Mpox infection protects against re-challenge in rhesus macaques.

The mpox outbreak of 2022-2023 involved rapid global spread in men who have sex with men. We infected 18 rhesus macaques with mpox by the intravenous, intradermal, and intrarectal routes and observed robust antibody and T cell responses following all three routes of infection. Numerous skin lesions and high plasma viral loads were observed following intravenous and intradermal infection. Skin lesions peaked on day 10 and resolved by day 28 following infection. On day 28, we re-challenged all convalescent and 3 naive animals with mpox. All convalescent animals were protected against re-challenge. Transcriptomic studies showed upregulation of innate and inflammatory responses and downregulation of collagen formation and extracellular matrix organization following challenge, as well as rapid activation of T cell and plasma cell responses following re-challenge. These data suggest key mechanistic insights into mpox pathogenesis and immunity. This macaque model should prove useful for evaluating mpox vaccines and therapeutics.

Adeno-associated virus 2 infection in children with non-A-E hepatitis.

An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland1 in April 2022 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case-control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4+ T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10-12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a 'helper virus' to support AAV2 replication) and disease susceptibility related to HLA class II status.

Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma.

BACKGROUND: Lymphocyte-activation gene 3 (LAG-3) and programmed death 1 (PD-1) are distinct inhibitory immune checkpoints that contribute to T-cell exhaustion. The combination of relatlimab, a LAG-3-blocking antibody, and nivolumab, a PD-1-blocking antibody, has been shown to be safe and to have antitumor activity in patients with previously treated melanoma, but the safety and activity in patients with previously untreated melanoma need investigation. METHODS: In this phase 2-3, global, double-blind, randomized trial, we evaluated relatlimab and nivolumab as a fixed-dose combination as compared with nivolumab alone when administered intravenously every 4 weeks to patients with previously untreated metastatic or unresectable melanoma. The primary end point was progression-free survival as assessed by blinded independent central review. RESULTS: The median progression-free survival was 10.1 months (95% confidence interval [CI], 6.4 to 15.7) with relatlimab-nivolumab as compared with 4.6 months (95% CI, 3.4 to 5.6) with nivolumab (hazard ratio for progression or death, 0.75 [95% CI, 0.62 to 0.92]; P = 0.006 by the log-rank test). Progression-free survival at 12 months was 47.7% (95% CI, 41.8 to 53.2) with relatlimab-nivolumab as compared with 36.0% (95% CI, 30.5 to 41.6) with nivolumab. Progression-free survival across key subgroups favored relatlimab-nivolumab over nivolumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the relatlimab-nivolumab group and in 9.7% of patients in the nivolumab group. CONCLUSIONS: The inhibition of two immune checkpoints, LAG-3 and PD-1, provided a greater benefit with regard to progression-free survival than inhibition of PD-1 alone in patients with previously untreated metastatic or unresectable melanoma. Relatlimab and nivolumab in combination showed no new safety signals. (Funded by Bristol Myers Squibb; RELATIVITY-047 ClinicalTrials.gov number, NCT03470922.).

Comparative pathogenesis of three Mayaro virus genotypes in the cynomolgus macaque.

Mayaro virus (MAYV), a mosquito-borne alphavirus, is considered an emerging threat to public health with epidemic potential. Phylogenetic studies show the existence of three MAYV genotypes. In this study, we provide a preliminary analysis of the pathogenesis of all three MAYV genotypes in cynomolgus macaques (Macaca facicularis, Mauritian origin). Significant MAYV-specific RNAemia and viremia were detected during acute infection in animals challenged intravenously with the three MAYV genotypes, and strong neutralizing antibody responses were observed. MAYV RNA was detected at high levels in lymphoid tissues, joint muscle and synovia over 1 month after infection, suggesting that this model could serve as a promising tool in studying MAYV-induced chronic arthralgia, which can persist for years. Significant leucopenia was observed across all MAYV genotypes, peaking with RNAemia. Notable differences in the severity of acute RNAemia and composition of cytokine responses were observed among the three MAYV genotypes. Our model showed no outward signs of clinical disease, but several major endpoints for future MAYV pathology and intervention studies are described. Disruptions to normal blood cell counts and cytokine responses were markedly distinct from those observed in macaque models of CHIKV infection, underlining the importance of developing non-human primate models specific to MAYV infection.

The Relationship Between Health-Related Quality of Life and Overall Survival in Patients With Advanced Renal Cell Carcinoma in CheckMate 214.

BACKGROUND: In CheckMate 214 (median follow-up, 25.2 months), nivolumab plus ipilimumab yielded greater overall survival (OS) benefit than sunitinib in patients with intermediate-/poor-risk advanced renal cell carcinoma (aRCC). Health-related quality of life (HRQoL) assessed by the Functional Assessment of Cancer Therapy-Kidney Symptom Index-19 (FKSI-19) was also more favorable for the nivolumab plus ipilimumab group than the sunitinib group. We investigated whether HRQoL scores can predict OS of patients with 5 years follow-up in CheckMate 214. PATIENTS AND METHODS: CheckMate 214 was an open-label, phase III trial in previously untreated aRCC (N = 1096). Patients with intermediate-/poor-risk disease (International mRCC Database Consortium prognostic score ≥ 1; n = 847) were randomized to either nivolumab plus ipilimumab or sunitinib monotherapy. Pooled data for OS and FKSI-19 total and subscales (disease-related symptoms [DRS], DRS-physical [DRS-P], and function/well-being [FWB]) were analyzed. Relationships between HRQoL and OS were assessed using Cox proportional hazard models with baseline and longitudinal scores. Associations between HRQoL changes and OS were assessed by landmark analyses. RESULTS: Patients with higher FKSI-19 total and subscale scores at baseline had longer OS than patients with lower scores (HR ≤ 0.834; P < .0001). Longitudinal models indicated stronger associations between HRQoL and OS (HR ≤ 0.69; P < .001 for each). At 3 months after randomization, patients with stable/improved HRQoL versus baseline had longer median OS than patients with worsened/unobserved HRQoL versus baseline (55.9 and 26.0 months, respectively; HR = 0.56; 95% CI, 0.46-0.67; P < .0001). Results at 6-, 9-, and 12-month landmarks were consistent with these findings. CONCLUSION: In aRCC, patient-reported outcomes are important for HRQoL and prognostic evaluation. CLINICALTRIALS.GOV IDENTIFIER: NCT02231749; https://clinicaltrials.gov/ct2/show/NCT02231749.

Patient-reported outcomes with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced renal cell carcinoma treated in CheckMate 9ER: an open-label, randomised, phase 3 trial.

BACKGROUND: In the CheckMate 9ER trial, patients with advanced renal cell carcinoma who received first-line nivolumab plus cabozantinib had significantly better progression-free survival compared with those given sunitinib. In this study, we aimed to describe the patient-reported outcome (PRO) results from CheckMate 9ER. METHODS: In this open-label, randomised, phase 3 trial done in 125 cancer centres, urology centres, and hospitals across 18 countries, patients aged 18 years or older with previously untreated advanced renal cell carcinoma with a clear-cell component, a Karnofsky performance status of 70% or more, and available tumour tissue were randomly assigned (1:1) via interactive response technology to nivolumab 240 mg intravenously every 2 weeks plus oral cabozantinib 40 mg per day, or oral sunitinib 50 mg per day monotherapy for 4 weeks in 6-week cycles. The primary endpoint of progression-free survival was reported previously. PROs were analysed as prespecified exploratory endpoints at common timepoints (at baseline and every 6 weeks) until week 115. Disease-related symptoms were evaluated using the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19), and global health status was assessed with the three-level EQ-5D (EQ-5D-3L) visual analogue scale (VAS) and UK utility index. PRO analyses were done in the intention-to-treat population. Change from baseline was assessed using mixed-model repeated measures. A time-to-deterioration analysis was done for first and confirmed deterioration events. This study is registered with ClinicalTrials.gov, NCT03141177, and is closed to recruitment. FINDINGS: Between Sept 11, 2017, and May 14, 2019, 323 patients were randomly assigned to nivolumab plus cabozantinib and 328 to sunitinib. Median follow-up was 23·5 months (IQR 21·0-26·5). At baseline, patients in both groups reported low symptom burden (FKSI-19 disease-related symptoms version 1 mean scores at baseline were 30·24 [SD 5·19] for the nivolumab plus cabozantinib group and 30·06 [5·03] for the sunitinib group). Change from baseline in PRO scores indicated that nivolumab plus cabozantinib was associated with more favourable outcomes versus sunitinib (treatment difference 2·38 [95% CI 1·20-3·56], nominal p<0·0001, effect size 0·33 [95% CI 0·17-0·50] for FKSI-19 total score; 1·33 [0·84-1·83], nominal p<0·0001, 0·45 [0·28-0·61] for FKSI-19 disease-related symptoms version 1; 3·48 [1·58-5·39], nominal p=0·0004, 0·30 [0·14-0·47] for EQ-5D-3L VAS; and 0·04 [0·01-0·07], nominal p=0·0036, 0·25 [0·08-0·41] for EQ-5D-3L UK utility index), reaching significance at most timepoints. Nivolumab plus cabozantinib was associated with decreased risk of clinically meaningful deterioration for FKSI-19 total score compared with sunitinib (first deterioration event hazard ratio 0·70 [95% CI 0·56-0·86], nominal p=0·0007; confirmed deterioration event 0·63 [0·50-0·80], nominal p=0·0001). INTERPRETATION: PROs were maintained or improved with nivolumab plus cabozantinib versus sunitinib. Compared with sunitinib, nivolumab plus cabozantinib significantly delayed time to deterioration of patient-reported outcome scores. These results suggest a benefit for nivolumab plus cabozantinib compared with sunitinib in the treatment of patients with advanced renal cell carcinoma. FUNDING: Bristol Myers Squibb.

Treatment patterns and outcomes following disease progression on anti-PD-1 therapies for advanced melanoma.

Background: Anti-PD-1-based therapies prolong survival in advanced melanoma, but disease progression is common. This study evaluated treatment patterns and overall survival (OS) after anti-PD-1 progression. Methods: Retrospective data from patients with advanced melanoma and progression on anti-PD-1 treatment between 2014 and 2019 were taken from Flatiron Health, which reflects largely community practice. Treatment patterns and OS were analyzed for BRAF mutant (mt) and wild-type (wt) subgroups; OS was also examined across all patients. Results: Progression following anti-PD-1 was recorded for 679 patients. Median OS ranged from 5.0 to 11.3 months. Of 275 BRAFmt and 374 BRAFwt patients, 113 (41.1%) and 228 (61.0%) received no subsequent therapy, respectively. However, 48.4% of BRAFmt and 57.8% of BRAFwt patients continued anti-PD-1 treatment beyond progression. Conclusion: This real-world study underscores the need for effective treatments for advanced melanoma post-progression on anti-PD-1 therapy.

Overall survival in the real-world and clinical trials: a case study validating external controls in advanced melanoma.

Aims: We assessed the suitability of real-world data (RWD) as an external control for analysis of overall survival (OS) compared with clinical trial data (CTD) in advanced melanoma. Methods: OS among adults receiving ipilimumab for advanced melanoma was compared between trials (CTD group) and the Flatiron Health database (RWD group) using Cox models. Adjusted analyses accounted for differences in baseline factors; missing data were addressed through multiple imputation. Results: After adjusting for baseline factors and accounting for missingness, OS was similar in the CTD (n = 241) versus RWD groups (n = 816; hazard ratio: 0.98; 95% CI: 0.75-1.26). Conclusion: Flatiron Health data is suitable to construct external control groups for OS in advanced melanoma trials after adjusting for baseline factors and missing data.

Clinical trials are the gold standard for measuring the efficacy and safety of new treatments. Comparisons between clinical trials and external controls drawn from real-world data are potentially valuable ­ especially when randomized trials are not available or feasible ­ but carry important risks of bias stemming from differences across populations, care settings and measurement of patient characteristics and outcomes. As a case study, we assessed the suitability of a particular real-world database (the Flatiron Health Database) for analyzing overall survival among patients in clinical trials of treatments for metastatic melanoma. Challenges included differences in patient baseline prognostic factors across populations, including high proportions with missing information in real-world data. After accounting for these differences, we observed similar survival between patients receiving ipilimumab monotherapy in clinical trials and in real-world data. We conclude that real-world external controls can be suitable for metastatic melanoma.

Judicial gatekeeping on scientific validity with risk assessment tools.

Risk assessment tools driven by algorithms offer promising advantages in predicting the recidivism risk of defendants. Jurisdictions are increasingly relying upon risk tool outcomes to help judges at sentencing with their decisions on whether to incarcerate or whether to use community-based sanctions. Yet as sentencing has significant consequences for public safety and individual rights, care must be taken that the tools relied upon are appropriate for the task. Judges are encouraged to act as gatekeepers to evaluate whether the forensic risk assessment tool offered has a sufficient level of validity in that it is fit for the purposes of sentencing, provides an acceptable level of accuracy in its predictions, and achieves an adequate standard of reliability with regard to its outcomes.

The Potential Dangers of Recruitment Maneuvers During One Lung Ventilation Surgery.

BACKGROUND: Existing evidence regarding lung-protective ventilation (LPV) during one-lung ventilation (OLV) focuses on surrogate outcomes. Our objective was to assess whether an LPV protocol during OLV surgery is associated with reduced respiratory complications. MATERIALS AND METHODS: This was a matched control retrospective cohort study of patients undergoing pulmonary resection at a tertiary Canadian hospital. The experimental group (n = 50) was derived from primary data of two crossover RCTs, which utilized protocolized LPV strategies with varying levels of positive end-expiratory pressure and recruitment maneuvers. The control group was drawn from a prospectively maintained database; these patients received conventional nonprotocolized ventilation (2000-2010). Each experimental group patient was matched 1:1 with a control group patient with respect to clinically relevant variables (age, sex, diagnosis, smoking status, cardiovascular disease status, comorbidity, BMI, preoperative forced expiratory volume in 1 s, surgery type). Major respiratory complications were defined as composite of acute respiratory distress syndrome, need for new positive-pressure ventilation, and atelectasis requiring bronchoscopy. Paired and unpaired statistical tests were used. RESULTS: Patients appeared well matched. Major respiratory complications occurred in 8% (n = 4) and 2% (n = 1) of patients in experimental and control groups, respectively (P = 0.50). There was a trend toward increased mortality (4 versus 0, P = 0.06) with protocolized LPV. The patients who died had respiratory complications; one had acute respiratory distress syndrome and two had profound hypoxemia. CONCLUSIONS: There was a nonsignificant trend toward increased mortality with LPV during OLV. Although limited by a small sample size, our findings identify a potential danger to excessive recruitment maneuvers. Larger studies, with clinically important outcomes are needed to better define the risk/benefit trade-offs for LPV during OLV.

The sexist algorithm.

Algorithmic risk assessment tools are informed by scientific research concerning which factors are predictive of recidivism and thus support the evidence-based practice movement in criminal justice. Automated assessments of individualized risk (low, medium, high) permit officials to make more effective management decisions. Computer-generated algorithms appear to be objective and neutral. But are these algorithms actually fair? The focus herein is on gender equity. Studies confirm that women typically have far lower recidivism rates than men. This differential raises the question of how well algorithmic outcomes fare in terms of predictive parity by gender. This essay reports original research using a large dataset of offenders who were scored on the popular risk assessment tool COMPAS. Findings indicate that COMPAS performs reasonably well at discriminating between recidivists and non-recidivists for men and women. Nonetheless, COMPAS algorithmic outcomes systemically overclassify women in higher risk groupings. Multiple measures of algorithmic equity and predictive accuracy are provided to support the conclusion that this algorithm is sexist.

Effectiveness and Safety of Oral Anticoagulants Among Nonvalvular Atrial Fibrillation Patients.

Background and Purpose- This ARISTOPHANES study (Anticoagulants for Reduction in Stroke: Observational Pooled Analysis on Health Outcomes and Experience of Patients) used multiple data sources to compare stroke/systemic embolism (SE) and major bleeding (MB) among a large number of nonvalvular atrial fibrillation patients on non-vitamin K antagonist oral anticoagulants (NOACs) or warfarin. Methods- A retrospective observational study of nonvalvular atrial fibrillation patients initiating apixaban, dabigatran, rivaroxaban, or warfarin from January 1, 2013, to September 30, 2015, was conducted pooling Centers for Medicare and Medicaid Services Medicare data and 4 US commercial claims databases. After 1:1 NOAC-warfarin and NOAC-NOAC propensity score matching in each database, the resulting patient records were pooled. Cox models were used to evaluate the risk of stroke/SE and MB across matched cohorts. Results- A total of 285 292 patients were included in the 6 matched cohorts: 57 929 apixaban-warfarin, 26 838 dabigatran-warfarin, 83 007 rivaroxaban-warfarin, 27 096 apixaban-dabigatran, 62 619 apixaban-rivaroxaban, and 27 538 dabigatran-rivaroxaban patient pairs. Apixaban (hazard ratio [HR], 0.61; 95% CI, 0.54-0.69), dabigatran (HR, 0.80; 95% CI, 0.68-0.94), and rivaroxaban (HR, 0.75; 95% CI, 0.69-0.82) were associated with lower rates of stroke/SE compared with warfarin. Apixaban (HR, 0.58; 95% CI, 0.54-0.62) and dabigatran (HR, 0.73; 95% CI, 0.66-0.81) had lower rates of MB, and rivaroxaban (HR, 1.07; 95% CI, 1.02-1.13) had a higher rate of MB compared with warfarin. Differences exist in rates of stroke/SE and MB across NOACs. Conclusions- In this largest observational study to date on NOACs and warfarin, the NOACs had lower rates of stroke/SE and variable comparative rates of MB versus warfarin. The findings from this study may help inform the discussion on benefit and risk in the shared decision-making process for stroke prevention between healthcare providers and nonvalvular atrial fibrillation patients. Clinical Trial Registration- URL: https://www.clinicaltrials.gov/ . Unique identifier: NCT03087487.

Ischemic Stroke in Nonvalvular Atrial Fibrillation at Warfarin Initiation: Assessment via a Large Insurance Database.

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 CHADS2 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.

Diagnosis of childhood tuberculosis and host RNA expression in Africa.

BACKGROUND: Improved diagnostic tests for tuberculosis in children are needed. We hypothesized that transcriptional signatures of host blood could be used to distinguish tuberculosis from other diseases in African children who either were or were not infected with the human immunodeficiency virus (HIV). METHODS: The study population comprised prospective cohorts of children who were undergoing evaluation for suspected tuberculosis in South Africa (655 children), Malawi (701 children), and Kenya (1599 children). Patients were assigned to groups according to whether the diagnosis was culture-confirmed tuberculosis, culture-negative tuberculosis, diseases other than tuberculosis, or latent tuberculosis infection. Diagnostic signatures distinguishing tuberculosis from other diseases and from latent tuberculosis infection were identified from genomewide analysis of RNA expression in host blood. RESULTS: We identified a 51-transcript signature distinguishing tuberculosis from other diseases in the South African and Malawian children (the discovery cohort). In the Kenyan children (the validation cohort), a risk score based on the signature for tuberculosis and for diseases other than tuberculosis showed a sensitivity of 82.9% (95% confidence interval [CI], 68.6 to 94.3) and a specificity of 83.6% (95% CI, 74.6 to 92.7) for the diagnosis of culture-confirmed tuberculosis. Among patients with cultures negative for Mycobacterium tuberculosis who were treated for tuberculosis (those with highly probable, probable, or possible cases of tuberculosis), the estimated sensitivity was 62.5 to 82.3%, 42.1 to 80.8%, and 35.3 to 79.6%, respectively, for different estimates of actual tuberculosis in the groups. In comparison, the sensitivity of the Xpert MTB/RIF assay for molecular detection of M. tuberculosis DNA in cases of culture-confirmed tuberculosis was 54.3% (95% CI, 37.1 to 68.6), and the sensitivity in highly probable, probable, or possible cases was an estimated 25.0 to 35.7%, 5.3 to 13.3%, and 0%, respectively; the specificity of the assay was 100%. CONCLUSIONS: RNA expression signatures provided data that helped distinguish tuberculosis from other diseases in African children with and those without HIV infection. (Funded by the European Union Action for Diseases of Poverty Program and others).

Cost-effectiveness of apixaban versus low molecular weight heparin/vitamin k antagonist for the treatment of venous thromboembolism and the prevention of recurrences.

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.

Unnatural amino acid analogues of membrane-active helical peptides with anti-mycobacterial activity and improved stability.

OBJECTIVES: The emergence of MDR-TB, coupled with shrinking antibiotic pipelines, has increased demands for new antimicrobials with novel mechanisms of action. Antimicrobial peptides have increasingly been explored as promising alternatives to antibiotics, but their inherent poor in vivo stability remains an impediment to their clinical utility. We therefore systematically evaluated unnatural amino acid-modified peptides to design analogues with enhanced anti-mycobacterial activities. METHODS: Anti-mycobacterial activities were evaluated in vitro and intracellularly against drug-susceptible and MDR isolates of Mycobacterium tuberculosis using MIC, killing efficacy and intracellular growth inhibition studies. Toxicity profiles were assessed against mammalian cells to verify cell selectivity. Anti-mycobacterial mechanisms were investigated using microfluidic live-cell imaging with time-lapse fluorescence microscopy and confocal laser-scanning microscopy. RESULTS: Unnatural amino acid incorporation was well tolerated without an appreciable effect on toxicity profiles and secondary conformations of the synthetic peptides. The modified peptides also withstood proteolytic digestion by trypsin. The all d-amino acid peptide, i(llkk)2i (II-D), displayed superior activity against all six mycobacterial strains tested, with a 4-fold increase in selectivity index as compared with the unmodified l-amino acid peptide in broth. II-D effectively reduced the intracellular bacterial burden of both drug-susceptible and MDR clinical isolates of M. tuberculosis after 4 days of treatment. Live-cell imaging studies demonstrated that II-D permeabilizes the mycobacterial membrane, while confocal microscopy revealed that II-D not only permeates the cell membrane, but also accumulates within the cytoplasm. CONCLUSIONS: Unnatural amino acid modifications not only decreased the susceptibility of peptides to proteases, but also enhanced mycobacterial selectivity.

Anti-alpha-toxin monoclonal antibody and antibiotic combination therapy improves disease outcome and accelerates healing in a Staphylococcus aureus dermonecrosis model.

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.

Comparison of costs and discharge outcomes for patients hospitalized for ischemic or hemorrhagic stroke with or without atrial fibrillation in the United States.

This retrospective analysis investigated the impact of baseline clinical characteristics, including atrial fibrillation (AF), on hospital discharge status (to home or continuing care), mortality, length of hospital stay, and treatment costs in patients hospitalized for stroke. The analysis included adult patients hospitalized with a primary diagnosis of ischemic or hemorrhagic stroke between January 2006 and June 2011 from the premier alliance database, a large nationally representative database of inpatient health records. Patients included in the analysis were categorized as with or without AF, based on the presence or absence of a secondary listed diagnosis of AF. Irrespective of stroke type (ischemic or hemorrhagic), AF was associated with an increased risk of mortality during the index hospitalization event, as well as a higher probability of discharge to a continuing care facility, longer duration of stay, and higher treatment costs. In patients hospitalized for a stroke event, AF appears to be an independent risk factor of in-hospital mortality, discharge to continuing care, length of hospital stay, and increased treatment costs.

Feeding butter with elevated content of trans-10, cis-12 conjugated linoleic acid to obese-prone rats impairs glucose and insulin tolerance.

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.

Mapping genes to chicken microchromosome 16 and discovery of olfactory and scavenger receptor genes near the major histocompatibility complex.

Trisomy mapping is a powerful method for assigning genes to chicken microchromosome 16 (GGA 16). The single chicken nucleolar organizer region (NOR), the 2 major histocompatibility complex regions (MHC-Y and MHC-B), and CD1 genes were all previously assigned to GGA 16 using trisomy mapping. Here, we combined array comparative genomic hybridization with trisomy mapping to screen unassigned genomic scaffolds (consigned temporarily to chrUn_random) for sequences originating from GGA 16. A number of scaffolds mapped to GGA 16. Among these were scaffolds that contain genes for olfactory (OR) and cysteine-rich domain scavenger (SRCR) receptors, along with a number of genes that encode putative immunoglobulin-like receptors and other molecules. We used high-resolution cytogenomic analyses to confirm assignment of OR and SRCR genes to GGA 16 and to pinpoint members of these gene families to the q-arm in partially overlapping regions between the centromere and the NOR. Southern blots revealed sequence polymorphism within the OR/SRCR region and linkage with the MHC-Y region, thereby providing evidence for conserved linkage between OR genes and the MHC within birds. This work localizes OR genes to the vicinity of the chicken MHC and assigns additional genes, including immune defense genes, to GGA 16.