Topics in Antivax and Provax Discourse: Yearlong Synoptic Study of COVID-19 Vaccine Tweets.

BACKGROUND: Developing an understanding of the public discourse on COVID-19 vaccination on social media is important not only for addressing the ongoing COVID-19 pandemic but also for future pathogen outbreaks. There are various research efforts in this domain, although, a need still exists for a comprehensive topic-wise analysis of tweets in favor of and against COVID-19 vaccines. OBJECTIVE: This study characterizes the discussion points in favor of and against COVID-19 vaccines posted on Twitter during the first year of the pandemic. The aim of this study was primarily to contrast the views expressed by both camps, their respective activity patterns, and their correlation with vaccine-related events. A further aim was to gauge the genuineness of the concerns expressed in antivax tweets. METHODS: We examined a Twitter data set containing 75 million English tweets discussing the COVID-19 vaccination from March 2020 to March 2021. We trained a stance detection algorithm using natural language processing techniques to classify tweets as antivax or provax and examined the main topics of discourse using topic modeling techniques. RESULTS: Provax tweets (37 million) far outnumbered antivax tweets (10 million) and focused mostly on vaccine development, whereas antivax tweets covered a wide range of topics, including opposition to vaccine mandate and concerns about safety. Although some antivax tweets included genuine concerns, there was a large amount of falsehood. Both stances discussed many of the same topics from opposite viewpoints. Memes and jokes were among the most retweeted messages. Most tweets from both stances (9,007,481/10,566,679, 85.24% antivax and 24,463,708/37,044,507, 66.03% provax tweets) came from dual-stance users who posted both provax and antivax tweets during the observation period. CONCLUSIONS: This study is a comprehensive account of COVID-19 vaccine discourse in the English language on Twitter from March 2020 to March 2021. The broad range of discussion points covered almost the entire conversation, and their temporal dynamics revealed a significant correlation with COVID-19 vaccine-related events. We did not find any evidence of polarization and prevalence of antivax discourse over Twitter. However, targeted countering of falsehoods is important because only a small fraction of antivax discourse touched on a genuine issue. Future research should examine the role of memes and humor in driving web-based social media activity.

Monitoring anatomical changes of individual patients using statistical process control during head-and-neck radiotherapy.

BACKGROUND AND PURPOSE: Reduced toxicity while maintaining loco-regional control rates have been reported after reducing planning target volume (PTV) margins for head-and-neck radiotherapy (HNRT). In this context, quantifying anatomical changes to monitor patient treatment is preferred. This retrospective feasibility study investigated the application of deformable image registration (DIR) and Exponentially Weighted Moving Average (EWMA) Statistical Process Control (SPC) charts for this purpose. MATERIALS AND METHODS: DIR between the computed tomography for treatment planning (pCT) images of twelve patients and their daily on-treatment cone beam computed tomography (CBCT) images quantified anatomical changes during treatment. EWMA charts investigated corresponding trends. Uncertainty analysis provided 90% confidence limits which were used to confirm whether a trend previously breached a threshold. RESULTS: Trends in patient positioning reproducibility occurred before the end of treatment week four in 54% of cases. Using SPC process limits, only 24% of these were confirmed at a 90% confidence level before the end of treatment. Using an a priori clinical limit of 2 mm, absolute changes in patient pose were detected in 39% of cases, of which 82% were confirmed. Soft tissue trends outside SPC process limits occurring before the end of treatment week four were confirmed in 90% of cases. CONCLUSION: Structure specific action thresholds enabled detection of systematic anatomical changes during the first four weeks of treatment. Investigation of the dosimetric impact of the observed deviations is needed to show the efficacy of SPC to timely indicate required treatment adaptation and provide a safety net for PTV margin reduction.

Mental health and debt collection: a story of progress? Exploring changes in debt collectors' attitudes and practices when working with customers with mental health problems, 2010-2016.

BACKGROUND: In recent years, the UK debt collection industry has taken steps to improve its policies and practices in relation to customers with mental health problems. Little data, however, have been collected to evidence change. AIMS: This paper examines whether the reported attitudes and practices of debt collection staff when working with customers with mental health problems have changed between 2010 and 2016. METHOD: This paper draws on descriptive and regression analyses of two cross-sectional surveys of debt collection staff: one conducted in 2010 and one conducted in 2016. RESULTS: All variables analysed show statistically significant changes between 2010 and 2016 indicative of improved reported attitudes and practices. CONCLUSIONS: While results suggest an improvement in attitudes and practice may have occurred between 2010 and 2016, research is required to understand this potential shift, its likely causes, and concrete impact on customers.

Validation of Varian's SmartAdapt® deformable image registration algorithm for clinical application.

BACKGROUND: Re-contouring of structures on consecutive planning computed tomography (CT) images for patients that exhibit anatomical changes is elaborate and may negatively impact the turn-around time if this is required for many patients. This study was therefore initiated to validate the accuracy and usefulness of automatic contour propagation for head and neck cancer patients using SmartAdapt® which is the deformable image registration (DIR) application in Varian's Eclipse™ treatment planning system. METHODS: CT images of eight head and neck cancer patients with multiple planning CTs were registered using SmartAdapt®. The contoured structures of target volumes and OARs of the primary planning CT were deformed accordingly and subsequently compared with a reference structure set being either: 1) a structure set independently contoured by the treating Radiation Oncologist (RO), or 2) the DIR-generated structure set after being reviewed and modified by the RO. RESULTS: Application of DIR offered a considerable time saving for ROs in delineation of structures on CTs that were acquired mid-treatment. Quantitative analysis showed that 84% of the volume of the DIR-generated structures overlapped with the independently re-contoured structures, while 94% of the volume overlapped with the DIR-generated structures after review by the RO. This apparent intra-observer variation was further investigated resulting in the identification of several causes. Qualitative analysis showed that 92% of the DIR-generated structures either need no or only minor modification during RO reviews. CONCLUSIONS: SmartAdapt is a powerful tool with sufficient accuracy that saves considerable time in re-contouring structures on re-CTs. However, careful review of the DIR-generated structures is mandatory, in particular in areas where tumour regression plays a role.

Primary human CD4+ T cells have diverse levels of membrane lipid order that correlate with their function.

Membrane lipid microdomains (lipid rafts) play an important role in T cell function by forming areas of high lipid order that facilitate activation. However, their role in regulating T cell differentiation and function remains controversial. In this study, by applying a new approach involving microscopy and flow cytometry, we characterize membrane lipid order in ex vivo primary human CD4(+) T cells. We reveal that differential membrane lipid order dictates the response to TCR stimulation. T cells with high membrane order formed stable immune synapses and proliferated robustly, intermediate order cells had reduced proliferative ability accompanied by unstable immune synapse formation, whereas low order T cells were profoundly unresponsive to TCR activation. We also observed that T cells from patients with autoimmune rheumatic disease had expanded intermediate order populations compared with healthy volunteers. This may be important in dictating the nature of the immune response since most IFN-γ(+)CD4(+) T cells were confined within intermediate membrane order populations, whereas IL-4(+)CD4(+) T cells were contained within the high order populations. Importantly, we were able to alter T cell function by pharmacologically manipulating membrane order. Thus, the results presented from this study identify that ex vivo CD4(+) T cells sustain a gradient of plasma membrane lipid order that influences their function in terms of proliferation and cytokine production. This could represent a new mechanism to control T cell functional plasticity, raising the possibility that therapeutic targeting of membrane lipid order could direct altered immune cell activation in pathology.

Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment.

In several murine models of autoimmune arthritis, Th17 cells are the dominant initiators of inflammation. In human arthritis the majority of IL-17-secreting cells within the joint express a cytokine phenotype intermediate between Th17 and Th1. Here we show that Th17/1 cells from the joints of children with inflammatory arthritis express high levels of both Th17 and Th1 lineage-specific transcription factors, RORC2 and T-bet. Modeling the generation of Th17/1 in vitro, we show that Th17 cells "convert" to Th17/1 under conditions that mimic the disease site, namely low TGFbeta and high IL-12 levels, whereas Th1 cells cannot convert to Th17. Th17/1 cells from the inflamed joint share T-cell receptor (TCR) clonality with Th17 cells, suggesting a shared clonal origin between Th17 and Th17/1 cells in arthritis. Using CD161, a lectin-like receptor that is a marker of human Th17, we show synovial Th17 and Th17/1 cells, and unexpectedly, a large proportion of Th1 cells express CD161. We provide evidence to support a Th17 origin for Th1 cells expressing CD161. In vitro, Th17 cells that convert to a Th1 phenotype maintain CD161 expression. In the joint CD161+ Th1 cells share features with Th17 cells, with shared TCR clonality, expression of RORC2 and CCR6 and response to IL-23, although they are IL-17 negative. We propose that the Th17 phenotype may be unstable and that Th17 cells may convert to Th17/1 and Th1 cells in human arthritis. Therefore therapies targeting the induction of Th17 cells could also attenuate Th17/1 and Th1 effector populations within the inflamed joint.

High expression of the ectonucleotidase CD39 on T cells from the inflamed site identifies two distinct populations, one regulatory and one memory T cell population.

The ectonucleotidase CD39 has recently been described as being highly expressed on regulatory Foxp3(+) CD4 T cells. Through hydrolysis of proinflammatory extracellular ATP, CD39 activity represents a newly described mechanism of regulatory T cell action. We report a novel population of human CD4 T cells that express CD39 yet are Foxp3 negative. These cells produce the proinflammatory cytokines IFN-gamma and IL-17 and fail to suppress proliferation; however, they still have high ATP hydrolysis activity. In the inflammatory site in human juvenile idiopathic arthritis, the CD39(+)Foxp3(-) population is greatly increased compared with peripheral blood of patients or healthy controls. We also show that cells expressing the AMPase CD73 are less frequent in the joint than in blood. To our knowledge, this is the first study to describe and characterize CD39 function on CD4 T cells from the target site in a human autoinflammatory condition. Our data suggest that in human CD4(+) T cells from the inflamed site, CD39 can be highly expressed on two populations, one regulatory and the other of a memory phenotype.

Selective targeting of B cells with agonistic anti-CD40 is an efficacious strategy for the generation of induced regulatory T2-like B cells and for the suppression of lupus in MRL/lpr mice.

We have previously reported that IL-10(+) regulatory B cells, known to play an important role in controlling autoimmunity and inflammatory disorders, are contained within the transitional 2 immature (T2) B cell pool (T2 Bregs). Therapeutic strategies facilitating their enrichment or enhancing their suppressive activity are highly attractive. In this study, we report that agonistic anti-CD40 specifically targets T2 B cells and enriches Bregs upon short-term in vitro culture. Although transfer of unmanipulated T2 B cells, isolated from mice with established lupus, failed to confer protection to diseased mice, transfer of in vitro anti-CD40-generated T2 B cells (T2-like-Bregs) significantly improved renal disease and survival by an IL-10-dependent mechanism. T2-like-Bregs readily accumulated in the spleen after transfer, suppressed Th1 responses, induced the differentiation of IL-10(+)CD4(+)T cells, and conveyed a regulatory effect to CD4(+)T cells. In addition, in vivo administration of agonistic anti-CD40, currently on trial for the treatment of cancer, halted and reversed established lupus. Taken together, our results suggest a novel cellular approach for the amelioration of experimental lupus.

Novel suppressive function of transitional 2 B cells in experimental arthritis.

The immune system contains natural regulatory cells important in the maintenance of tolerance. Although this suppressive function is usually attributed to CD4 regulatory T cells, recent reports have revealed an immunoregulatory role for IL-10-producing B cells in the context of several autoimmune diseases including collagen-induced arthritis. In the present study, we attribute this suppressive function to a B cell subset expressing high levels of CD21, CD23, and IgM, previously identified as transitional 2-marginal zone precursor (T2-MZP) B cells. T2-MZP B cells are present in the spleens of naive mice and increase during the remission phase of arthritis. Following adoptive transfer to immunized DBA/1 mice, T2-MZP B cells significantly prevented new disease and ameliorated established disease. The suppressive effect on arthritis was paralleled by an inhibition of Ag-specific T cell activation and a reduction in cells exhibiting Th1-type functional responses. We also provide evidence that this regulatory subset mediates its suppression through the secretion of suppressive cytokines and not by cell-to-cell contact. The ability to regulate an established immune response by T2-MZP B cells endows this subset of B cells with a striking and previously unrecognized immunoregulatory potential.

Chromatic dispersion and PMD mitigation at 10 Gb/s using Viterbi equalization for DPSK and DQPSK modulation formats.

We explore the potential of chromatic dispersion and polarization-mode dispersion (PMD) mitigation using Viterbi equalization in 10 Gb/s nonreturn-to-zero differential phase-shift keying (NRZ-DPSK) and differential quadrature phase-shift keying (NRZ-DQPSK) systems. We show through Monte Carlo simulations that using Viterbi equalization improves the performance of NRZ-OOK, NRZ-DPSK and NRZ-DQPSK receivers. For NRZ-DQPSK receiver with a Viterbi equalizer, the chromatic dispersion tolerance is about 5000 ps/nm and the 1st order PMD tolerance is about 160 ps at 3 dB OSNR penalty.

Expression and alternative processing of IL-18 in human neutrophils.

Interleukin-18 (IL-18), a member of the IL-1 cytokine superfamily, is an important regulator of both innate and acquired immune responses. We demonstrate here constitutive expression of IL-18 by human neutrophils. Unexpectedly, we observed that neutrophils from peripheral blood or rheumatoid synovial compartments contained not only pro and mature IL-18, but also several novel smaller-molecular-weight IL-18-derived species. Using specific protease inhibitors, and serine protease gene-targeted mice, we demonstrate that these IL-18-derived products arose through caspase-independent cleavage events mediated by the serine proteases, elastase and cathepsin G. Moreover, we report that the net effect of elastase treatment of mature recombinant IL-18 was to reduce its IFN-gamma-inducing activity. Thus, human neutrophils contain IL-18 and IL-18-derived molecular species that can arise through novel enzymatic processing pathways. Through cytosolic, membrane or secretory expression of such processing enzymes, together with generation of IL-18 itself, neutrophils likely play a critical role in regulating IL-18 activities during early innate immune responses.

Prophylaxis of acute chemotherapy-induced nausea and vomiting in children with cancer: what is the evidence?

BACKGROUND: Nausea and vomiting are preventable side effects of cancer chemotherapy for children. Antiemetics are essential, especially as treatment becomes more intensive. Many drugs are available, but adequate evidence-based recommendations are lacking. We aimed (1) to consider an evidence-based approach for pharmacological prophylaxis of chemotherapy-induced nausea and vomiting (CINV) in children, and (2) to compare this approach with antiemetic prescribing in two paediatric oncology centres. PROCEDURE: Relevant publications (Medline, Embase, CancerLit:1966-2002) were critically evaluated using pre-defined criteria. Evidence-based statements summarising their findings were formulated, and evidence basis proposed. Current prescribing practice was then compared with this evidence basis in Welsh children under 16 receiving chemotherapy at Llandough Hospital, Cardiff or Alder Hey Children's Hospital, Liverpool between 1 January 2001 and 31 December 2001. RESULTS: Of 213 studies retrieved, 82 provided evidence. Our evidence basis recommends combination 5HT3-antagonist/corticosteroid for highly emetogenic chemotherapy, 5HT3-antagonist alone for moderate emetogenicity, and no antiemetic for other chemotherapy. Forty-four children in Cardiff (0.6-16.9 yrs) and 14 in Liverpool (0.8-16.2 yrs) were included in the audit. Differences in prescribing practice between the centres were not significant. In 109/159 (69%) of chemotherapy courses (35, 87 and 100% of high, moderate and low emetogenicity, respectively), antiemetics were selected in accordance with evidence basis. Seventy percent of prescribed doses were as evidence basis recommended. CONCLUSIONS: We present an evidence basis for prescribing prophylactic antiemetics to children undergoing chemotherapy. Prescribing practices in these two centres treating Welsh children were similar. Both differed from the evidence basis we propose. Deviations were greatest for regimens of high emetogenicity, where effective emetic control is most crucial.

Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy.

Regulatory T cells have been clearly implicated in the control of disease in murine models of autoimmunity. The paucity of data regarding the role of these lymphocytes in human autoimmune disease has prompted us to examine their function in patients with rheumatoid arthritis (RA). Regulatory (CD4(+)CD25(+)) T cells isolated from patients with active RA displayed an anergic phenotype upon stimulation with anti-CD3 and anti-CD28 antibodies, and suppressed the proliferation of effector T cells in vitro. However, they were unable to suppress proinflammatory cytokine secretion from activated T cells and monocytes, or to convey a suppressive phenotype to effector CD4(+)CD25(-) T cells. Treatment with antitumor necrosis factor alpha (TNFalpha; Infliximab) restored the capacity of regulatory T cells to inhibit cytokine production and to convey a suppressive phenotype to "conventional" T cells. Furthermore, anti-TNFalpha treatment led to a significant rise in the number of peripheral blood regulatory T cells in RA patients responding to this treatment, which correlated with a reduction in C reactive protein. These data are the first to demonstrate that regulatory T cells are functionally compromised in RA, and indicate that modulation of regulatory T cells by anti-TNFalpha therapy may be a further mechanism by which this disease is ameliorated.

The prognostic value of a single hepatitis C virus RNA load measurement taken early after human immunodeficiency virus seroconversion.

Hepatitis C virus (HCV) RNA loads are measured sporadically in HCV-positive individuals. However, the prognostic value of these isolated measurements for predicting progression to acquired immune deficiency syndrome (AIDS) and all-cause mortality in coinfected individuals remains unclear. In this study, the prognostic value of a single HCV RNA load measurement taken early after human immunodeficiency virus (HIV) seroconversion was investigated in a cohort of 96 male patients with inherited bleeding disorders. Dates of HIV seroconversion had been estimated for all patients, and at least 4 HCV RNA load measurements per patient were done retrospectively after HIV seroconversion. HCV RNA load stabilized at 4 years after HIV seroconversion, and this point was used for analysis. There was a significant correlation between increased age and early HCV RNA load (r=0.25; P=.01). Adjusting for HIV RNA levels, CD4 cell counts, and the age effect, HCV RNA load >5.90 log(10) copies/mL was predictive of progression to AIDS and all-cause mortality over a period of at least 15 years.