Immunogenicity of COVID-19 vaccines in patients with follicular lymphoma receiving frontline chemoimmunotherapy.

Immune responses to primary COVID-19 vaccination were investigated in 58 patients with follicular lymphoma (FL) as part of the PETReA trial of frontline therapy (EudraCT 2016-004010-10). COVID-19 vaccines (BNT162b2 or ChAdOx1) were administered before, during or after cytoreductive treatment comprising rituximab (depletes B cells) and either bendamustine (depletes CD4+ T cells) or cyclophosphamide-based chemotherapy. Blood samples obtained after vaccine doses 1 and 2 (V1, V2) were analysed for antibodies and T cells reactive to the SARS-CoV-2 spike protein using the Abbott Architect and interferon-gamma ELISpot assays respectively. Compared to 149 healthy controls, patients with FL exhibited lower antibody but preserved T-cell responses. Within the FL cohort, multivariable analysis identified low pre-treatment serum IgA levels and V2 administration during induction or maintenance treatment as independent determinants of lower antibody and higher T-cell responses, and bendamustine and high/intermediate FLIPI-2 score as additional determinants of a lower antibody response. Several clinical scenarios were identified where dichotomous immune responses were estimated with >95% confidence based on combinations of predictive variables. In conclusion, the immunogenicity of COVID-19 vaccines in FL patients is influenced by multiple disease- and treatment-related factors, among which B-cell depletion showed differential effects on antibody and T-cell responses.

Changes in cytokine and cytokine receptor levels during postnatal development of the human dorsolateral prefrontal cortex.

In addition to their traditional roles in immune cell communication, cytokines regulate brain development. Cytokines are known to influence neural cell generation, differentiation, maturation, and survival. However, most work on the role of cytokines in brain development investigates rodents or focuses on prenatal events. Here, we investigate how mRNA and protein levels of key cytokines and cytokine receptors change during postnatal development of the human prefrontal cortex. We find that most cytokine transcripts investigated (IL1B, IL18, IL6, TNF, IL13) are lowest at birth and increase between 1.5 and 5 years old. After 5 years old, transcriptional patterns proceeded in one of two directions: decreased expression in teens and young adults (IL1B, p = 0.002; and IL18, p = 0.004) or increased mean expression with maturation, particularly in teenagers (IL6, p = 0.004; TNF, p = 0.002; IL13, p < 0.001). In contrast, cytokine proteins tended to remain elevated after peaking significantly around 3 years of age (IL1B, p = 0.012; IL18, p = 0.026; IL6, p = 0.039; TNF, p < 0.001), with TNF protein being highest in teenagers. An mRNA-only analysis of cytokine receptor transcripts found that early developmental increases in cytokines were paralleled by increases in their ligand-binding receptor subunits, such as IL1R1 (p = 0.033) and IL6R (p < 0.001) transcripts. In contrast, cytokine receptor-associated signaling subunits, IL1RAP and IL6ST, did not change significantly between age groups. Of the two TNF receptors, the 'pro-death' TNFRSF1A and 'pro-survival' TNFRSF1B, only TNFRSF1B was significantly changed (p = 0.028), increasing first in toddlers and again in young adults. Finally, the cytokine inhibitor, IL13, was elevated first in toddlers (p = 0.006) and again in young adults (p = 0.053). While the mean expression of interleukin-1 receptor antagonist (IL1RN) was highest in toddlers, this increase was not statistically significant. The fluctuations in cytokine expression reported here support a role for increases in specific cytokines at two different stages of human cortical development. The first is during the toddler/preschool period (IL1B, IL18, and IL13), and the other occurs at adolescence/young adult maturation (IL6, TNF and IL13).

A national service for delivering CD19 CAR-Tin large B-cell lymphoma - The UK real-world experience.

CD19 CAR-T have emerged as a new standard treatment for relapsed/refractory (r/r) large B-cell lymphoma (LBCL). CAR-T real-world (RW) outcomes published to date suggest significant variability across countries. We provide results of a large national cohort of patients intended to be treated with CAR-T in the UK. Consecutive patients with r/r LBCL approved for CAR-T by the National CAR-T Clinical Panel between December 2018 and November 2020 across all UK CAR-T centres were included. 404/432 patients were approved [292 axicabtagene ciloleucel (axi-cel), 112 tisagenlecleucel (tisa-cel)], 300 (74%) received the cells. 110/300 (38.3%) patients achieved complete remission (CR) at 6 months (m). The overall response rate was 77% (52% CR) for axi-cel, 57% (44% CR) for tisa-cel. The 12-month progression-free survival was 41.8% (axi-cel) and 27.4% (tisa-cel). Median overall survival for the intention-to-treat population was 10.5 m, 16.2 m for infused patients. The incidence of grade ≥3 cytokine release syndrome and neurotoxicity were 7.6%/19.6% for axi-cel and 7.9%/3.9% for tisa-cel. This prospective RW population of CAR-T eligible patients offers important insights into the clinical benefit of CD19 CAR-T in LBCL in daily practice. Our results confirm long-term efficacy in patients receiving treatment similar to the pivotal trials, but highlight the significance of early CAR-T failure.

Increased levels of midbrain immune-related transcripts in schizophrenia and in murine offspring after maternal immune activation.

The pathophysiology of dopamine dysregulation in schizophrenia involves alterations at the ventral midbrain level. Given that inflammatory mediators such as cytokines influence the functional properties of midbrain dopamine neurons, midbrain inflammation may play a role in schizophrenia by contributing to presynaptic dopamine abnormalities. Thus, we quantified inflammatory markers in dopaminergic areas of the midbrain of people with schizophrenia and matched controls. We also measured these markers in midbrain of mice exposed to maternal immune activation (MIA) during pregnancy, an established risk factor for schizophrenia and other psychiatric disorders. We found diagnostic increases in SERPINA3, TNFα, IL1ß, IL6, and IL6ST transcripts in schizophrenia compared with controls (p < 0.02-0.001). The diagnostic differences in these immune markers were accounted for by a subgroup of schizophrenia cases (~ 45%, 13/28) showing high immune status. Consistent with the human cohort, we identified increased expression of immune markers in the midbrain of adult MIA offspring (SERPINA3, TNFα, and IL1ß mRNAs, all p ≤ 0.01), which was driven by a subset of MIA offspring (~ 40%, 13/32) with high immune status. There were no diagnostic (human cohort) or group-wise (mouse cohort) differences in cellular markers indexing the density and/or morphology of microglia or astrocytes, but an increase in the transcription of microglial and astrocytic markers in schizophrenia cases and MIA offspring with high inflammation. These data demonstrate that immune-related changes in schizophrenia extend to dopaminergic areas of the midbrain and exist in the absence of changes in microglial cell number, but with putative evidence of microglial and astrocytic activation in the high immune subgroup. MIA may be one of the contributing factors underlying persistent neuroimmune changes in the midbrain of people with schizophrenia.

Trajectory of change in brain complement factors from neonatal to young adult humans.

Immune system components also regulate synapse formation and refinement in neurodevelopment. The complement pathway, associated with cell lysis and phagocytosis, is implicated in synaptic elimination. Aberrant adolescent synaptic pruning may underpin schizophrenia onset; thus, changes in cortical complement activity during human development are of major interest. Complement is genetically linked to schizophrenia via increased C4 copy number variants, but the developmental trajectory of complement expression in the human brain is undetermined. As complement increases during periods of active synaptic engulfment in rodents, we hypothesized that complement expression would increase during postnatal development in humans, particularly during adolescence. Using human postmortem prefrontal cortex, we observed that complement activator (C1QB and C3) transcripts peaked in early neurodevelopment, and were highest in toddlers, declining in teenagers (all ANCOVAs between F = 2.41 -3.325, p = .01-0.05). We found that C4 protein was higher at 1-5 years (H = 16.378, p = .012), whereas C3 protein levels were unchanged with age. The microglial complement receptor subunit CD11b increased in mRNA early in life and peaked in the toddler brain (ANCOVA: pH, F = 4.186, p = .003). Complement inhibitors (CD46 and CD55) increased at school age, but failed to decrease like complement activators (both ANCOVAs, F > 4.4, p < .01). These data suggest the activation of complement in the human prefrontal cortex occurs between 1 and 5 years. We did not find evidence of induction of complement factors during adolescence and instead found increased or sustained levels of complement inhibitor mRNA at maturation. Dysregulation of these typical patterns of complement may predispose the brain to neurodevelopmental disorders such as autism or schizophrenia.

Radiation safety practices among Canadian equine veterinary workers during diagnostic procedures with portable X-ray equipment.

The objective of this study was to report observed radiation safety practices among equine workers using portable X-ray units at 3 veterinary practices in Canada. Practice 1 was comprised of equine field service workers from an academic institution, whereas Practices 2 and 3 were comprised of workers from private equine referral practices. Out of 2969 exposure-worker observations, protective aprons were worn for > 99% (2968/2969), thyroid shields for 87% (2584/2969), and eyeglasses for 10% (310/2969). The cassette was held by hand for 97% (1078/1114) of observations, and the X-ray unit was held by hand for 100% (1293/1293) of observations. Gloves were used for 54% (606/1114) and < 1% (5/1293) of observations involving cassette holders and X-ray tube operators, respectively. Use of gloves was more frequent among technologists than DVMs (P = 0.004), and among workers in Practices 1 and 3 than in Practice 2 (P < 0.001). In conclusion, given that workers commonly hold cassettes and X-ray tubes by hand, improvement in shielding use is needed. Consideration should be given to specific behavior recommendations in radiation regulations.

Pratiques de radioprotection chez les travailleurs vétérinaires équins canadiens pendant les procédures de diagnostic avec un équipement de radiographie portable. L'objectif de la présente étude était de rapporter les pratiques de radioprotection observées chez les travailleurs équins utilisant des appareils de radiographie portatifs dans trois pratiques vétérinaires au Canada. La pratique 1 était composée de travailleurs équins sur le terrain d'une institution universitaire, tandis que les pratiques 2 et 3 étaient composées de travailleurs sur le terrain issus de pratiques de référence équines privées. Sur 2969 observations de travailleurs exposés, des tabliers de protection ont été portés pour > 99 % (2968/2969), des écrans thyroïdiens pour 87 % (2584/2969) et des lunettes pour 10 % (310/2969). La cassette a été tenue à la main pour 97 % (1078/1114) des observations et l'unité de radiographie a été tenue à la main pour 100 % (1293/1293) des observations. Des gants ont été utilisés pour 54 % (606/1114) et < 1 % (5/1293) des observations impliquant des porteurs de cassette et des opérateurs de tubes à rayons X, respectivement. L'utilisation de gants était plus fréquente chez les technologues que chez les vétérinaires (P = 0,004) et chez les travailleurs des Pratiques 1 et 3 que ceux de la Pratique 2 (P < 0,001). En conclusion, étant donné que les travailleurs tiennent généralement des cassettes et des tubes à rayons X à la main, une amélioration de l'utilisation du blindage est nécessaire. Il faudrait tenir compte des recommandations de comportement spécifiques dans les réglementations relatives aux rayonnements.(Traduit par Dr Serge Messier).

Skeletal muscle wasting in chronic kidney disease: the emerging role of microRNAs.

Skeletal muscle wasting is a common complication of chronic kidney disease (CKD), characterized by the loss of muscle mass, strength and function, which significantly increases the risk of morbidity and mortality in this population. Numerous complications associated with declining renal function and lifestyle activate catabolic pathways and impair muscle regeneration, resulting in substantial protein wasting. Evidence suggests that increasing skeletal muscle mass improves outcomes in CKD, making this a clinically important research focus. Despite extensive research, the pathogenesis of skeletal muscle wasting is not completely understood. It is widely recognized that microRNAs (miRNAs), a family of short non-coding RNAs, are pivotal in the regulation of skeletal muscle homoeostasis, with significant roles in regulating muscle growth, regeneration and metabolism. The abnormal expression of miRNAs in skeletal muscle during disease has been well described in cellular and animal models of muscle atrophy, and in recent years, the involvement of miRNAs in the regulation of muscle atrophy in CKD has been demonstrated. As this exciting field evolves, there is emerging evidence for the involvement of miRNAs in a beneficial crosstalk system between skeletal muscle and other organs that may potentially limit the progression of CKD. In this article, we describe the pathophysiological mechanisms of muscle wasting and explore the contribution of miRNAs to the development of muscle wasting in CKD. We also discuss advances in our understanding of miRNAs in muscle-organ crosstalk and summarize miRNA-based therapeutics currently in clinical trials.

Sun Protection for Preventing Basal Cell and Squamous Cell Skin Cancers.

Review question: What is the most effective form of sun protection (including sunscreens) to prevent basal cell carcinoma and cutaneous squamous cell carcinoma of the skin?

Development of the Rapid Assessment, Prioritisation and Referral Tool (RAPaRT) for multidisciplinary teams in emergency care settings.

OBJECTIVE: This investigation utilised the expertise of allied members of multidisciplinary teams working in emergency care settings to develop and validate a Rapid Assessment Prioritisation and Referral Tool (RAPaRT). This instrument is intended for use among patients (with non-life threatening acuity) presenting to emergency care settings to indicate when referral to an allied member of the multidisciplinary team is warranted. METHOD: This three stage instrument development and validation study included: a Delphi panel process to determine key criteria to guide instrument development and identify potential items to be carried forward for testing (stage 1); a prospective cohort of consecutive admissions (n=153) to investigate item sensitivity and specificity and retain only the most suitable items (stage 2); then final consultation with the Delphi panel to ensure the final instrument was clinically amenable (stage 3). RESULTS: 23 potential items were identified following stage 1. At the completion of item sensitivity and specificity analysis and in consultation with the Delphi panel, seven items were retained in the instrument. Area under the receiver operating characteristic curve was 0.803 for these seven items in predicting when a referral was warranted. Final consultation with the Delphi panel members also resulted in the addition of an open ended (eighth) item to allow description of any infrequent, but important, reason for referral. CONCLUSIONS: The RAPaRT has demonstrated substantial promise as an efficient clinically amenable instrument to assist multidisciplinary teams in emergency care settings. Further research to investigate the wider implementation of the RAPaRT is warranted.

Examining the levels of psychological support available to patients with haematological cancer in England: a mixed methods study.

OBJECTIVES: The psychological impact of a haematological malignancy is well documented. However, few studies have assessed the provision of psychological support to people with these diagnoses. This study explores the extent and nature of psychological support for people diagnosed with haematological cancer to inform future service provision. DESIGN: This study consisted of an online survey with healthcare professionals (phase 1) and qualitative interviews with patients (phase 2) and key health professionals (phase 3). A descriptive analysis of survey data and thematic analysis of interviews were conducted. PARTICIPANTS: Two hundred health professionals practising in England completed the survey. Twenty-five interviews were conducted with people diagnosed with haematological cancer in the past 3 years, and 10 with key health professionals, including haematologists, cancer nurse specialists and psychologists were conducted. PRIMARY OUTCOME MEASURES: Level of psychological assessment undertaken with people with haematological cancer, and level and nature of psychological support provided. RESULTS: Less than half (47.3%) of survey respondents strongly agreed/agreed that their patients were well supported in terms of their psychological well-being and approximately half (49.4%) reported providing routine assessment of psychological needs of patients, most commonly at the time of diagnosis or relapse. Patients described their need for psychological support, their experiences of support from health professionals and their experiences of support from psychological therapy services. There was considerable variation in the support patients described receiving. Barriers to providing psychological support reported by health professionals included time, skills, resources and patient barriers. Most doctors (85%) and 40% of nurse respondents reported receiving no training for assessing and managing psychological needs. CONCLUSIONS: Psychological well-being should be routinely assessed, and person-centred support should be offered regularly throughout the haematological cancer journey. Greater provision of healthcare professional training in this area and better integration of psychological support services into the patient care pathway are required.

Urban centre green metrics in Great Britain: A geospatial and socioecological study.

Green infrastructure plays a vital role in urban ecosystems. This includes sustaining biodiversity and human health. Despite a large number of studies investigating greenspace disparities in suburban areas, no known studies have compared the green attributes (e.g., trees, greenness, and greenspaces) of urban centres. Consequently, there may be uncharacterised socioecological disparities between the cores of urban areas (e.g., city centres). This is important because people spend considerable time in urban centres due to employment, retail and leisure opportunities. Therefore, the availability of--and disparities in--green infrastructure in urban centres can affect many lives and potentially underscore a socio-ecological justice issue. To facilitate comparisons between urban centres in Great Britain, we analysed open data of urban centre boundaries with a central business district and population of ≥100,000 (n = 68). Given the various elements that contribute to 'greenness', we combine a range of different measurements (trees, greenness, and accessible greenspaces) into a single indicator. We applied the normalised difference vegetation index (NDVI) to estimate the mean greenness of urban centres and the wider urban area (using a 1 km buffer) and determined the proportion of publicly accessible greenspace within each urban centre with Ordnance Survey Open Greenspace data. Finally, we applied a land cover classification algorithm using i-Tree Canopy to estimate tree coverage. This is the first study to define and rank urban centres based on multiple green attributes. The results suggest important differences in the proportion of green attributes between urban centres. For instance, Exeter scored the highest with a mean NDVI of 0.15, a tree coverage of 11.67%, and an OS Greenspace coverage of 0.05%, and Glasgow the lowest with a mean NDVI of 0.02, a tree cover of 1.95% and an OS Greenspace coverage of 0.00%. We also demonstrated that population size negatively associated with greenness and tree coverage, but not greenspaces, and that green attributes negatively associated with deprivation. This is important because it suggests that health-promoting and biodiversity-supporting resources diminish as population and deprivation increase. Disparities in green infrastructure across the country, along with the population and deprivation-associated trends, are important in terms of socioecological and equity justice. This study provides a baseline and stimulus to help local authorities and urban planners create and monitor equitable greening interventions in urban/city centres.

The Relationship of Risk to Rules, Values, Virtues, and Moral Complexity: What We can Learn from the Moral Struggles of Military Leaders.

Leaders are faced with ethical and moral dilemmas daily, like those within the military who must span from large-scale combat operations to security cooperation and deterrence. For businesses, these dilemmas can include social and environmental impact such as those in mining; and for governments, the social and economic impact of their decision-making in their response to COVID-19. The move by Western defence forces to align their foundational principles, policies, and "soldier" dispositions with the changing values of the countries they serve are starkly illustrative of challenges faced by all leaders. While admirable, such changes face the apparent contradiction of enhancing individual moral agency within a hierarchical organization that maintain enforceable codes of conduct. Ethical leadership theory provides aspirational goals, but lacks empirically based guidance on how to implement policies that facilitate values-based behavior. Using a discourse theory analysis of a moral dilemma vignette with Royal Australian Air Force personnel, this research identifies important aspects of agency and subject position that must be addressed if such policies are to succeed. These findings show that the potential contradiction can be addressed by acknowledging the contrasting tendency to bureaucratic process by leaders at upper levels, while lower-level leaders address moral issues by incorporating their subjectivity and making a conscious deontological choice between humanity and comrade loyalty.

X-ray tube operators can be exposed to equal or higher scattered radiation doses to the hand as cassette holders during diagnostic radiographic procedures of the equine vertebral column and limbs.

OBJECTIVE: The objectives of this study were to investigate scattered radiation doses to the hands of equine workers holding the cassette and the x-ray tube by hand, for both limb and vertebral column studies, and to compare the scattered radiation attenuation of lead with radiation protection lead-free gloves. Radiation doses to the hands of the cassette holder in the primary beam were also investigated. SAMPLE: A whole-body horse cadaver. PROCEDURES: A portable x-ray unit was used to simulate 6 radiographic study types in the horse cadaver. Doses were measured with no shielding and, for cassette holders, with the ion chamber enclosed in a lead glove and a lead-free glove. Thirty exposures were performed for each study view and condition (n = 1,920). RESULTS: Mean scattered doses to x-ray unit operators were higher than doses to cassette holders for ungula (hoof), thoracic vertebrae, and lumbar vertebrae studies, whereas doses to cassette holders were higher than doses to x-ray tube operators for studies of the metacarpophalangeal joint (fetlock) and tarsus (hock). Doses did not differ for the stifle joint. Mean percentage decrease in scattered radiation dose was 99.58% with lead gloves and 98.9% with lead-free gloves. CLINICAL RELEVANCE: X-ray tube operators can be exposed to equal or higher scattered radiation doses to the hand as cassette holders. Lead-free hand shielding should only be considered as an alternative to lead gloves if their lighter weight increases frequency of use by workers.

Pipeline for generating stable large genomic deletions in zebrafish, from small domains to whole gene excisions.

Here we describe a short feasibility study and methodological framework for the production of stable, CRISPR/Cas9-based, large genomic deletions in zebrafish, ranging from several base pairs (bp) to hundreds of kilobases (kb). Using a cocktail of four single guide RNAs (sgRNAs) targeting a single genomic region mixed with a marker-sgRNA against the pigmentation gene tyrosinase, we demonstrate that one can easily and accurately excise genomic regions such as promoters, protein domains, specific exons, or whole genes. We exemplify this technique with a complex gene family, neurexins, composed of three duplicated genes with multiple promoters and intricate splicing processes leading to thousands of isoforms. We precisely deleted small regions such as their transmembrane domains (150 bp deletion in average) to their entire genomic locus (300 kb deletion for nrxn1a for instance). We find that both the concentration and ratio of Cas9/sgRNAs are critical for the successful generation of these large deletions and, interestingly, that in our study, their transmission frequency does not seem to decrease with increasing distance between sgRNA target sites. Considering the growing reports and debate about genetically compensated small indel mutants, the use of large-deletion approaches is likely to be widely adopted in studies of gene function. This strategy will also be key to the study of non-coding genomic regions. Note that we are also describing here a custom method to produce the sgRNAs, which proved to be faster and more robust than the ones traditionally used in the community to date.