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Background: Intravenous lipid emulsion is recognised as a therapy for rescue in cases of local anaesthetic toxicity, but its use in reversing overdose or toxicity related to other drugs remains the subject of debate. This in vitro study sought to expand our understanding of the importance of partitioning in determining the impact of intravenous lipid emulsion on aqueous free drug concentrations. Methods: Twenty-seven drugs and associated metabolites were screened for the ability of intravenous lipid emulsion to reduce the amount of free drug in the aqueous phase, using specialised cassettes designed for this purpose. The relative amount of drug equilibrating across the membrane from plasma to phosphate-buffered saline was measured, using liquid chromatography–mass spectrometry, at a 6 h timepoint in plasma samples treated with intravenous lipid emulsion and paired, untreated controls. Results: The data obtained were plotted against measures of partition (LogP and cLogD7.4) and with log-transformed non-protein bound drug. There were significant inverse correlations between the capacity for intravenous lipid emulsion to reduce drug detected in the phosphate-buffered saline compartment and LogP and cLogD7.4, and a direct association with log [non-protein-bound drug]. However, a number of drugs showed substantial variance between different plasma samples. Conclusions: Modulation of free drug in the aqueous compartment is broadly predictable by the partition coefficient, although ramipril was identified to be an outlier in this regard. Further mechanistic and clinical exploration is merited to establish a standardised protocol for lipid emulsion therapy.

The use of handheld cannisters providing supplementary oxygen to use ‘track side’ is becoming popular. The aim of this study was to determine the optimal time to administer oxygen supplementation (O2Supp) during a repeat sprint protocol on cycling performance. Ten male recreationally active University students participated. Testing comprised four visits to the laboratory in a counterbalanced design. Each session entailed ten x 15s repeated sprints interspersed with 45s passive recovery, during which the air inspired was either 100% oxygen (H) or normal air, (N), thus the oxygen content inspired during the sprints and/or the recovery periods, determined the four conditions; NH, HN, HH, NN respectively. It was hypothesised that the HH condition would evoke the largest performance improvements. Repeated measures ANOVA were used to examine the difference between conditions in the outcome measures of mean power (W), rate of power decline (%) and blood lactate (mmol·L-1). There was no significant effect of O2Supp on mean power (W), blood lactate or performance decline (%) (p > .05), although. the HH condition did result in the lowest levels of lactate accumulation and the shallowest decline in performance. The NH and HN conditions resulted a greater decline in performance than both HH and NN. Continuous O2Supp during repeat sprint cycling is more effective on cycling performance, than when it is administered in short repeated bouts. It appears that the rapid changing of oxygen availability may have a detrimental effect on performance. O2Supp can be applied to training programmes that have extended (>1min) periods of recovery.

This study examined performance and physiological responses (power output, tissue saturation index) to repeat sprint cycling with oxygen supplementation (O2Supp [fraction of inspired oxygen 1.00]). Fourteen amateur male cyclists took part. Two visits to the laboratory entailed; 15min relative intensity warm-up, 10min of passive recovery, followed by 10x15s repeated sprints, during which air inspired had FiO2 1.00 oxygen or normal air. Outcome measures include, mean power (W) and change in Tissue Saturation Index (ΔTSI%). Repeated measures ANOVA were used to examine difference between conditions in mean power output. Paired samples t-tests were used to examine differences between conditions in ΔTSI (%) and rate of muscle reoxygenation and deoxygenation (%·s-1). Mean power output was 4% higher in the oxygen condition compared to normoxia (p < .01). There was a significant positive correlation between power output and reoxygenation rate during O2Supp (r = 0.65, p = .04). No correlation was seen between power output and reoxygenation rate during normoxia (r = -0.30, p = .40). A significantly increased deoxy rate was seen in the O2Supp condition compared to normoxia (p = .05). Oxygen supplementation appears to elicit the greatest performance improvements in mean power, potentially facilitated by an increasing muscle reoxygenation rate. This evidences the utility of oxygen as an ergogenic aid to in cycling performance.

Single-particle electron cryo-microscopy (cryo-EM) is an effective tool to determine high-resolution structures of macromolecular complexes. Its lower requirements for sample concentration and purity make it an accessible method to determine structures of low-abundant protein complexes, such as those isolated from native sources. While there are many approaches to protein purification for cryo-EM, attaining suitable particle quality and abundance is generally the major bottleneck to the typical single-particle project workflow. Here, we present a protocol using budding yeast (S. cerevisiae), in which a tractable immunoprecipitation tag (3xFLAG) is appended at the endogenous locus of a gene of interest (GOI). The modified gene is expressed under its endogenous promoter, and cells are grown and harvested using standard procedures. Our protocol describes the steps in which the tagged proteins and their associated complexes are isolated within three hours of thawing cell lysates, after which the recovered proteins are used directly for cryo-EM specimen preparation. The prioritization of speed maximizes the ability to recover intact, scarce complexes. The protocol is generalizable to soluble yeast proteins that tolerate C-terminal epitope tags. Graphical abstract Overview of lysate-to-grid workflow. Yeast cells are transformed to express a tractable tag on a gene of interest. Following cell culture and lysis, particles of interest are rapidly isolated by co-immunoprecipitation and prepared for cryo-EM imaging (created with BioRender.com).

Introduction Anthracyclines are included in chemotherapy regimens to treat several different types of cancer and are extremely effective. However, it is recognised that a significant side effect is cardiotoxicity; anthracyclines can cause irreversible damage to cardiac cells and ultimately impaired cardiac function and heart failure, which may only be evident years after exposure. The PROACT trial will establish the effectiveness of the ACE inhibitor enalapril maleate (enalapril) in preventing cardiotoxicity in patients with breast cancer and non-Hodgkin’s lymphoma (NHL) receiving anthracycline-based chemotherapy.Methods and analysis PROACT is a prospective, randomised, open-label, blinded end-point, superiority trial which will recruit adult patients being treated for breast cancer and NHL at NHS hospitals throughout England. The trial aims to recruit 106 participants, who will be randomised to standard care (high-dose anthracycline-based chemotherapy) plus enalapril (intervention) or standard care alone (control). Patients randomised to the intervention arm will receive enalapril (starting at 2.5 mg two times per day and titrating up to a maximum dose of 10 mg two times per day), commencing treatment at least 2 days prior to starting chemotherapy and finishing 3 weeks after their last anthracycline dose. The primary outcome is the presence or absence of cardiac troponin T release at any time during anthracycline treatment, and 1 month after the last dose of anthracycline. Secondary outcomes will focus on cardiac function measured using echocardiogram assessment, adherence to enalapril and side effects.Ethics and dissemination A favourable opinion was given following research ethics committee review by West Midlands—Edgbaston REC, Ref: 17/WM/0248. Trial findings will be disseminated through engagement with patients, the oncology and cardiology communities, NHS management and commissioning groups and through peer-reviewed publication.Trial registration number NCT03265574.

Objective Neonatal encephalopathy remains a major cause of infant mortality and neurodevelopmental impairment. Infection may exacerbate brain injury and mitigate the effect of therapeutic hypothermia (TH). Additionally, infants with sepsis treated with TH may be at increased risk of adverse effects. This study aimed to review the clinical characteristics and outcomes for infants with sepsis treated with TH.Design and setting Retrospective cohort study of infants treated with TH within Australia and New Zealand.Patients 1522 infants treated with TH, including 38 with culture-positive sepsis from 2014 to 2018.Intervention Anonymised retrospective review of data from Australian and New Zealand Neonatal Network. Infants with culture-positive sepsis within 48 hours were compared with those without sepsis.Main outcome measures Key outcomes include in-hospital mortality, intensive care support requirements and length of stay.Results Overall the rate of mortality was similar between the groups (13% vs 13%). Infants with sepsis received a higher rate of mechanical ventilation (89% vs 70%, p=0.01), high-frequency oscillatory ventilation (32% vs 13%, p=0.003) and inhaled nitric oxide for persistent pulmonary hypertension (38% vs 16%, p

Summary: The tetravalent dengue vaccine candidate, TAK-003, induces a functional antibody response, but the titers of antibodies against the four serotypes of the dengue virus (DENV) can vary. Here, through a transcriptomic analysis on whole blood collected from recipients of a two-dose schedule of TAK-003, we examine gene expression, splicing, and transcript isoform-level changes for both protein-coding and noncoding genes to broaden our understanding of the immune response. Our analysis reveals a dynamic pattern of vaccine-associated regulation of long noncoding RNAs (lncRNAs), differential splicing of interferon-stimulated gene exons, and gene expression changes related to multiple signaling pathways that detect viral infection. Co-expression networks isolate immune cell-type-related and interferon-response modules that represent specific biological processes that correlate with more robust antibody responses. These data provide insights into the early determinants of the variable immune response to the vaccine, highlighting the significance of splicing and isoform-level gene regulatory mechanisms in defining vaccine immunogenicity.

This study assessed the longitudinal impact of early preventive dental visits on the number of dental operative procedures in a prevention-oriented pediatric dental practice. Inclusion criteria consisted of patients zero to four years of age with at least two years of preventive services provided by the practice. Early preventive visits were the intervention and dental operative procedures were the assessed outcome. The goal was to determine if preventive visits at an early age decreased the number of operative procedures needed by the patient. The patients were divided into two groups: those with older siblings in the practice and those without older siblings in the practice. A secondary outcome was to compare these two patient groups to determine if a child who had older siblings previously treated in this preventive practice had better outcomes than those without siblings in the practice. ANCOVA tests were used to compare the average number of operative procedures in two age groups (p < 0.05). The average number of operative procedures in two age groups (p < 0.05) with those whose age at first visit ≥2 years experiencing more dental operative procedures than the younger group. The average number of operative procedures was similar between younger siblings (mean = 1.91; SD = 7.44) and children without siblings (mean = 1.54; SD = 2.1) (p > 0.05). The difference in the average number of operative procedures in children with insurance (mean = 1.59; SD = 5.25) and children without insurance (mean = 1.58; SD = 2.38) was non-significant (p > 0.05). More dental cleaning examinations were associated with fewer dental operative procedures (p < 0.05). These findings demonstrate that dental examinations before two years of age and more dental cleaning examinations lead to a decrease in the number of dental operative procedures needed by children.

Abstract The Córdoba Argentina Marx Meter Array (CAMMA), consisting of 10 second‐generation Huntsville Alabama Marx Meter Array (HAMMA 2) sensors, operated at Córdoba, Argentina, during the Remote sensing of Electrification, Lightning, And Mesoscale/microscale Processes with Adaptive Ground Observations (RELAMPAGO) field campaign in late 2018. Initial results obtained from the campaign demonstrate that the new sensor is able to provide a significantly more detailed depiction of various lightning processes than its first generation. The lightning flashes mapped by the CAMMA and a colocated Lightning Mapping Array (LMA) were compared. The overall flash structures mapped by the CAMMA and the LMA look similar for most of the flashes. However, comparisons at smaller time scale show that the majority of CAMMA and LMA sources are not concurrent, indicating that unmatched sources were possibly due to different physical processes in leader propagation dominating different frequencies and differences in data processing and location techniques.

Purpose: To determine the oncological implications of increased nodal dissection in node-negative bladder cancer during radical cystectomy in a contemporary Australian series. Materials and Methods: We performed a multicenter retrospective study, including more than 40 surgeons across 5 sites over a 10-year period. We identified 353 patients with primary bladder cancer undergoing radical cystectomy. Extent of lymphadenectomy was defined as follows; limited pelvic lymph node dissection (PLND) (perivesical, pelvic, and obturator), standard PLND (internal and external iliac) and extended PLND (common iliac). Multivariable cox proportional hazards and logistic regression models were used to determine LNY effect on cancer-specific survival. Results: Over the study period, the extent of dissection and lymph node yield increased considerably. In node-negative patients, lymph node yield (LNY) conferred a significantly improved cancer-specific survival. Compared to cases where LNY of 1 to 5 nodes were taken, the hazard ratio (HR) for 6 to 15 nodes harvested was 0.78 (95% confidence interval [CI], 0.43–1.39) and for greater than 15 nodes the HR was 0.31 (95% CI, 0.17–0.57), adjusted for age, sex, T stage, margin status, and year of surgery. The predicted probability of cancer-specific death within 2 years of cystectomy was 16% (95% CI, 13%–19%) with 10 nodes harvested, falling to 5.5% (95% CI, 0%–12%) with 30 nodes taken. Increasing harvest in all PLND templates conferred a survival benefit. Conclusions: The findings of the current study highlight the improved oncological outcomes with increased LNY, irrespective of the dissection template. Further prospective research is needed to aid LND data interpretation.

Adeno-associated virus (AAV) vectors are preeminent in emerging clinical gene therapies. Generalizing beyond the most tractable genetic diseases will require modulation of cell specificity and immune neutralization. Interactions of AAV with its cellular receptor, AAVR, are key to understanding cell-entry and trafficking with the rigor needed to engineer tissue-specific vectors. Cryo-electron tomography shows ordered binding of part of the flexible receptor to the viral surface, with distal domains in multiple conformations. Regions of the virus and receptor in close physical proximity can be identified by cross-linking/mass spectrometry. Cryo-electron microscopy with a two-domain receptor fragment reveals the interactions at 2.4 Å resolution. AAVR binds between AAV’s spikes on a plateau that is conserved, except in one clade whose structure is AAVR-incompatible. AAVR’s footprint overlaps the epitopes of several neutralizing antibodies, prompting a re-evaluation of neutralization mechanisms. The structure provides a roadmap for experimental probing and manipulation of viral-receptor interactions.

The characteristics of spontaneous emission can be strongly modified by the mode structure of the vacuum. In waveguide quantum-electrodynamics based on photonic crystals, this modification is exploited to engineer atom-photon interactions near a band edge, but the physics of coupling to an entire band has not yet been explored in experiments. Using ultracold atoms in an optical lattice, we study the decay dynamics of matter-wave quantum emitters coupled to a single band of an effective photonic crystal waveguide structure with tunable characteristics. Depending on the ratio between vacuum coupling and bandwidth, we observe a transition from irreversible decay to fully oscillatory dynamics linked to the interplay of matter-wave bound states near the band edges, whose spatial structure we characterize. Our results shed light on the emergence of coherence in an open quantum system in a controllable environment and are of relevance for the understanding of vacuum-induced decay phenomena in photonic systems.

This essay examines the ways in which politics and leisure were entangled in early San Francisco punk. Although San Francisco is perhaps uniquely associated with the counterculture of the 1960s, the city was, by the late 1970s, also home to a punk scene largely defined by its fierce engagement with political issues. At the same time, punks experienced this scene — which existed at a time of sustained national, state, and local crisis — as deliriously fun. Their idea of fun was vastly different than mainstream ideas of American leisure, but there is no denying that punk, like most subcultures, was experienced at least in part as a leisure activity. I argue that punks acted deliberately to not only intertwine fun and politics, but to make fun and play vehicles for political struggle, if not revolution. At least in this one major American city, punk was equal parts political engagement and diversion, equally confrontational and escapist. More importantly, the leisure and fun elements contributed to the building of a prefigurative community as a micro-model of what punks hoped could be achieved on a larger scale. In that way, fun and politics contributed to a fundamentally utopian vision in a subculture marked not by nihilism — as punk is so often cast — but by possibility.

Unlike traditional transmission control protocol/Internet protocol–based networks, delay/disruption tolerant networks may experience connectivity disruptions and guarantee no end-to-end connectivity between source and destination. As the popularity of delay/disruption tolerant networks continues to rise, so does the need for a robust and low-latency routing protocol. A one-copy, shortest path delay/disruption tolerant network routing protocol that addresses congestion avoidance and maximizes total network bandwidth utility is crucial to efficient packet delivery in high-load networks and is the motivation behind the development of the congestion avoidance shortest path routing. Congestion avoidance shortest path routing is designed to either route undeliverable packets “closer” to their destinations or hold onto them when advantageous to do so. Congestion avoidance and bottleneck minimization are integrated into its design. Moreover, congestion avoidance shortest path routing negotiates node queue differentials between neighbors similar to backpressure algorithms and maps shortest paths without any direct knowledge of node connectivity outside of its own neighborhood. Simulation results show that congestion avoidance shortest path routing outperforms well-known protocols in terms of packet delivery probability and latency and is still quite efficient in terms of overhead requirements. Finally, we explore the effectiveness of modeling a variant of congestion avoidance shortest path routing based on the resistance to current flow of electrical circuits in an attempt to further reduce network congestion. Preliminary results indicate a noticeable performance increase when this method is used.

Michael Stewart1, BJ Ferguson2, Len Fromer31Department of Otorhinolaryngology, Weill Cornell Medical College, New York-Presbyterian Hospital/Weill Cornell Medical Center, USA; 2Department of Otolaryngology, University of Pittsburgh School of Medicine, USA; 3University of California, Los Angeles; David Geffen School of Medicine Los Angeles, California, USAAbstract: Nasal congestion, which may be described as fullness, obstruction, reduced airflow, or being “stuffed up,” is a commonly encountered symptom in clinical practice. Systematic study of congestion has largely considered it as a component of a disease state. Conditions associated with congestion include nasal polyposis, obstructive sleep apnea, and anatomic variation; however, most information on the burden of congestion comes from studies of allergic rhinitis and rhinosinusitis, diseases of which congestion is the major symptom. Congestion can be caused by other rhinologic conditions, such as non-allergic rhinitis, viral or bacterial rhinitis, and vasomotor rhinitis. Allergic rhinitis affects as much as one quarter of the population worldwide and imposes a significant economic burden. Additionally, allergic rhinitis significantly impairs quality of life; congestion causes allergic rhinitis sufferers decreased daytime productivity at work or school and reduces night-time sleep time and quality. Annually, rhinosinusitis affects tens of millions of Americans and leads to approximately $6 billion in overall health care expenditures; it has been found to be one of the most costly physical conditions for US employers. Given the high prevalence and significant social and economic burden of nasal congestion, this symptom should be a key consideration in treating patients with rhinologic disease, and there continues to be a significant unmet medical need for effective treatment options for this condition.Keywords: allergic rhinitis, congestion, epidemiology, obstruction, rhinosinusitis

May-Thurner syndrome is a rare condition requiring both clinical acumen and correct imaging studies to diagnose. We present a case of a 49-year-old male who was initially admitted for chest pain and was later found to have extensive left-lower-extremity deep vein thrombosis. Subsequent computed tomography (CT) imaging was able to reveal a right common iliac aneurysm compressing the left common iliac vein. Radiologic findings and procedural angiographic studies are reviewed with reference to pertinent literature.

This paper provides an introduction to a software package called waved making available all code necessary for reproducing the figures in the recently published articles on the WaveD transform for wavelet deconvolution of noisy signals. The forward WaveD transforms and their inverses can be computed using any wavelet from the Meyer family. The WaveD coefficients can be depicted according to time and resolution in several ways for data analysis. The algorithm which implements the translation invariant WaveD transform takes full advantage of the fast Fourier transform (FFT) and runs in O(n(log n)2)