Near-universal hospitalization of US emergency department patients with cancer and febrile neutropenia

IMPORTANCE: Febrile neutropenia (FN) is the most common oncologic emergency and is among the most deadly. Guidelines recommend risk stratification and outpatient management of both pediatric and adult FN patients deemed to be at low risk of complications or mortality, but our prior single-center research demonstrated that the vast majority (95%) are hospitalized. OBJECTIVE: From a nationwide perspective, to determine the proportion of cancer patients of all ages hospitalized after an emergency department (ED) visit for FN, and to analyze variability in hospitalization rates. Our a priori hypothesis was that >90% of US cancer-associated ED FN visits would end in hospitalization. DESIGN: Analysis of data from the Nationwide Emergency Department Sample, 2006-2014. SETTING: Stratified probability sample of all US ED visits. PARTICIPANTS: Inclusion criteria were: (1) Clinical Classification Software code indicating cancer, (2) diagnostic code indicating fever, and (3) diagnostic code indicating neutropenia. We excluded visits ending in transfer. EXPOSURE: The hospital at which the visit took place. MAIN OUTCOMES AND MEASURES: Our main outcome is the proportion of ED FN visits ending in hospitalization, with an a priori hypothesis of >90%. Our secondary outcomes are: (a) hospitalization rates among subsets, and (b) proportion of variability in the hospitalization rate attributable to which hospital the patient visited, as measured by the intra-class correlation coefficient (ICC). RESULTS: Of 348,868 visits selected to be representative of all US ED visits, 94% ended in hospitalization (95% Confidence Interval [CI] 93-94%). Each additional decade of age conferred 1.23x increased odds of hospitalization. Those with private (92%), self-pay (92%), and other (93%) insurance were less likely to be hospitalized than those with public insurance (95%, odds ratios [OR] 0.74-0.76). Hospitalization was least likely at non-metropolitan hospitals (84%, OR 0.15 relative to metropolitan teaching hospitals), and was also less likely at metropolitan non-teaching hospitals (94%, OR 0.64 relative to metropolitan teaching hospitals). The ICC adjusted for hospital random effects and patient and hospital characteristics was 26% (95%CI 23-29%), indicating that 26% of the variability in hospitalization rate was attributable to which hospital the patient visited. CONCLUSIONS AND RELEVANCE: Nearly all cancer-associated ED FN visits in the US end in hospitalization. Inter-hospital variation in hospitalization practices explains 26% of the limited variability in hospitalization decisions. Simple, objective tools are needed to improve risk stratification for ED FN patients

Serum measures of hexabromocyclododecane (HBCDD) and polyborminated diphenyl ethers (PBDEs) in reproductive-aged women in the United Kingdom

We investigated the serum concentrations of two brominated flame retardants (BFRs) – polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCDD) –in 59 women aged between 23 and 42 from the United Kingdom. We also collected demographic data, including age, bodyweight and height in order to test for associations with BFR levels. Temporal and global differences were also assessed using previously published data.HBCDD was detected in 68% of samples with a mean concentration of 2.2 ng/g lipid (range =< 0.3–13 ng/g lipid). The dominant stereoisomer was α-HBCDD with an average contribution of 82% (0–100%) towards ΣHBCDD, was followed by γ-HBCDD (average contribution = 17%). PBDEs were detected in 95% of samples with a mean ∑PBDE (sum of BDEs −28, −47, −99, −100, −153, −154 and −183) concentration of 2.4 ng/g lipid (range = 2.5 since 2010. Whilst the human body burden appear to be decreasing, both PBDEs and HBCDD are still consistently detected in human serum, despite legislative action limiting their production and use. This highlights the need to continuously assess human exposure and the effectiveness of policy aimed at reducing exposure

Variable domain N-linked glycosylation and negative surface charge are key features of monoclonal ACPA: implications for B-cell selection

Autoreactive B cells have a central role in the pathogenesis of rheumatoid arthritis (RA), and recent findings have proposed that anti-citrullinated protein autoantibodies (ACPA) may be directly pathogenic. Herein, we demonstrate the frequency of variable-region glycosylation in single-cell cloned mAbs. A total of 14 ACPA mAbs were evaluated for predicted N-linked glycosylation motifs in silico and compared to 452 highly-mutated mAbs from RA patients and controls. Variable region N-linked motifs (N-X-S/T) were strikingly prevalent within ACPA (100%) compared to somatically hypermutated (SHM) RA bone marrow plasma cells (21%), and synovial plasma cells from seropositive (39%) and seronegative RA (7%). When normalized for SHM, ACPA still had significantly higher frequency of N-linked motifs compared to all studied mAbs including highly-mutated HIV broadly-neutralizing and malaria-associated mAbs. The Fab glycans of ACPA-mAbs were highly sialylated, contributed to altered charge, but did not influence antigen binding. The analysis revealed evidence of unusual B-cell selection pressure and SHM-mediated decreased in surface charge and isoelectric point in ACPA. It is still unknown how these distinct features of anti-citrulline immunity may have an impact on pathogenesis. However, it is evident that they offer selective advantages for ACPA+ B cells, possibly also through non-antigen driven mechanisms

Effect of resistance training on muscle properties and function in women with generalized joint hypermobility: a single-blind pragmatic randomized controlled trial.

BACKGROUND Generalized joint hypermobility is defined as an excessive range of motion in several joints. Having joint hypermobility is not a pathology, but when associated with pain and other symptoms, it might affect health and function. Evidence for physiotherapy management is sparse and resistance training might be a possible intervention. Thus, the effects of 12-week resistance-training on muscle properties and function in women with generalized joint hypermobility were evaluated. METHODS In this single-blind randomized controlled trial women between 20 and 40 years with generalized joint hypermobility (Beighton score at least 6/9) were included. Participants were randomly allocated to 12-week resistance training twice weekly (experimental) or no lifestyle change (control). Resistance training focused on leg and trunk muscles. Primary outcome was muscle strength; additional outcomes included muscle properties, like muscle mass and density, functional activities, pain and disability. Training adherence and adverse events were recorded. RESULTS Of 51 participating women 27 were randomised to training and 24 into the control group. In each group 11 women had joint hypermobility syndrome, fulfilling the Brighton criteria, while 24 (89%) in the training group and 21 (88%) in the control group mentioned any pain. The mean strength of knee extensors varied in the training group from 0.63 (sd 0.16) N/bm before training to 0.64 (sd 0.17) N/bm after training and in the control group from 0.53 (sd 0.14) N/bm to 0.54 (sd 0.15) N/bm. For this and all other outcome measures, no significant differences between the groups due to the intervention were found, with many variables showing high standard deviations. Adherence to the training was good with 63% of participants performing more than 80% of sessions. One adverse event occurred during training, which was not clearly associated to the training. Four participants had to stop the training early. CONCLUSIONS No improvement in strength or muscle mass by self-guided resistance training was found. Low resistance levels, as well as the choice of outcome measures were possible reasons. A more individualized and better guided training might be important. However, program adherence was good with few side effects or problems triggered by the resistance training. TRIAL REGISTRATION This trial was prospectively registered in the ISRCTN registry ( www.isrctn.com , BMC, Springer Nature) on July 16, 2013 as ISRCTN90224545 . The first participant was enrolled at October 25, 2013

Preserving Derivative Information while Transforming Neuronal Curves

The international neuroscience community is building the first comprehensive atlases of brain cell types to understand how the brain functions from a higher resolution, and more integrated perspective than ever before. In order to build these atlases, subsets of neurons (e.g. serotonergic neurons, prefrontal cortical neurons etc.) are traced in individual brain samples by placing points along dendrites and axons. Then, the traces are mapped to common coordinate systems by transforming the positions of their points, which neglects how the transformation bends the line segments in between. In this work, we apply the theory of jets to describe how to preserve derivatives of neuron traces up to any order. We provide a framework to compute possible error introduced by standard mapping methods, which involves the Jacobian of the mapping transformation. We show how our first order method improves mapping accuracy in both simulated and real neuron traces under random diffeomorphisms. Our method is freely available in our open-source Python package brainlit

Chemical differentiation in regions of high-mass star formation I. CS, dust and N2H^+ in southern sources

Aims. Our goals are to compare the CS, N2H+ and dust distributions in a representative sample of high-mass star forming dense cores and to determine the physical and chemical properties of these cores. Methods. We compare the results of CS(5-4) and 1.2 mm continuum mapping of twelve dense cores from the southern hemisphere presented in this work, in combination with our previous N2H+(1-0) and CS(2-1) data. We use numerical modeling of molecular excitation to estimate physical parameters of the cores. Results. Most of the maps have several emission peaks (clumps). We derive basic physical parameters of the clumps and estimate CS and N2H+ abundances. Masses calculated from LVG densities are higher than CS virial masses and masses derived from continuum data, implying small-scale clumpiness of the cores. For most of the objects, the CS and continuum peaks are close to the IRAS point source positions. The CS(5-4) intensities correlate with continuum fluxes per beam in all cases, but only in five cases with the N2H+(1-0) intensities. The study of spatial variations of molecular integrated intensity ratios to continuum fluxes reveals that I(N2H+)/F{1.2} ratios drop towards the CS peaks for most of the sources, which can be due to a N2H+ abundance decrease. For CS(5-4), the I(CS)/F{1.2} ratios show no clear trends with distance from the CS peaks, while for CS(2-1) such ratios drop towards these peaks. Possible explanations of these results are considered. The analysis of normalized velocity differences between CS and N2H+ lines has not revealed indications of systematic motions towards CS peaks.Comment: 13 pages, 5 figures, accepted by Astronomy and Astrophysic

Enhancing therapeutic vaccination by blocking PD-1–mediated inhibitory signals during chronic infection

Therapeutic vaccination is a potentially promising strategy to enhance T cell immunity and viral control in chronically infected individuals. However, therapeutic vaccination approaches have fallen short of expectations, and effective boosting of antiviral T cell responses has not always been observed. One of the principal reasons for the limited success of therapeutic vaccination is that virus-specific T cells become functionally exhausted during chronic infections. We now provide a novel strategy for enhancing the efficacy of therapeutic vaccines. In this study, we show that blocking programmed death (PD)-1/PD-L1 inhibitory signals on exhausted CD8+ T cells, in combination with therapeutic vaccination, synergistically enhances functional CD8+ T cell responses and improves viral control in mice chronically infected with lymphocytic choriomeningitis virus. This combinatorial therapeutic vaccination was effective even in the absence of CD4+ T cell help. Thus, our study defines a potent new approach to augment the efficacy of therapeutic vaccination by blocking negative signals. Such an approach may have broad applications in developing treatment strategies for chronic infections in general, and perhaps also for tumors