran; MB risk was similar between rivaroxaban and warfarin. Among DOACs, the risk of MB with apixaban was consistently lower than with rivaroxaban, but similar to dabigatran.

Background and Purpose— Stroke risk may increase shortly after warfarin initiation in nonvalvular atrial fibrillation patients. Because of the brief period and limited number of events, large samples are needed to study this effect. We compared 30-day rates of ischemic stroke between nonvalvular atrial fibrillation patients initiating warfarin to nonwarfarin comparators using an insurance claims database. Methods— We identified nonvalvular atrial fibrillation patients via 1 inpatient/2 outpatient diagnosis claims from the MarketScan database, January 1, 2009, to December 31, 2010. We studied patients initiating warfarin using prescription claims and 1:1 matched 22 669 initiators to comparators based on age, sex, diagnosis date, and warfarin propensity score. Follow-up began on initiation date; patients were censored at discontinuation/switch of therapy, disenrollment, or end of the study. The median follow-up was 415 days. Cox regression was used to study differences in ischemic stroke risks between warfarin initiators and comparators while controlling for important prognostic factors. Results— Warfarin initiators were generally similar to comparators in clinical features but had higher CHADS 2 scores (1.26 versus 1.19). The first 30-day ischemic stroke rate was higher among warfarin initiators than comparators (1.47%/y (27/1836) versus 0.98%/y (18/1837); P =0.18) but lower subsequently (0.81%/y [134/16 543] versus 1.09%/y [406/37 248]; P =0.002). Multivariable regression confirmed a significant interaction between follow-up and warfarin use with the adjusted hazard ratios (95% confidence intervals) for warfarin/comparator as 1.46 (0.80–2.65) in the first 30 days and 0.70 (0.57–0.85) afterward. Conclusions— Warfarin effect was qualitatively different in the first 30 days after initiation than subsequently. This is consistent with a modest increase in stroke risk occurring briefly after starting warfarin.

Broad-spectrum antibiotic use may adversely affect a patient's beneficial microbiome and fuel cross-species spread of drug resistance. Although alternative pathogen-specific approaches are rationally justified, a major concern for this precision medicine strategy is that co-colonizing or co-infecting opportunistic bacteria may still cause serious disease. In a mixed-pathogen lung infection model, we find that the Staphylococcus aureus virulence factor α toxin potentiates Gram-negative bacterial proliferation, systemic spread, and lethality by preventing acidification of bacteria-containing macrophage phagosomes, thereby reducing effective killing of both S. aureus and Gram-negative bacteria. Prophylaxis or early treatment with a single α toxin neutralizing monoclonal antibody prevented proliferation of co-infecting Gram-negative pathogens and lethality while also promoting S. aureus clearance. These studies suggest that some pathogen-specific, antibody-based approaches may also work to reduce infection risk in patients colonized or co-infected with S. aureus and disparate drug-resistant Gram-negative bacterial opportunists.

A human antibody facilitates opsonophagocytic killing, inhibits attachment of Pseudomonas aeruginosa, and exerts protective effects in several animal models of P. aeruginosa infection., Pseudomonas aeruginosa is a leading cause of hospital-associated infections in the seriously ill, and the primary agent of chronic lung infections in cystic fibrosis patients. A major obstacle to effective control of P. aeruginosa infections is its intrinsic resistance to most antibiotic classes, which results from chromosomally encoded drug-efflux systems and multiple acquired resistance mechanisms selected by years of aggressive antibiotic therapy. These factors demand new strategies and drugs to prevent and treat P. aeruginosa infections. Herein, we describe a monoclonal antibody (mAb) selection strategy on whole P. aeruginosa cells using single-chain variable fragment phage libraries derived from healthy individuals and patients convalescing from P. aeruginosa infections. This approach enabled identification of mAbs that bind three distinct epitopes on the product of the Psl. This exopolysaccharide is important for P. aeruginosa attachment to mammalian cells, and for the formation and maintenance of biofilms produced by nonmucoid and mucoid P. aeruginosa isolates. Functional screens revealed that mAbs to one epitope exhibit superior activity in opsonophagocytic killing and cell attachment assays, and confer significant protection in multiple animal models. Our results indicate that Psl is an accessible serotype-independent surface feature and promising novel protective antigen for preventing P. aeruginosa infections. Furthermore, our mAb discovery strategy holds promise for application to other bacterial pathogens.

Purpose This subgroup analysis of ARISTOPHANES study used multiple datasources to compare S/SE, MB, and their respective components among NVAF patients (pts) prescribed NOACs stratified by index dosage. Methods A retrospective observational study of NVAF pts initiating api, dabi, riva or warfarin from 01/01/2013–09/30/2015 was conducted using CMS Medicare data and four other US commercial claims databases, covering > 180 million beneficiaries. After propensity score matching (PSM) in each database between standard-dose NOACs (5 mg BID api–150 mg BID dabi, 5 mg BID api–20 mg QD riva, and 150 mg BID dabi–20 mg QD riva) and lower-dose NOACs (2.5 mg BID api-75 mg BID dabi, 2.5 mg BID api–10 or 15 mg QD riva, and 75 mg BID dabi–10 or 15 mg QD riva), the resulting patient records were pooled. Cox models were used to estimate hazard ratios of S/SE and MB. S/SE included ischemic stroke, hemorrhagic stroke, and SE; MB included gastrointestinal (GI) bleeding, intracranial hemorrhage (ICH), and other MB. Results Standard-dose api pts had a similar rate of S/SE but a lower rate of MB vs. standard-dose dabi; lower-dose api pts had a lower rate of S/SE and MB versus lower-dose dabi. In both standard and lower dose analyses, api was associated with a lower rate of S/SE and MB compared to riva. Compared to standard-dose riva, standard-dose dabi was associated with a similar rate of S/SE and lower rate of MB. Lower-dose dabi was associated with a higher rate of S/SE and similar rate of MB compared to lower-dose riva. Conclusions Among NVAF pts, both standard- and lower-dose api pts had lower rates of MB compared to corresponding doses of dabi and riva, respectively; both doses of api demonstrated lower rates of S/SE vs. corresponding doses of riva. The comparisons between dabi and riva showed varying results for S/SE and MB across dosage levels. Dose selection criteria cannot be ascertained from the current data sources. Future studies of pts who were appropriately dosed are warranted.

Background Limited real-world evidence exists on comparative effectiveness and safety of NOACs vs warf by NOAC dosage. Methods A retrospective observational study of NVAF patients (pts) newly initiating apixaban, dabigatran, rivaroxaban, or warfarin from 01 January 2013–30 September 2015 was conducted using CMS Medicare data and four other US commercial claims databases, covering > 180 million beneficiaries annually (∼56% of US population). After propensity score matching in each database between each standard NOAC dose and warfarin (5 mg BID api-warf, 150 mg BID dabi-warf, 20 mg QD riva-warf), as well as each lower NOAC dose and warf (2.5 mg BID api-warf, 75 mg BID dabi-warf, and 10 or 15 mg QD riva-warf), the resulting pts records were pooled. Cox models were used to estimate S/SE and MB hazard ratios. S/SE included ischemic stroke, hemorrhagic stroke, and SE; MB included gastrointestinal (GI) bleeding, intracranial hemorrhage (ICH), and other MB. Results Pts initiating lower and standard NOAC doses had different baseline characteristics, such as age and renal disease. Pts data were assessed for a mean of 7–8 months. Standard- and lower-dose api pts were each associated with lower rates of S/SE and MB vs warf. Standard and lower-dose dabi pts each had similar rates of S/SE compared to warf. Standard-dose dabi pts had a lower rate of MB and lower-dose dabi pts had a similar rate of MB vs warf. Standard-dose riva pts were associated with a lower S/SE rate, and lower-dose riva pts had a similar rate of S/SE compared to warf. Standard- and lower-dose riva pts were each associated with higher MB rates compared to warf. All doses of NOACs were associated with lower rates of ICH compared to warf. Conclusions In this large observational study, api was the only NOAC associated with lower rates of S/SE and MB for both doses compared to warf. Dose selection criteria cannot be ascertained from current data sources. Future studies of pts who were appropriately dosed should be warranted.

Adult female targets of domestic violence by male perpetrators have commonly been described as helpless and passive. This is consistent with the criminal justice system's perception that true “victims” have little culpability or agency in a violent assault. Otherwise, the “victims” are more likely to be defined as participants in the violent act, and thus unworthy of official protection. This study examines court opinions involving convictions of male offenders of domestic violence against their female partners and ex-partners. The purpose is to understand the development of judicial knowledge as to whether women in relationships with violent men are socially constructed as worthy and legitimate victims of violence. The 60+ appellate case opinions in the analysis are those where a California trial court accepted expert testimony on domestic violence in prosecuting the male offenders to explain the women's actions regarding their violent relationships. California was chosen because of the state's progressive and unique evidentiary statutes that permit a broad range of evidence in criminal prosecutions of domestic violence, including expert witnesses. In reviewing the judicial opinions that comprise the corpus, I found that an underlying assumption evident in the judicial discourses is that abused women would, should or could easily exercise agency in ending an abusive relationship and, once it was ended, refuse to reengage in their abusive relationships. Using critical discourse analysis, this study shows that, in constructing women's agency in resisting abusive relationships, judicial discourse tended to rely more heavily upon expert testimony and, in a few cases, on prosecutorial arguments, than on the testimony (i.e. voice) of the female victims themselves. In this process, the women's voices were silenced or marginalized as experts’ constructions of victimized women were preferred.

The AMPLIFY trial showed that apixaban was non-inferior to low-molecular-weight heparin followed by warfarin in the treatment of acute venous thromboembolism (VTE), and was associated with less bleeding. The purpose of this study was to compare risks of major bleeding and recurrent VTE with apixaban

Most observational studies on direct oral anticoagulants (DOACs) used single data sources with limited generalizability. This ARISTOPHANES (Anticoagulants for Reduction In STroke: Observational Pooled analysis on Health outcomes ANd Experience of patientS) study aimed to use multiple data sources to

To identify factors associated with all-cause discontinuation (patient discontinued on their own or physician discontinuation) of oral anticoagulants (OACs) among nonvalvular atrial fibrillation (NVAF) patients.Retrospective cohort study.We analyzed the MarketScan claims database from October 2009 to July 2012. Adult patients were eligible if they newly initiated an OAC in the study period, had an atrial fibrillation diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification code 427.31 or 472.32), and had at least 6 months of continuous enrollment after OAC initiation. Multivariable Cox proportional hazards regression was used to assess factors associated with discontinuation. Adjusted hazard ratios (HRs) and 95% CIs were reported.Among 12,129 eligible patients, 8143 (67.1%) initiated warfarin and 3986 (32.9%) initiated direct oral anticoagulants (DOACs). Overall, 47.3% of patients independently discontinued during follow-up (mean number of days of follow-up = 416.6 [SD ± 141.7]) with mean time to discontinuation of 120 days (SD ± 114.7). Patients significantly less likely to discontinue included those taking DOACs versus warfarin (HR, 0.91; 95% CI, 0.86-0.97), older patients (≥65 years vs 18 to 34 years) (HR, 0.32; 95% CI, 0.24-0.43), those with diabetes (HR, 0.84; 95% CI, 0.77-0.90), those with prior stroke/transient ischemic attack (HR, 0.65; 95% CI, 0.56-0.75), those with prior pulmonary embolism (HR, 0.71; 95% CI, 0.58-0.88), and those with congestive heart failure (HR, 0.80; 95% CI, 0.74-0.87). Patients with prior bleeding events were significantly more likely to independently discontinue (HR, 1.20; 95% CI, 1.08-1.34).The risk of independent discontinuation of OAC treatment among NVAF patients was high. Patients on DOACs compared with warfarin and those with several comorbid conditions had significantly lower risk of discontinuation, while those with prior bleeding were more likely to discontinue.

Historically, warfarin or aspirin have been the recommended therapeutic options for the extended treatment (3 months) of VTE. Data from Phase III randomised controlled trials (RCTs) are now available for non-VKA oral anticoagulants (NOACs) in this indication. The current systematic review and network meta-analysis (NMA) were conducted to compare the efficacy and safety of anticoagulants for the extended treatment of VTE.Electronic databases (accessed July 2014 and updated April 2016) were systematically searched to identify RCTs evaluating apixaban, aspirin, dabigatran, edoxaban, rivaroxaban, and warfarin for the extended treatment of VTE. Eligible studies included adults with an objectively confirmed deep vein thrombosis, pulmonary embolism or both. A fixed-effect Bayesian NMA was conducted, and results were presented as relative risks (RRs). Sensitivity analyses examining (i) the dataset employed according to the time frame for outcome assessment (ii) the model used for the NMA were conducted.Eleven Phase III RCTs (examining apixaban, aspirin, dabigatran, rivaroxaban, warfarin and placebo) were included. The risk of the composite efficacy outcome (VTE and VTE-related death) was statistically significantly lower with the NOACs and warfarin INR 2.0-3.0 compared with aspirin, with no significant differences between the NOACs. Treatment with apixaban (RR 0.23, 95% CrI 0.10, 0.55) or dabigatran (RR 0.55, 95% Crl 0.43, 0.71) was associated with a statistically significantly reduced risk of 'major or clinically relevant non-major bleed' compared with warfarin INR 2.0-3.0. Apixaban also showed a significantly reduced risk compared with dabigatran (RR 0.42, 95% Crl 0.18, 0.97) and rivaroxaban (RR 0.23, 95% Crl 0.09, 0.59). Sensitivity analyses indicate that results were dependent on the dataset, but not on the type of NMA model employed.Results from the NMA indicate that NOACs are an effective treatment for prevention of VTE or VTE-related death) in the extended treatment setting. However, bleeding risk differs between potential treatments, with apixaban reporting the most favourable profile compared with other NOACs, warfarin INR 2.0-3.0, and aspirin.

Background Prior analyses beyond clinical trials are yet to evaluate the projected lifetime benefit of apixaban treatment compared to low-molecular-weight heparin (LMWH)/vitamin K antagonist (VKA) for treatment of venous thromboembolism (VTE) and prevention of recurrences. The objective of this study is to assess the cost-effectiveness of initial plus extended treatment with apixaban versus LMWH/VKA for either initial treatment only or initial plus extended treatment. Methods A Markov cohort model was developed to evaluate the lifetime clinical and economic impact of treatment of VTE and prevention of recurrences with apixaban (starting at 10 mg BID for 1 week, then 5 mg BID for 6 months, then 2.5 mg BID for an additional 12 months) versus LMWH/VKA for 6 months and either no further treatment or extended treatment with VKA for an additional 12 months. Clinical event rates to inform the model were taken from the AMPLIFY and AMPLIFY-EXT trials and a network meta-analysis. Background mortality rates, costs, and utilities were obtained from published sources. The analysis was conducted from the perspective of the United Kingdom National Health Service. The evaluated outcomes included the number of events avoided in a 1000-patient cohort, total costs, life-years, quality-adjusted life-years (QALYs), and cost per QALY gained. Results Initial plus extended treatment with apixaban was superior to both treatment durations of LMWH/VKA in reducing the number of bleeding events, and was superior to initial LMWH/VKA for 6 months followed by no therapy, in reducing VTE recurrences. Apixaban treatment was cost-effective compared to 6-month treatment with LMWH/VKA at an incremental cost-effectiveness ratio (ICER) of £6692 per QALY. When initial LMWH/VKA was followed by further VKA therapy for an additional 12 months (i.e., total treatment duration of 18 months), apixaban was cost-effective at an ICER of £8528 per QALY gained. Sensitivity analysis suggested these findings were robust over a wide range of inputs and scenarios for the model. Conclusions In the UK, initial plus extended treatment with apixaban for treatment of VTE and prevention of recurrences appears to be economical and a clinically effective alternative to LMWH/VKA, whether used for initial or initial plus extended treatment. Electronic supplementary material The online version of this article (doi:10.1186/s12913-017-1995-8) contains supplementary material, which is available to authorized users.

Objectives: To describe the role of anticoagulant use, active cancer and venous thromboembolism (VTE) type on bleeding risk and VTE recurrence among cancer patients diagnosed with VTE. Methods: A retrospective observational analysis of the Humedica database between 01JAN2008 and 31MARCH2014 was conducted including adult patients (aged >18 years) with ≥2 VTE diagnosis claims (ICD-9-CM codes) in an outpatient setting or with one VTE diagnosis in an inpatient setting who had continuous health plan enrollment 6 months pre-index date. Active cancer patients were differentiated from cancer patients based on diagnosis codes during the baseline period. The incidence rate (in person-years) was calculated for major bleeding and VTE recurrence. Time-to-major bleeding and time-to-VTE recurrence were estimated using Kaplan-Meier curves; a Cox regression was applied to adjust for baseline demographic and clinical characteristics. Results: A total of 72,224 cancer patients were identified, which included 8,222 active cancer patients. More than 70% of cancer patients were prescribed anticoagulants. The incidence rate of VTE recurrence (24.7 vs. 14.3 per 100 person-years) and major bleeding events (31.2 vs. 15.9 per 100 person-years) was higher among active cancer patients than all VTE cancer patients. The use of combination parenteral and oral anticoagulant treatment (hazard ratio [HR]=1.30, p Discussion: Active cancer and having both PE and DVT as prior diagnoses were associated with increased VTE recurrence and bleeding risk. The bleeding risk was also highest among patients undergoing parenteral and oral anticoagulant therapy. However, anticoagulant treatment was shown to be associated with a lower risk of VTE recurrence.

The irreversible loss of estrogen (specifically 17‐ β ‐estradiol; E2) compromises whole‐body glucose tolerance in women. Hormone replacement therapy (HRT) is frequently prescribed to treat estrogen deficiency, but has several deleterious side effects. Exercise has been proposed as an HRT substitute, however, their relative abilities to treat glucose intolerance are unknown. Thirty ovariectomized (OVX) and 20 SHAM (control) rats underwent glucose tolerance tests (GTT) 10 weeks post surgery. Area under the curve (AUC) for OVX rats was 60% greater than SHAM controls ( P = 0.0005). Rats were then randomly assigned to the following treatment groups: SHAM sedentary (sed) or exercise (ex; 60 min, 5×/weeks), OVX sed, ex, or E2 (28 μ g/kg bw/day) for 4 weeks. OVX ex rats experienced a ~45% improvement in AUC relative to OVX sed rats, whereas OVX E2 underwent a partial reduction (17%; P = 0.08). Maximal insulin‐stimulated glucose uptake in soleus and EDL was not impaired in OVX rats, or augmented with exercise or E2. Akt phosphorylation did not differ in soleus, EDL, or liver of any group. However, OVX ex and OVX E2 experienced greater increases in p‐Akt Ser473 in VAT and SQ tissues compared with SHAM and OVX sed groups. Mitochondrial markers CS, COXIV, and core1 were increased in soleus posttraining in OVX ex rats. The content of COXIV was reduced by 52% and 61% in SQ of OVX sed and E2 rats, compared to SHAM controls, but fully restored in OVX ex rats. In summary, exercise restores glucose tolerance in OVX rats more effectively than E2. This is not reflected by alterations in muscle maximal insulin response, but increased insulin signaling in adipose depots may underlie whole‐body improvements.

Background We recently demonstrated that feeding a natural CLAt10,c12-enriched butter to lean female rats resulted in small, but significant increases in fasting glucose and insulin concentrations, and impaired insulin tolerance. Our goal was to extend these findings by utilizing the diabetes-prone female fatty Zucker rat. Rats were fed custom diets containing 45 % kcal of fat derived from control and CLAt10,c12-enriched butter for 8 weeks. Methods CLA t10,c12-enriched butter was prepared from milk collected from cows fed a high fermentable carbohydrate diet to create subacute rumen acidosis (SARA); control (non-SARA) butter was collected from cows fed a low grain diet. Female fatty Zucker rats (10 weeks old) were randomly assigned to one of four diet treatments: i) low fat (10 % kcal), ii) 45 % kcal lard, iii) 45 % kcal SARA butter, or iv) 45 % kcal non-SARA butter. A low fat fed lean Zucker group was used as a control group. After 8 weeks, i) glucose and insulin tolerance tests, ii) insulin signaling in muscle, adipose and liver, and iii) metabolic caging measurements were performed. Results Glucose and insulin tolerance were significantly impaired in all fatty Zucker groups, but to the greatest extent in the LARD and SARA conditions. Insulin signaling (AKT phosphorylation) was impaired in muscle, visceral (perigonadal) adipose tissue and liver in fatty Zucker rats, but was generally similar across dietary groups. Physical activity, oxygen consumption, food intake and weight gain were also similar amongst the various fatty Zucker groups. Conclusions Increasing the consumption of a food naturally enriched with CLAt10,c12 significantly worsens glucose and insulin tolerance in a diabetes-prone rodent model. This outcome is not explained by changes in tissue insulin signaling, physical activity, energy expenditure, food intake or body mass.

Introduction: Loss of estrogen in females increases the risk for insulin resistance. Hormone replacement therapy (HRT) is often prescribed to treat estrogen deficiency but has several detrimental s...

A systematic review and network meta-analysis (NMA) were conducted to compare oral anticoagulants and aspirin for the secondary prevention of venous thromboembolism (VTE). Databases were searched (July 2014) to identify phase III randomized controlled trials (RCTs) evaluating the novel oral anti

To assess the predictive validity of apixaban cost-effectiveness model by comparing key event rates from model to those seen in AMPLIFY and AMPLIFY-EXT trials in patients with venous thromboembolism (VTE). Markov model was developed to extrapolate the observed clinical impact of apixaban versus

Introduction: This study estimated venous thromboembolism (VTE) recurrence and risk factors in a European population, given limited data in this region. Methods: This retrospective cohort study included data collected from physicians recruited from an online panel in France, Spain, Italy, and Germany. Physicians completed case report forms for the next 3-4 patients seen in consultation for any reason who had an initial VTE event in the prior 3 to 24 months (i.e., patients who survived 90 days since their initial VTE). Included were 376 general practitioners and 307 specialists, providing 2,184 patient records and information on patient demographics, comorbidities, and VTE recurrence. Kaplan-Meier estimation provided cumulative incidence survival functions accounting for censored data (patient records varied from 3-24 months post-initial VTE). Risk factors for VTE were assessed. Results: Patients’ mean age was 61.3 years (SD=14.3) and 47.4% were female. Of 2,184 patients, 379 developed recurrent VTE over 1,298 person-years of follow-up. The table shows cumulative incidence of VTE in the overall population and by risk categories. The 6-month cumulative incidence of VTE recurrence was 11.7%; the 12-month cumulative incidence was 27.6%. VTE cumulative incidence did not differ by age, gender or initial VTE type. However, it was higher in patients with moderate-to-strong vs. weak Anderson & Spencer summary risk scores (p=.001); e.g., 12-month rates of 33.8%, vs. 20.9%, respectively. Conclusions: VTE recurrence is high in this European population and increases with time since initial VTE event, suggesting the need for targeted anticoagulant treatment following an initial VTE event and longer term prevention of VTE recurrence. Among risk factors investigated, Anderson & Spencer scores help differentiate patients more likely to experience recurrence within 12 months of initial VTE.

Alpha-toxin (AT) is a major virulence determinant in Staphylococcus aureus skin and soft tissue infection models. We previously demonstrated that prophylactic administration of 2A3, an AT-neutralizing monoclonal antibody (MAb), prevents S. aureus disease in a mouse dermonecrosis model by neutralizing AT-mediated tissue necrosis and immune evasion. In the present study, MEDI4893*, an affinity-optimized version of 2A3, was characterized for therapeutic activity in the dermonecrosis model as a single agent and in combination with two frontline antibiotics, vancomycin and linezolid. MEDI4893* postinfection therapy was found to exhibit a therapeutic treatment window similar to that for linezolid but longer than that for vancomycin. Additionally, when combined with either vancomycin or linezolid, MEDI4893* resulted in reduced tissue damage, increased neutrophil and macrophage infiltration and abscess formation, and accelerated healing relative to those with the antibiotic monotherapies. These data suggest that AT neutralization with a potent MAb holds promise for both prophylaxis and adjunctive therapy with antibiotics and may be a valuable addition to currently available options for the treatment of S. aureus skin and soft tissue infections.

Background Traditionally the provision of elective external direct current cardioversion (EDCCV) for patients with atrial arrhythmias has been doctor-led. Increasing demands on hospital beds and time pressures for doctors has driven the desire for an alternative approach. We established a nurse-led cardioversion service in 2006 and present our experience. Methods A prospective database of patients undergoing elective EDCCV between July 2006 and July 2013 was collected. Demographic data, arrhythmia, success and immediate complications of cardioversion were recorded. Results A total of 974 EDCCV were performed on 772 patients. The mean patient age was 62.7 years, 564 (73.1%) were male. In 530 patients (69.0%) AF was the primary arrhythmia, in 242 (31.0%) atrial flutter. All EDCCVs were performed in a high dependency unit. Sinus rhythm was obtained in 692 patients (89.6%). Of 640 outpatients, 629 (98.3%) were discharged on the same day of their procedure. Eleven patients (1.7%) required admission to hospital. No patients required urgent temporary transvenous or permanent pacing, and there were no deaths in association with this procedure. Conclusions Nurse-led elective EDCCV is a safe and effective way of restoring sinus rhythm in patients with AF or atrial flutter, with additional benefits to resource provision.

Across jurisdictions, the criminal justice system is enamored with the evidence-based practices movement. The idea is to utilize the best scientific data to identify and classify individuals based on their potential future risk of reoffending, and then to manage offender populations according to risk and criminogenic needs. Risk-needs tools now inform a variety of criminal justice decisions, ranging from pre-trial outcomes, to sentencing, to post-conviction supervision. While evidence-based methodologies are widely exalted as representing best practices, constitutional and moral objections have been raised. Risk-needs tools incorporate a host of constitutionally and morally sensitive factors, such as demographic and other immutable characteristics. The constitutional analysis herein engages equal protection, prisoners’ rights, due process, and sentencing law. In addition, the text examines the philosophical polemic aimed uniquely at sentencing as to whether risk should play any role at all in determining punishment. The Article then appraises potential alternatives for risk-needs methodologies if the concerns so raised by critics prove legitimate. Any option comes with significant consequences. Retaining offensive variables incites political and ethical reproaches, while simply excising them weakens statistical validity of the underlying models and diminishes the promise of evidence-based practices. Promoting an emphasis on risk at sentencing dilutes the focus of punishment on blameworthiness, while neglecting risk and needs sabotages a core objective of the new penological model of harnessing the ability to identify and divert low risk offenders to appropriate community-based alternatives.

An optimal host response against Staphylococcus aureus skin and soft tissue infections (SSTI) is dependent on IL-1β and IL-17 mediated abscess formation. Alpha toxin (AT), an essential virulence factor for SSTI, has been reported to damage tissue integrity; however its effect on the immune response has not been investigated. Here, we demonstrate that infection with USA300 AT isogenic mutant (Δhla), or passive immunization with an AT neutralizing mAb, 2A3, 24 h prior to infection with wild type USA300 (WT), resulted in dermonecrotic lesion size reduction, and robust neutrophil infiltration. Infiltration correlates with increase in proinflammatory cytokines and chemokines, as well as enhanced bacterial clearance relative to immunization with a negative control mAb. In addition, infection with Δhla, or with WT +2A3, resulted in an early influx of innate IL-17(+)γδT cells and a more rapid induction of an adaptive immune response as measured by Th1 and Th17 cell recruitment at the site of infection. These results are the first direct evidence of a role for AT in subverting the innate and adaptive immune responses during a S. aureus SSTI. Further, these effects of AT can be overcome with a high affinity anti-AT mAb resulting in a reduction in disease severity.

Studies on Mycobacterium tuberculosis (MTB) antigens are of interest in order to improve vaccine efficacy and to define biomarkers for diagnosis and treatment monitoring. The methodologies used for these investigations differ greatly between laboratories and discordant results are common. The IFN-gamma response to two well characterized MTB antigens ESAT-6 and CFP-10, in the form of recombinant proteins and synthetic peptides, was evaluated in HIV-1 uninfected persons in both long-term (7 day) and 24 hour, commercially available QuantiFERON TB Gold in Tube (QFT-GIT), whole blood assays. Our findings showed differences in the IFN-gamma response between 24 hour and 7 day cultures, with recombinant proteins inducing a significantly higher response than the peptide pools in 7 day whole blood assays. The activity of peptides and recombinant proteins did not differ in 24 hour whole blood or peripheral blood mononuclear cell (PBMC) based assays, nor in the ELISpot assay. Further analysis by SELDI-TOF mass spectrometry showed that the peptides are degraded over the course of 7 days of incubation in whole blood whilst the recombinant proteins remain intact. This study therefore demonstrates that screening antigenic candidates as synthetic peptides in long-term whole blood assays may underestimate immunogenicity.

The objective of this study was to examine venous thromboembolism (VTE) prophylaxis use, risk reduction, and readmission in medically ill patients during hospitalization and after discharge. This 5-year retrospective study linked outpatient files from MarketScan Commercial and Medicare Supplemental databases. Patients were categorized into prophylaxis and non-prophylaxis groups based on guideline-recommended anticoagulant use from the index date to 180 days posthospital discharge and before the first VTE event date. Outcome variables were VTE events and rehospitalization. Risk adjustment was conducted within the prophylaxis group and between the prophylaxis and non-prophylaxis groups using propensity score matching. Among 4467 patients, 28.99% of the patients (n = 1295) were admitted with cancer, 18.03% (n = 805) with pneumonia, 14.06% (n = 628) with heart failure, 11.06% (n = 494) with stroke, 11.11% (n = 496) with sepsis, 8.08% (n = 361) with infectious diseases, 5.6% (n = 250) with severe respiratory disorders, 1.81% (n = 81) with inflammatory bowel disease, 1.05% (n = 47) with obesity, 0.20% (n = 9) with neurologic disorders, and 0.02% (n = 1) with acute rheumatic fever. Among those with 180-day continuous enrollment after the index date (n = 3511), 51.81% (n = 1819) received anticoagulant therapy only, 2.48% (n = 87) received mechanical compression treatment only (stocking or pneumatic compression), and 4.41% (n = 155) received both during hospitalization. Anticoagulant therapy rates ranged from 88.64% (obesity) to 32.39% (inflammatory bowel disease). Among anticoagulant therapy patients, 740 patients (40.68%) received low-molecular weight heparin only and 806 patients (44.31%) received unfractionated heparin. After risk adjustment, compared with patients without VTE prophylaxis, anticoagulant prophylaxis patients had lower VTE (3.62% vs. 4.27%, P < 0.04) and readmission rates (24.22% vs. 27.95%, P < 0.02) during the 6 months post-index hospital admission. In conclusion anticoagulant prophylaxis is underutilized and is associated with reduced VTE risk and a decrease in rehospitalizations for medically ill patients.

Information about the risk of bleeding and bleeding-related resource use and costs among non-Vitamin K antagonist oral anticoagulants (NOACs) in the real-world setting is scarce. This study aim was to compare inpatient bleeding risks, bleeding-related hospitalization rates and costs among non

Purpose To assess the cost-effectiveness of apixaban versus rivaroxaban, low-molecular-weight heparin (LMWH)/dabigatran, and LMWH/vitamin K antagonist (VKA) for the initial treatment and prevention of recurrent thromboembolic events in patients with venous thromboembolism (VTE). Methods A Markov model was developed to evaluate the pharmacoeconomic effect of 6 months of treatment with apixaban versus other anticoagulants over a lifetime horizon. Network meta-analyses were conducted using the results of the Apixaban after the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy (AMPLIFY), EINSTEIN-pooled, and RE-COVER I and II trials for the following end points: recurrent VTE, major bleeds, clinically relevant non-major bleeds, and treatment discontinuations. The analysis was conducted from the perspective of the United Kingdom National Health Service. The outcomes evaluated were the number of events avoided in a 1000-patient cohort, total costs, life years, quality-adjusted life years (QALYs), and cost per QALY gained over a patient’s lifetime. Findings Treatment for 6 months with apixaban was projected to result in fewer recurrent VTE and bleeding events in comparison to rivaroxaban, LMWH/dabigatran, and LMWH/VKA. Apixaban was cost-effective compared with LMWH/VKA at an incremental cost-effectiveness ratio of £2520 per QALY gained and was a dominant (ie, lower costs and higher QALYs) alternative to either rivaroxaban or LMWH/dabigatran. Sensitivity analysis indicated that results were robust over a wide range of inputs. Implications The assessment of the effects and costs of apixaban in this study predicted that apixaban is a dominant alternative to rivaroxaban and LMWH/dabigatran and a cost-effective alternative to LMWH/VKA for 6 months of treatment of VTE and the prevention of recurrence.

The development of an effective malaria vaccine is a high global health priority. Vaccine vectors based on adenovirus type 5 are capable of generating robust and protective T cell and antibody responses in animal models and are currently being evaluated in clinical trials for HIV and malaria. They appear to be more effective in terms of inducing antigen-specific immune responses as compared with non-Ad5 serotype vectors. However, the high prevalence of neutralizing antibodies to Ad5 in the human population, particularly in the developing world, has the potential to limit the effectiveness of Ad5-based vaccines. We have generated novel Ad5-based vectors that precisely replace the hexon hypervariable regions with those derived from Ad43, a subgroup D serotype with low prevalence of neutralizing antibody in humans. We have demonstrated that these hexon-modified adenovectors are not neutralized efficiently by Ad5 neutralizing antibodies in vitro using sera from mice, rabbits and human volunteers. We have also generated hexon-modified adenovectors that express a rodent malaria parasite antigen, PyCSP, and demonstrated that they are as immunogenic as an unmodified vector. Furthermore, in contrast to the unmodified vector, the hexon-modified adenovectors induced robust T cell responses in mice with high levels of Ad5 neutralizing antibody. We also show that the hexon-modified vector can be combined with unmodified Ad5 vector in prime-boost regimens to induce protective responses in mice. Our data establish that these hexon-modified vectors are highly immunogenic even in the presence of pre-existing anti-adenovirus antibodies. These hexon-modified adenovectors may have advantages in sub-Saharan Africa where there is a high prevalence of Ad5 neutralizing antibody in the population.

The article provides evidence that the current criminal justice approach to sex crimes is based on a presumption that individuals who commit sex-based offenses are both pathological and evil and, therefore, at high risk of recidivism. This model relies on a law-psychiatry interface by drawing from psychiatry’s Diagnostic and Statistical Manual of Mental Disorders (DSM). To justify a particularly punitive approach to sex offenders, officials use the DSM’s mental disorders of sexual deviance. A diagnosis of a DSM-based mental disorder can drive various legal consequences in that they impact such issues as bail, sentencing, parole, and civil commitment.This article provides legal, empirical, and theoretical critiques of the law-psychiatry interface employed to control the sex offender population. Defendants have contended, but generally without success, the use of the DSM-based disorders of sexual deviance violates the due process clause or the Frye/Daubert evidentiary standards for the admissibility of scientific expert testimony. The article reasons that these DSM disorders lack sufficient empirical support and diagnostic integrity. Vagueness in the DSM criteria have led to forensic experts basing their diagnoses — not on evidence of any underlying pathology — but merely upon a history of sexual offending. Thus, sex crimes become conflated with mental disease. The law-psychiatry interface here appears pretextual in preferentially serving the interests of the prosecution. Various examples are offered, including the recent introduction in case law of new disorders, such as hebephilia (sexual interest in teenagers) and rape paraphilia. The article posits that the mental diseases of sexual deviance are a poor fit to answer legal questions when constitutional rights of liberty and privacy are at risk.

Recent legal reform has changed the ways that police respond to domestic disputes. Studies show that such shifts in legislation have usually resulted in an increased likelihood of arrest for both parties involved. However, most research to date has focused on incidents of male perpetrators assaulting female intimate partners. Few studies have investigated potential differences in police officers’ decisions to arrest when considering both the gender (male versus female) of the suspect and the sexual orientation (heterosexual versus homosexual) of the couples involved. This study utilizes data from a quantitative dataset where police officers completed a mandated checklist after responding to a domestic dispute. We explore the ways that both gender and sexual orientation affect police decision to arrest in intimate partner violence. Results demonstrate that a variety of factors, including the suspect’s prior assaultive behavior, suspect’s hostile attitude, suspect’s race, and presence of an injury are important in the arrest outcome among all groups. However, there are some significant differences in arrest when considering the intersections of gender and sexuality. Findings suggest that future policy and research should continue to consider the impacts of gender and sexuality on official responses to intimate partner violence.

Ocular neovascularization, the growth of abnormal blood vessels in the eye, is a factor shared by the most common blinding diseases in developed countries. Pigment epithelium-derived factor (PEDF) is a potent antiangiogenic and neuroprotective protein that is normally produced in the eye. When delivered via an adenovector, PEDF can block the growth of new blood vessels and trigger the selective regression of abnormal vessels in animal models of ocular disease. Because of the absence of adenoviral genes, high-capacity (HC) adenovectors offer the potential for persistent transgene expression and enhanced tolerability. We have assessed the durability of PEDF expression and the induction of ocular inflammation following delivery of a PEDF-expressing HC adenovector compared to earlier generation vectors. The HC vector mediated prolonged PEDF expression in tissue-cultured pigmented epithelial cells and when delivered by intravitreal injection into the mouse eye. Delivery of first-generation adenovectors resulted in a dose-dependent increase in cytokine/chemokine gene expression, which correlated with the infiltration of inflammatory cells in the eye. In comparison, the levels of inflammatory gene expression and the intraocular infiltrate were substantially reduced following delivery of the HC vector. These results support the development of the HC adenovector gene delivery system for ocular disease.

Delivery of therapeutic proteins, such as antiangiogenic proteins, to the eye is a demonstrated method for the control of age-related macular degeneration (AMD). However, one of the key limitations is the requirement for frequent and repeated intraocular injections. In this article, we demonstrate that repeated protein production in the eye can be stimulated from the cytomegalovirus (CMV) promoter without repeat intraocular injections using a small molecule, all-trans retinoic acid (ATRA). ATRA by systemic delivery can stimulate protein production multiple times in the eye. Administration of ATRA resulted in stimulation of gene expression to relevant levels that block abnormal blood vessel growth in an experimental animal model for AMD. These data support the principles of this technological discovery to therapeutic applications for chronic ocular diseases.

Introduction: The management of venous thromboembolism (VTE) and the prevention of recurrent VTE consists of anticoagulation primarily with Vitamin K Antagonists (VKA). The main adverse effect of anticoagulation is bleeding. This study aimed to investigate the predictors of major bleeding in patients with first VTE treated with VKA. Methods: A cohort study was undertaken using the United Kingdom's Clinical Practice Research Datalink with additional data from hospitalizations and causes of death. Patients with incident first VTE between 2008-2013 treated with VKA, i.e. starting VKA treatment within 60 days after first VTE, were included in the cohort. Major bleeding was defined in accordance with the International Society of Thrombosis and Haemostasis recommendations comprising fatal bleeds, bleeds at a critical site, and bleeding events in association with anemia or blood transfusions. Patients were followed until the end of the first VKA treatment episode. Hazard ratios of potential predictors for major bleeding during the first VKA treatment episode were estimated from Cox regression models which included recognized predictors for major bleeding before the diagnosis of VTE, and a list of potential predictors during VKA treatment. Results: Among 10,118 VKA-treated VTE patients the incidence rate of major bleeding was 2.6 (95% confidence interval (CI), 2.2-3.1) per 100 person-years (145 major bleeds during 5,548 person-years of VKA use). Among baseline characteristics, predictors for major bleeding (Table) included increasing age, and history of a major bleeding and of a non-major clinically relevant bleeding. Furthermore the following events after the first VTE (80 of 145 cases) were also associated with an increased risk of major bleeding: non-major clinically relevant bleeding, HR 2.88 (95% CI, 1.85 - 4.46), active cancer 4.13 (2.48-6.89), trauma 14.05 (7.96-24.82), surgery 3.27 (1.29-8.28), and medical illness 3.03 (1.87-4.90). Additional predictors for major bleeding were new onset or history of moderate/severe liver disease, 7.44 (2.93-18.92), or renal disease, 1.73 (1.19-2.52). Conclusions: Assessment for and awareness of these predictors prior to and during VKA treatment is needed to prevent major bleeding events. Caution is warranted in patients with these independent risk factors. Table 1. Association between factors at first VTE and during VKA treatment and major bleeding Incident major bleeding after first VTE n (%) Crude hazard ratio (95%-CI) Adjusted hazard ratio (95%-CI) Total 145 (100) Age1 Disclosures Cohen: BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Portola: Consultancy, Honoraria, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jannsen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Honoraria, Research Funding, Speakers Bureau; Boeheringer Ingelheim: Consultancy, Honoraria. Hamilton:BMS: Employment, Equity Ownership. Unniachan:BMS: Employment, Equity Ownership. Martinez:Bayer: Research Funding; CSL Behring: Research Funding; Pfizer: Research Funding; BMS: Research Funding; Boehringer Ingelheim: Consultancy; Merz Pharma: Research Funding.