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Patients with inflammatory arthritis (IA) are at high risk for atherosclerotic cardiovascular disease (ASCVD), yet management of dyslipidemia is infrequently prioritized. We applied Canadian dyslipidemia guidelines to determine how many patients with IA would be eligible for primary prevention with statins.We conducted a cross-sectional study of patients with IA in a cardio-rheumatology clinic, with no known CVD and without statin therapy at cohort entry. We stratified patients by Framingham Risk Score (FRS) and summarized the proportion meeting guideline statin-indicated criteria. Multivariable logistic regression analyses determined the association of variables with statin indication after adjustment for age, sex, traditional ASCVD risk factors, and arthritis characteristics.Among 302 patients, most had rheumatoid arthritis (59%). Mean age was 58 years, and 71% were female. Overall, 50% of the cohort was eligible for statin therapy. The majority was low FRS risk category (68%), and the most frequent qualifier for statins was elevated apolipoprotein B (ApoB) levels or low-density lipoprotein cholesterol (LDL-c) levels. In the intermediate FRS group, 91% met criteria for statin therapy based on the presence of a coronary artery calcification (CAC) score0 or an elevated high-sensitivity C-reactive protein. Male sex, hypertension, elevated ApoB, and a CAC score0 were the factors most strongly associated with indication for statin therapy.Statin therapy is suboptimal in IA despite a significant number of patients meeting indication based on lipoprotein thresholds or CAC scores. Understanding the barriers and potential facilitators of implementing and interpreting these CVD screening tools in IA is needed.

Local executives in electoral authoritarian regimes can perform important regime-sustaining functions, including by delivering votes to the ruling party at election-time. Furthermore, when local executives are themselves elected, regimes can benefit from improved legitimacy and efficiency in local government. Yet elected local executives can create principal-agent problems and increase the risk that opposition groups gain office. How do authoritarian governments manage this tension? Prior research on Russia shows that elections are used to co-opt strong local mayors, while weak mayors are replaced with appointed managers. This paper argues that strong mayors are more likely to see elections canceled if their local machine is not delivering manufactured electoral support to the national party, while weak mayors are unlikely to be targeted. This hypothesis is supported using data from 207 Russian cities, including election-forensic estimates of election manipulation. The findings improve our understanding of cooptation of local leaders in electoral authoritarian regimes.

Different techniques exist to provide tip support in rhinoplasty. There is little evidence to provide a consensus on the most effective choice.Evaluating columellar strut graft (CSG) and septal extension grafts (SEG) for their influence on airway function, patient satisfaction and tip support.A retrospective cohort study was undertaken on 165 adult patients who underwent open rhinoplasty with either a CSG or SEG, from February 2012 to August 2019 in a single tertiary facial-plastic practice in Sydney, Australia. Operations were for both cosmetic and functional indications, and both primary and revision cases were assessed. Airway testing and patient-reported outcomes (PROMs) were performed preoperatively and at least 6 months following the procedure. Photographic tip analysis was taken from approximately 4 and 12-month postoperative photographs.Nasal peak inspiratory flow (NPIF) and total nasal airway resistance (NAR) were the primary airway functional outcomes. The primary PROMs analysed were a visual analogue scale (VAS) for nasal obstruction and 13-point Likert scale for global cosmesis, the Nose Outcome Symptom Evaluation (NOSE), and the nasal obstruction score. Tip support was determined by the nasolabial angle (NLA) and Simon's ratio as assessed by Rhinobase developed by Apaydin et al. on lateral Frankfort plane photographs. Data normalised as an improvement over preoperative baseline, accounting for individual variability.A total of 165 patients was assessed (35.2 ± 12.9 yrs, 72% female), 100 (61%) of which received SEG. There were similar nasal airway assessments between CSG and SEG groups, with ΔNPIF (20.0 ± 42.1 L/min v 19.9 ± 44.9 L/min, p = 0.983) and Δ "obstructed" NAR (-1.13 ± 1.90 v -1.02 ± 4.33 Pa/cm3/s, p = 0.849). Amongst PROMs, a greater cosmetic outcome was seen in the SEG group (7.20 ± 2.97 v 5.69 ± 3.45, p 0.01) with all other assessments similar between CSG and SEG techniques. Photographic analysis of tip projection showed reduced NLA distortion in the SEG.While greater patient-perceived cosmesis was seen in patients with a SEG, there were similar airflow and patient-reported nasal function between groups. Photographic analysis of tip projection showed SEG patients additionally benefited from less NLA distortion and greater tip maintenance.

Patients with emergency spinal pathologies such as suspected cauda equina syndrome are often admitted under non-spinal orthopaedic surgeons at district general hospitals (DGHs). Emergent investigation in the form of magnetic resonance imaging (MRI) is frequently required prior to potential referral to the tertiary spinal centre despite many DGHs not having out-of-hours MRI provision. Anecdotally, there is considerable anxiety among non-spinal orthopaedic surgeons working in DGHs around the admission and investigation of emergency spinal pathologies under their care. We sought to survey and formalise the opinions of non-spinal on-call orthopaedic consultants at three DGHs with regard to admission, investigation, local infrastructure and regional support provided to them when emergency spinal pathologies are admitted under their care. The consultants surveyed reported being very uncomfortable managing emergency spinal cases admitted under their care. It was felt that the hospitals provided inadequate infrastructure, especially in terms of obtaining timely imaging. There is a lack of local outpatient spinal provision, a lack of consistent advice from the regional centre, and a feeling of patient, personal and organisational vulnerability with the current implementation of the regional spinal pathway. There was a high preference for a restructuring of the spinal pathway as well as a desire for on-site spinal opinions. The results of this survey demonstrate the considerable unease experienced by non-spinal trauma and orthopaedic consultants at district general hospitals with regard to the management of spinal pathology. We hypothesise that this is not limited to this region but is a sentiment echoed nationally.

The weak acid sorbic acid is a common preservative used in soft drink beverages to control microbial spoilage. Consumers and industry are increasingly transitioning to low-sugar food formulations, but potential impacts of reduced-sugar on preservative efficacy are barely characterised. In this study, we report enhanced sorbic acid resistance of spoilage yeasts in low-glucose conditions. We had anticipated that low glucose may induce respiratory metabolism, previously shown to be targeted by sorbic acid. However, a shift from respiratory to fermentative metabolism was correlated with the sorbic acid resistance in low glucose. Fermentation-deficient yeast species did not show the low-glucose resistance phenotype. Phenotypes observed for certain yeast deletion strains suggested roles for glucose signalling and repression pathways in the sorbic acid resistance at low glucose. This low-glucose induced sorbic acid resistance was alleviated by supplementing yeast cultures with succinic acid, a metabolic intermediate of respiratory metabolism (and a food-safe additive) that promoted respiration. The results indicate that metabolic adaptation of spoilage yeasts promotes sorbic acid resistance at low glucose, providing new insight into potential spoilage, and preservation, of foodstuffs as both food producers and consumers move towards a reduced-sugar landscape.

We report on progress implementing and testing cryogenically cooled platforms for Magnetized Liner Inertial Fusion (MagLIF) experiments. Two cryogenically cooled experimental platforms were developed: an integrated platform fielded on the Z pulsed power generator that combines magnetization, laser preheat, and pulsed-power-driven fuel compression and a laser-only platform in a separate chamber that enables measurements of the laser preheat energy using shadowgraphy measurements. The laser-only experiments suggest that ∼89% ± 10% of the incident energy is coupled to the fuel in cooled targets across the energy range tested, significantly higher than previous warm experiments that achieved at most 67% coupling and in line with simulation predictions. The laser preheat configuration was applied to a cryogenically cooled integrated experiment that used a novel cryostat configuration that cooled the MagLIF liner from both ends. The integrated experiment, z3576, coupled 2.32 ± 0.25 kJ preheat energy to the fuel, the highest to-date, demonstrated excellent temperature control and nominal current delivery, and produced one of the highest pressure stagnations as determined by a Bayesian analysis of the data.

In magneto-inertial fusion, the ratio of the characteristic fuel length perpendicular to the applied magnetic field R to the α-particle Larmor radius ϱα is a critical parameter setting the scale of electron thermal-conduction loss and charged burn-product confinement. Using a previously developed deep-learning-based Bayesian inference tool, we obtain the magnetic-field fuel-radius product BR∝R/ϱα from an ensemble of 16 magnetized liner inertial fusion (MagLIF) experiments. Observations of the trends in BR are consistent with relative trade-offs between compression and flux loss as well as the impact of mix from 1D resistive radiation magneto-hydrodynamics simulations in all but two experiments, for which 3D effects are hypothesized to play a significant role. Finally, we explain the relationship between BR and the generalized Lawson parameter χ. Our results indicate the ability to improve performance in MagLIF through careful tuning of experimental inputs, while also highlighting key risks from mix and 3D effects that must be mitigated in scaling MagLIF to higher currents with a next-generation driver.

Background Trends of increasing area burned in many regions worldwide are leading to more locations experiencing short-interval reburns (i.e., fires occurring two or more times in the same place within 1–3 decades). Field and satellite indices of burn severity are well tested in forests experiencing a single recent fire, but the reliability of these indices in short-interval reburns is poorly understood. We tested how a commonly used field index (the Composite Burn Index, CBI) and satellite index (the Relative differenced Normalized Burn Ratio, RdNBR) compared to eight individual field measures of burn severity in short-interval reburns vs. areas burned in one recent fire, and whether results depended on whether the first fire was stand replacing (fire that is lethal to most dominant trees). Results Correspondence between both CBI and RdNBR with individual burn severity measures differed in short-interval reburns compared to single fires for some metrics of burn severity. Divergence in the relationship between both CBI and RdNBR vs. field measures was greatest when short-interval reburns followed a prior stand-replacing fire, and measures were more comparable to single fires when the first fire was non-stand replacing (i.e., lower severity). When short-interval reburns followed prior stand-replacing fires, CBI and RdNBR underestimated burn severity in the second fire for tree-canopy metrics (e.g., canopy cover loss, tree mortality), as young forests in early developmental stages are more sensitive to a second fire. Conversely, when short-interval reburns followed prior less-than-stand-replacing fires, both CBI and RdNBR overestimated burn severity for forest-floor metrics, as past low severity fires leave behind live fire-resistant trees and can stimulate resprouting understory vegetation. Finally, neither CBI nor RdNBR accurately detected deep wood charring—an important phenomenon that occurs in short-interval reburns. Conclusion Our findings inform interpretability of commonly used indices of burn severity in short-interval reburns by identifying how individual burn severity metrics can be under- or over-estimated, depending on the severity of the fire preceding a reburn. Adjustments to burn severity measurements made in short-interval reburns are particularly critical as reburned areas increase.

Independent automated scoring of sleep-wake and seizures have recently been achieved; however, the combined scoring of both states has yet to be reported. Mouse models of epilepsy typically demonstrate an abnormal electroencephalographic (EEG) background with significant variability between mice, making combined scoring a more difficult classification problem for manual and automated scoring. Given the extensive EEG variability between epileptic mice, large group sizes are needed for most studies. As large datasets are unwieldy and impractical to score manually, automatic seizure and sleep-wake classification are warranted. To this end, we developed an accurate automated classifier of sleep-wake states, seizures, and the post-ictal state. Our benchmark was a classification accuracy at or above the 93% level of human inter-rater agreement. Given the failure of parametric scoring in the setting of altered baseline EEGs, we adopted a machine-learning approach. We created several multi-layer neural network architectures that were trained on human-scored training data from an extensive repository of continuous recordings of electrocorticogram (ECoG), left and right hippocampal local field potential (HPC-L and HPC-R), and electromyogram (EMG) in the murine intra-amygdala kainic acid model of medial temporal lobe epilepsy. We then compared different network models, finding a bidirectional long short-term memory (BiLSTM) design to show the best performance with validation and test portions of the dataset. The SWISC (sleep-wake and the ictal state classifier) achieved >93% scoring accuracy in all categories for epileptic and non-epileptic mice. Classification performance was principally dependent on hippocampal signals and performed well without EMG. Additionally, performance is within desirable limits for recording montages featuring only ECoG channels, expanding its potential scope. This accurate classifier will allow for rapid combined sleep-wake and seizure scoring in mouse models of epilepsy and other neurologic diseases with varying EEG abnormalities, thereby facilitating rigorous experiments with larger numbers of mice.

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XLSX file - 29K, Supplementary Table S1: Expression values for myeloid cell signature genes from the heatmap in Figure 1E.

PDF file - 42K, Supplementary Figure S2: Additional figures on myeloid cell characterization based on tumor type and anatomical location.

XLSX file - 4K, Supplementary Table S4: Expression values for neutrophil cytokine-chemokine genes from the heatmap in Figure 6B.

XLSX file - 1K, Supplementary Table S6: Expression values for neutrophil granular effector molecules from the heatmap in Figure 7A.

PDF file - 136K, Supplementary Figure S1: Additional figures on myeloid cell characterization in different tumor models.

XLSX file - 12K, Supplementary Table S3: Expression values for neutrophil-associated genes from the heatmap in Figure 5B.

XLSX file - 2K, Supplementary Table S5: Expression values for PPARa-associated genes from the heatmap in Figure 6C.

Myeloid cells play important regulatory roles within the tumor environment by directly promoting tumor progression and modulating the function of tumor-infiltrating lymphocytes, and as such, they represent a potential therapeutic target for the treatment of cancer. Although distinct subsets of tumor-associated myeloid cells have been identified, a broader analysis of the complete myeloid cell landscape within individual tumors and also across different tumor types has been lacking. By establishing the developmental and transcriptomic signatures of infiltrating myeloid cells from multiple primary tumors, we found that tumor-associated macrophages (TAM) and tumor-associated neutrophils (TAN), while present within all tumors analyzed, exhibited strikingly different frequencies, gene expression profiles, and functions across cancer types. We also evaluated the impact of anatomic location and circulating factors on the myeloid cell composition of tumors. The makeup of the myeloid compartment was determined by the tumor microenvironment rather than the anatomic location of tumor development or tumor-derived circulating factors. Protumorigenic and hypoxia-associated genes were enriched in TAMs and TANs compared with splenic myeloid-derived suppressor cells. Although all TANs had an altered expression pattern of secretory effector molecules, in each tumor type they exhibited a unique cytokine, chemokine, and associated receptor expression profile. One such molecule, haptoglobin, was uniquely expressed by 4T1 TANs and identified as a possible diagnostic biomarker for tumors characterized by the accumulation of myeloid cells. Thus, we have identified considerable cancer-specific diversity in the lineage, gene expression, and function of tumor-infiltrating myeloid cells. Cancer Immunol Res; 2(7); 655–67. ©2014 AACR.

Supplementary Data from First-in-Human Phase I/II ICONIC Trial of the ICOS Agonist Vopratelimab Alone and with Nivolumab: ICOS-High CD4 T-Cell Populations and Predictors of Response

Supplementary Fig. S3 from Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor

Purpose:The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costimulator (ICOS) agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors.Patients and Methods:In phase I, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, MTD, and recommended phase II dose (RP2D). Phase II enriched for ICOS-positive (ICOS+) tumors; patients were treated with vopratelimab at the monotherapy RP2D alone or with nivolumab. Pharmacokinetics, pharmacodynamics, and predictive biomarkers of response to vopratelimab were assessed.Results:ICONIC enrolled 201 patients. Vopratelimab alone and with nivolumab was well tolerated; phase I established 0.3 mg/kg every 3 weeks as the vopratelimab RP2D. Vopratelimab resulted in modest objective response rates of 1.4% and with nivolumab of 2.3%. The prospective selection for ICOS+ tumors did not enrich for responses. A vopratelimab-specific peripheral blood pharmacodynamic biomarker, ICOS-high (ICOS-hi) CD4 T cells, was identified in a subset of patients who demonstrated greater clinical benefit versus those with no emergence of these cells [overall survival (OS), P = 0.0025]. A potential genomic predictive biomarker of ICOS-hi CD4 T-cell emergence was identified that demonstrated improvement in clinical outcomes, including OS (P = 0.0062).Conclusions:Vopratelimab demonstrated a favorable safety profile alone and in combination with nivolumab. Efficacy was observed only in a subset of patients with a vopratelimab-specific pharmacodynamic biomarker. A potential predictive biomarker of response was identified, which is being prospectively evaluated in a randomized phase II non–small cell lung cancer trial.See related commentary by Lee and Fong, p. 3633

Signaling through the erbB receptor family of tyrosine kinases contributes to the proliferation, differentiation, migration, and survival of a variety of cell types. Abnormalities in members of this receptor family have been shown to play a role in oncogenesis, thus making them attractive targets for anticancer treatments. PF-00299804 is a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor currently in phase I clinical trials. PF-00299804 is believed to irreversibly inhibit erbB tyrosine kinase activity through binding at the ATP site and covalent modification of nucleophilic cysteine residues in the catalytic domains of erbB family members. Oral administration of PF-00299804 causes significant antitumor activity, including marked tumor regressions in a variety of human tumor xenograft models that express and/or overexpress erbB family members or contain the double mutation (L858R/T790M) in erbB1 (EGFR) associated with resistance to gefitinib and erlotinib. Furthermore, PF-00299804 shows exceptional distribution to human tumor xenografts and excellent pharmacokinetic properties across species. [Mol Cancer Ther 2008;7(7):1880–9]

Introduction: Antimicrobial stewardship (AMS) strategies, such as intravenous-to-oral switch (IVOS), promote optimal antimicrobial use, contributing to safer and more effective patient care and tackling antimicrobial resistance (AMR). Aim: This study aimed to achieve nationwide multidisciplinary expert consensus on antimicrobial IVOS criteria for timely switch in hospitalised adult patients and to design an IVOS decision aid to operationalise agreed IVOS criteria in the hospital setting. Method: A four-step Delphi process was chosen to achieve expert consensus on IVOS criteria and decision aid; it included (Step One) Pilot/1st round questionnaire, (Step Two) Virtual meeting, (Step Three) 2nd round questionnaire and (Step 4) Workshop. This study follows the Appraisal of Guidelines for Research and Evaluation II instrument checklist. Results: The Step One questionnaire of 42 IVOS criteria had 24 respondents, 15 of whom participated in Step Two, in which 37 criteria were accepted for the next step. Step Three had 242 respondents (England n = 195, Northern Ireland n = 18, Scotland n = 18, Wales n = 11); 27 criteria were accepted. Step Four had 48 survey respondents and 33 workshop participants; consensus was achieved for 24 criteria and comments were received on a proposed IVOS decision aid. Research recommendations include the use of evidence-based standardised IVOS criteria. Discussion and Conclusion: This study achieved nationwide expert consensus on antimicrobial IVOS criteria for timely switch in the hospitalised adult population. For criteria operationalisation, an IVOS decision aid was developed. Further research is required to provide clinical validation of the consensus IVOS criteria and to expand this work into the paediatric and international settings.