Use of Daptomycin for the Treatment of Methicillin-Resistant Coagulase-Negative Staphylococcal Ventriculitis

Coagulase-negative staphylococci (CoNS) are the main pathogens causing hospital-acquired external-ventricular-drain- (EVD-) and lumbar-drain- (LD-) associated meningitis and ventriculitis. The treatment of these infections can be challenging and may require combination of intraventricular and intravenous administration of antibiotics. Limited animal data demonstrate rapid daptomycin bactericidal activity, adequate penetration in the setting of inflamed meninges, and extended half-life in the ventricles Steenbergen et al. (2009). There are limited clinical data using daptomycin intravenously and/or intraventricularly for the treatment of central nervous system infections (CNS) Elvy et al. (2008), Stucki et al. (2007), Lee et al. (2008) and Wallace et al. (2009). We report here our experience in the treatment of an EVD-related infection

Technical Review Panel for the Pension Insurance Modeling System (PIMS)

In April of 2013, the Pension Research Council of the Wharton School at the University of Pennsylvania convened a Technical Review Panel, comprising ten experts whose task it was to review the Pension Benefit Guaranty Corporation’s (PBGC) Pension Insurance Modeling System (PIMS), including inputs, outputs, and model assumptions. The review was intended to provide a formal evaluation of the technical adequacy of the model by outside experts. Each expert participating on the Technical Panel was asked to review background material (see References) and focus on a particular aspect of the PIMS model. The list of panelists and topics was developed by the Council in discussion with the Social Security Administration (SSA). This report and the appended papers herein from our Technical Panel comprise the Final Report under this project. The Panel’s key findings may be summarized as follows: (1) The PIMS models are an important and valuable tool in modeling the Agency’s liability risk. To the best of our knowledge, there is no other model that can do a comparable job. (2) Nevertheless, some improvements could be integrated in the Agency’s approach to modeling. Those deserving highest priority attention in the experts’ view are the following: (a) Incorporating systematic mortality risk (i.e., treat mortality and longevity as stochastic variables); (b) Including new asset classes increasingly found in defined benefit plan portfolios (e.g., commercial real estate, private equity funds, infrastructure, hedge funds, and others); (c) Developing a more complex model for the term structure of interest rates; and (d) Incorporating an option value approach to pricing the insurance provided. (3) The Agency could also do more to communicate the range of uncertainty and potential for problems associated with the PBGC’s financial status. This could include additional information including the Conditional Value at Risk (CVaR), and perhaps an ‘intermediate,’ ‘optimistic,’ and ‘pessimistic’ set of projected outcomes, as well as the expected ‘date of exhaustion’ for assets backing pension benefits insured by the PBGC.Social Security Administrationhttp://deepblue.lib.umich.edu/bitstream/2027.42/102265/1/wp290.pd

Rilpivirine vs. efavirenz-based single-tablet regimens in treatment-naive adults: Week 96 efficacy and safety from a randomized phase 3b study

Objectives: To compare efficacy, safety, tolerability, and patient-reported outcomes between two single-tablet regimens, rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) and efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF), in HIV-1-infected, treatment-naive adults. Design: This was a phase 3b, 96-week, randomized, open-label, international, noninferiority trial. Methods: A total of 799 participants were randomized (1: 1) to receive RPV/FTC/TDF or EFV/FTC/TDF. The primary efficacy endpoint evaluated proportions of participants with HIV-1 RNA less than 50 copies/ml using the Snapshot algorithm. Additional assessments included CD4 cell counts, genotypic/phenotypic resistance, adverse events, patient-reported outcomes, and quality of life questionnaires. Results: At week 96, trial completion rates were 80.2% (316/394; RPV/FTC/TDF) and 74.0% (290/392; EFV/FTC/TDF). Overall, RPV/FTC/TDF was noninferior to EFV/FTC/TDF [HIV-1 RNA <50 copies/ml: 77.9 vs. 72.4%, respectively; difference-5.5; 95%CI (-0.6, 11.5); P=0.076]. RPV/FTC/TDF was significantly more efficacious compared with EFV/FTC/TDF in participants with baseline HIV-1 RNA equal to or less than 100 000 copies/ml (78.8 vs. 71.2%; P=0.046) and in those with CD4 cell count greater than 200 cells/ml (80.6 vs. 73.0%; P=0.018). There was no significant betweengroup difference in the CD4 cell count increase (278189 vs. 259191 cells/ml; P=0.17). Few participants developed resistance after week 48 (1.0% RPV/FTC/TDF; 0.3% EFV/FTC/TDF). Compared with EFV/FTC/TDF, RPV/FTC/TDF was associated with fewer adverse event-related discontinuations (3.0 vs. 11.0%; P<0.001), significantly fewer adverse events due to central nervous system issues and rash, greater improvements in patient-reported symptoms, and significant improvements in the SF-12v2 quality of life questionnaire mental health composite score (P=0.014). Conclusion: In treatment-naive, HIV-1-infected participants, 96-week RPV/FTC/TDF treatment demonstrated noninferior efficacy and better tolerability than EFV/FTC/TDF

Large-Scale Mapping and Validation of Escherichia coli Transcriptional Regulation from a Compendium of Expression Profiles

Machine learning approaches offer the potential to systematically identify transcriptional regulatory interactions from a compendium of microarray expression profiles. However, experimental validation of the performance of these methods at the genome scale has remained elusive. Here we assess the global performance of four existing classes of inference algorithms using 445 Escherichia coli Affymetrix arrays and 3,216 known E. coli regulatory interactions from RegulonDB. We also developed and applied the context likelihood of relatedness (CLR) algorithm, a novel extension of the relevance networks class of algorithms. CLR demonstrates an average precision gain of 36% relative to the next-best performing algorithm. At a 60% true positive rate, CLR identifies 1,079 regulatory interactions, of which 338 were in the previously known network and 741 were novel predictions. We tested the predicted interactions for three transcription factors with chromatin immunoprecipitation, confirming 21 novel interactions and verifying our RegulonDB-based performance estimates. CLR also identified a regulatory link providing central metabolic control of iron transport, which we confirmed with real-time quantitative PCR. The compendium of expression data compiled in this study, coupled with RegulonDB, provides a valuable model system for further improvement of network inference algorithms using experimental data

A Selective Interplay between Aberrant EPSPKA and INaP Reduces Spike Timing Precision in Dentate Granule Cells of Epileptic Rats

Spike timing precision is a fundamental aspect of neuronal information processing in the brain. Here we examined the temporal precision of input–output operation of dentate granule cells (DGCs) in an animal model of temporal lobe epilepsy (TLE). In TLE, mossy fibers sprout and establish recurrent synapses on DGCs that generate aberrant slow kainate receptor–mediated excitatory postsynaptic potentials (EPSPKA) not observed in controls. We report that, in contrast to time-locked spikes generated by EPSPAMPA in control DGCs, aberrant EPSPKA are associated with long-lasting plateaus and jittered spikes during single-spike mode firing. This is mediated by a selective voltage-dependent amplification of EPSPKA through persistent sodium current (INaP) activation. In control DGCs, a current injection of a waveform mimicking the slow shape of EPSPKA activates INaP and generates jittered spikes. Conversely in epileptic rats, blockade of EPSPKA or INaP restores the temporal precision of EPSP–spike coupling. Importantly, EPSPKA not only decrease spike timing precision at recurrent mossy fiber synapses but also at perforant path synapses during synaptic integration through INaP activation. We conclude that a selective interplay between aberrant EPSPKA and INaP severely alters the temporal precision of EPSP–spike coupling in DGCs of chronic epileptic rats

Strength Training for Arthritis Trial (START): design and rationale

Background Muscle loss and fat gain contribute to the disability, pain, and morbidity associated with knee osteoarthritis (OA), and thigh muscle weakness is an independent and modifiable risk factor for it. However, while all published treatment guidelines recommend muscle strengthening exercise to combat loss of muscle mass and strength in knee OA patients, previous strength training studies either used intensities or loads below recommended levels for healthy adults or were generally short, lasting only 6 to 24 weeks. The efficacy of high-intensity strength training in improving OA symptoms, slowing progression, and affecting the underlying mechanisms has not been examined due to the unsubstantiated belief that it might exacerbate symptoms. We hypothesize that in addition to short-term clinical benefits, combining greater duration with high-intensity strength training will alter thigh composition sufficiently to attain long-term reductions in knee-joint forces, lower pain levels, decrease inflammatory cytokines, and slow OA progression. Methods/Design This is an assessor-blind, randomized controlled trial. The study population consists of 372 older (age ≥ 55 yrs) ambulatory, community-dwelling persons with: (1) mild-to-moderate medial tibiofemoral OA (Kellgren-Lawrence (KL) = 2 or 3); (2) knee neutral or varus aligned knee ( -2° valgus ≤ angle ≤ 10° varus); (3) 20 kg.m-2 ≥ BMI ≤ 45 kg.m-2; and (3) no participation in a formal strength-training program for more than 30 minutes per week within the past 6 months. Participants are randomized to one of 3 groups: high-intensity strength training (75-90% 1Repetition Maximum (1RM)); low-intensity strength training (30-40%1RM); or healthy living education. The primary clinical aim is to compare the interventions’ effects on knee pain, and the primary mechanistic aim is to compare their effects on knee-joint compressive forces during walking, a mechanism that affects the OA disease pathway. Secondary aims will compare the interventions’ effects on additional clinical measures of disease severity (e.g., function, mobility); disease progression measured by x-ray; thigh muscle and fat volume, measured by computed tomography (CT); components of thigh muscle function, including hip abductor strength and quadriceps strength, and power; additional measures of knee-joint loading; inflammatory and OA biomarkers; and health-related quality of life. Discussion Test-retest reliability for the thigh CT scan was: total thigh volume, intra-class correlation coefficients (ICC) = 0.99; total fat volume, ICC = 0.99, and total muscle volume, ICC = 0.99. ICC for both isokinetic concentric knee flexion and extension strength was 0.93, and for hip-abductor concentric strength was 0.99. The reliability of our 1RM testing was: leg press, ICC = 0.95; leg curl, ICC = 0.99; and leg extension, ICC = 0.98. Results of this trial will provide critically needed guidance for clinicians in a variety of health professions who prescribe and oversee treatment and prevention of OA-related complications. Given the prevalence and impact of OA and the widespread availability of this intervention, assessing the efficacy of optimal strength training has the potential for immediate and vital clinical impact

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all &gt;0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Is That Me or My Twin? Lack of Self-Face Recognition Advantage in Identical Twins

Despite the increasing interest in twin studies and the stunning amount of research on face recognition, the ability of adult identical twins to discriminate their own faces from those of their co-twins has been scarcely investigated. One’s own face is the most distinctive feature of the bodily self, and people typically show a clear advantage in recognizing their own face even more than other very familiar identities. Given the very high level of resemblance of their faces, monozygotic twins represent a unique model for exploring self-face processing. Herein we examined the ability of monozygotic twins to distinguish their own face from the face of their co-twin and of a highly familiar individual. Results show that twins equally recognize their own face and their twin’s face. This lack of self-face advantage was negatively predicted by how much they felt physically similar to their co-twin and by their anxious or avoidant attachment style. We speculate that in monozygotic twins, the visual representation of the self-face overlaps with that of the co-twin. Thus, to distinguish the self from the co-twin, monozygotic twins have to rely much more than control participants on the multisensory integration processes upon which the sense of bodily self is based. Moreover, in keeping with the notion that attachment style influences perception of self and significant others, we propose that the observed self/co-twin confusion may depend upon insecure attachment

Optimal primary care management of clinical osteoarthritis and joint pain in older people: a mixed-methods programme of systematic reviews, observational and qualitative studies, and randomised controlled trials

Background Osteoarthritis (OA) is the most common long-term condition managed in UK general practice. However, care is suboptimal despite evidence that primary care and community-based interventions can reduce OA pain and disability. Objectives The overall aim was to improve primary care management of OA and the health of patients with OA. Four parallel linked workstreams aimed to (1) develop a health economic decision model for estimating the potential for cost-effective delivery of primary care OA interventions to improve population health, (2) develop and evaluate new health-care models for delivery of core treatments and support for self-management among primary care consulters with OA, and to investigate prioritisation and implementation of OA care among the public, patients, doctors, health-care professionals and NHS trusts, (3) determine the effectiveness of strategies to optimise specific components of core OA treatment using the example of exercise and (4) investigate the effect of interventions to tackle barriers to core OA treatment, using the example of comorbid anxiety and depression in persons with OA. Data sources The North Staffordshire Osteoarthritis Project database, held by Keele University, was the source of data for secondary analyses in workstream 1. Methods Workstream 1 used meta-analysis and synthesis of published evidence about effectiveness of primary care treatments, combined with secondary analysis of existing longitudinal population-based cohort data, to identify predictors of poor long-term outcome (prognostic factors) and design a health economic decision model to estimate cost-effectiveness of different hypothetical strategies for implementing optimal primary care for patients with OA. Workstream 2 used mixed methods to (1) develop and test a ‘model OA consultation’ for primary care health-care professionals (qualitative interviews, consensus, training and evaluation) and (2) evaluate the combined effect of a computerised ‘pop-up’ guideline for general practitioners (GPs) in the consultation and implementing the model OA consultation on practice and patient outcomes (parallel group intervention study). Workstream 3 developed and investigated in a randomised controlled trial (RCT) how to optimise the effect of exercise in persons with knee OA by tailoring it to the individual and improving adherence. Workstream 4 developed and investigated in a cluster RCT the extent to which screening patients for comorbid anxiety and depression can improve OA outcomes. Public and patient involvement included proposal development, project steering and analysis. An OA forum involved public, patient, health professional, social care and researcher representatives to debate the results and formulate proposals for wider implementation and dissemination. Results This programme provides evidence (1) that economic modelling can be used in OA to extrapolate findings of cost-effectiveness beyond the short-term outcomes of clinical trials, (2) about ways of implementing support for self-management and models of optimal primary care informed by National Institute for Health and Care Excellence recommendations, including the beneficial effects of training in a model OA consultation on GP behaviour and of pop-up screens in GP consultations on the quality of prescribing, (3) against adding enhanced interventions to current effective physiotherapy-led exercise for knee OA and (4) against screening for anxiety and depression in patients with musculoskeletal pain as an addition to current best practice for OA. Conclusions Implementation of evidence-based care for patients with OA is feasible in general practice and has an immediate impact on improving the quality of care delivered to patients. However, improved levels of quality of care, changes to current best practice physiotherapy and successful introduction of psychological screening, as achieved by this programme, did not substantially reduce patients’ pain and disability. This poses important challenges for clinical practice and OA research. Limitations The key limitation in this work is the lack of improvement in patient-reported pain and disability despite clear evidence of enhanced delivery of evidence-based care. Future work recommendations (1) New thinking and research is needed into the achievable and desirable long-term goals of care for people with OA, (2) continuing investigation into the resources needed to properly implement clinical guidelines for management of OA as a long-term condition, such as regular monitoring to maintain exercise and physical activity and (3) new research to identify subgroups of patients with OA as a basis for stratified primary care including (i) those with good prognosis who can self-manage with minimal investigation or specialist treatment, (ii) those who will respond to, and benefit from, specific interventions in primary care, such as physiotherapy-led exercise, and (iii) develop research into effective identification and treatment of clinically important anxiety and depression in patients with OA and into the effects of pain management on psychological outcomes in patients with OA. Trial registration Current Controlled Trials ISRCTN06984617, ISRCTN93634563 and ISRCTN40721988. Funding This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research Programme and will be published in full in Programme Grants for Applied Research Programme; Vol. 6, No. 4. See the NIHR Journals Library website for further project information. </jats:sec

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival