TGFβ2 Induces the Soluble Isoform of CTLA-4 – Implications for CTLA-4 Based Checkpoint Inhibitor Antibodies in Malignant Melanoma

Malignant melanoma is an aggressive form of cancer, which can be treated with anti-CTLA-4 and anti-PD-1 checkpoint inhibitor antibodies but while anti-CTLA-4 antibodies have clear benefits for some patients with melanoma, productive responses are difficult to predict and often associated with serious immune related adverse events. Antibodies specific to CTLA-4 bind two major isoforms of CTLA-4 in humans, the receptor isoform and a second naturally secretable, soluble isoform - sCTLA-4. The primary aim here was to examine the effect of selectively blocking the function of sCTLA-4 on in vitro immune responses from volunteer healthy or melanoma patient PBMC samples. Addition of recombinant sCTLA-4 to healthy PBMC samples demonstrated sCTLA-4 to have immunosuppressive capacity comparable to recombinant CTLA4-Ig, partially reversible upon antibody blockade. Further, we identified a mechanistic relationship where melanoma patient TGFβ2 serum levels correlated with sCTLA-4 levels and provided the basis for a novel protocol to enhance sCTLA-4 production and secretion by T cells with TGFβ2. Finally, a comparison of selective antibody blockade of sCTLA-4 demonstrated that both healthy and melanoma patient effector cytokine responses can be significantly increased. Overall, the data support the notion that sCTLA-4 is a contributory factor in cancer immune evasion.

Evaluating the citywide Edinburgh 20mph speed limit intervention effects on traffic speed and volume: A pre-post observational evaluation

Objectives Traffic speed is important to public health as it is a major contributory factor to collision risk and casualty severity. 20mph (32km/h) speed limit interventions are an increasingly common approach to address this transport and health challenge, but a more developed evidence base is needed to understand their effects. This study describes the changes in traffic speed and traffic volume in the City of Edinburgh, pre- and 12 months post-implementation of phased city-wide 20mph speed limits from 2016–2018. Methods The City of Edinburgh Council collected speed and volume data across one full week (24 hours a day) pre- and post-20mph speed limits for 66 streets. The pre- and post-speed limit intervention data were compared using measures of central tendency, dispersion, and basic t-tests. The changes were assessed at different aggregations and evaluated for statistical significance (alpha = 0.05). A mixed effects model was used to model speed reduction, in the presence of key variables such as baseline traffic speed and time of day. Results City-wide, a statistically significant reduction in mean speed of 1.34mph (95% CI 0.95 to 1.72) was observed at 12 months post-implementation, representing a 5.7% reduction. Reductions in speed were observed throughout the day and across the week, and larger reductions in speed were observed on roads with higher initial speeds. Mean 7-day volume of traffic was found to be lower by 86 vehicles (95% CI: -112 to 286) representing a reduction of 2.4% across the city of Edinburgh (p = 0.39) but with the direction of effect uncertain. Conclusions The implementation of the city-wide 20mph speed limit intervention was associated with meaningful reductions in traffic speeds but not volume. The reduction observed in road traffic speed may act as a mechanism to lessen the frequency and severity of collisions and casualties, increase road safety, and improve liveability.

Applying Care Coordination Principles to Reduce Cardiovascular Disease Risk Factors in People With Serious Mental Illness: A Case Study Approach

People with serious mental illness (SMI) have a 2–3-fold higher mortality than the general population, much of which is driven by largely preventable cardiovascular disease. One contributory factor is the disconnect between the behavioral and physical health care systems. New care models have sought to integrate physical health care into primary mental health care settings. However, few examples of successful care coordination interventions to improve health outcomes with the SMI population exist. In this paper, we examine challenges faced in coordinating care for people with SMI and explore pragmatic, multi-disciplinary strategies for overcoming these challenges used in a cardiovascular risk reduction intervention shown to be effective in a clinical trial.

Longitudinal dietary trajectories from preconception to mid-childhood in women and children in the Southampton Women’s Survey and their relation to offspring adiposity: a group-based trajectory modelling approach

Background Rates of childhood obesity are increasing globally, with poor dietary quality an important contributory factor. Evaluation of longitudinal diet quality across early life could identify timepoints and subgroups for nutritional interventions as part of effective public health strategies. Objective This research aimed to: (1) define latent classes of mother-offspring diet quality trajectories from pre-pregnancy to child age 8–9 years, (2) identify early life factors associated with these trajectories, and (3) describe the association between the trajectories and childhood adiposity outcomes. Design Dietary data from 2963 UK Southampton Women’s Survey mother-offspring dyads were analysed using group-based trajectory modelling of a diet quality index (DQI). Maternal diet was assessed pre-pregnancy and at 11- and 34-weeks’ gestation, and offspring diet at ages 6 and 12 months, 3, 6-7- and 8–9-years using interviewer-administered food frequency questionnaires. At each timepoint, a standardised DQI was derived using principal component analysis. Adiposity age 8–9 years was assessed using dual-energy X-ray absorptiometry (DXA) and BMI z-scores. Results A five-trajectory group model was identified as optimal. The diet quality trajectories were characterised as stable, horizontal lines and were categorised as poor (n = 142), poor-medium (n = 667), medium (n = 1146), medium-better (n = 818) and best (n = 163). A poorer dietary trajectory was associated with higher maternal pre-pregnancy BMI, smoking, multiparity, lower maternal age and lower educational attainment. Using linear regression adjusted for confounders, a 1-category decrease in the dietary trajectory was associated with higher DXA percentage body fat (0.08 SD (95% confidence interval 0.01, 0.15) and BMI z-score (0.08 SD (0.00, 0.16) in the 1216 children followed up at age 8–9 years. Conclusion Mother-offspring dietary trajectories are stable across early life, with poorer diet quality associated with maternal socio-demographic and other factors and childhood adiposity. The preconception period may be an important window to promote positive maternal dietary changes in order to improve childhood outcomes.

Helicobacter pylori and gastric cancer: a lysosomal protease perspective

The intimate involvement of pathogens with the heightened risk for developing certain cancers is an area of research that has captured a great deal of attention over the last 10 years. One firmly established paradigm that highlights this aspect of disease progression is in the instance of Helicobacter pylori infection and the contribution it makes in elevating the risk for developing gastric cancer. Whilst the molecular mechanisms that pinpoint the contribution that this microorganism inflicts towards host cells during gastric cancer initiation have come into greater focus, another picture that has also emerged is one that implicates the host’s immune system, and the chronic inflammation that can arise therefrom, as being a central contributory factor in disease progression. Consequently, when taken with the underlying role that the extracellular matrix plays in the development of most cancers, and how this dynamic can be modulated by proteases expressed from the tumor or inflammatory cells, a complex and detailed relationship shared between the individual cellular components and their surroundings is coming into focus. In this review article, we draw attention to the emerging role played by the cathepsin proteases in modulating the stage-specific progression of Helicobacter pylori-initiated gastric cancer and the underlying immune response, while highlighting the therapeutic significance of this dynamic and how it may be amenable for novel intervention strategies within a basic research or clinical setting.

Importance of Autoimmune Responses in Progression of Retinal Degeneration Initiated by Gene Mutations

Inherited retinal diseases (IRDs) are clinically and genetically heterogeneous rare disorders associated with retinal dysfunction and death of retinal photoreceptor cells, leading to blindness. Among the most frequent and severe forms of those retinopathies is retinitis pigmentosa (RP) that affects 1:4,000 individuals worldwide. The genes that have been implicated in RP are associated with the proteins present in photoreceptor cells or retinal pigment epithelium (RPE). Asymmetric presentation or sudden progression in retinal disease suggests that a gene mutation alone might not be responsible for retinal degeneration. Immune responses could directly target the retina or be site effect of immunity as a bystander deterioration. Autoantibodies against retinal autoantigens have been found in RP, which led to a hypothesis that autoimmunity could be responsible for the progression of photoreceptor cell death initiated by a genetic mutation. The other contributory factor to retinal degeneration is inflammation that activates the innate immune mechanisms, such as complement. If autoimmune responses contribute to the progression of retinopathy, this could have an implication on treatment, such as gene replacement therapy. In this review, we provide a perspective on the current role of autoimmunity/immunity in RP pathophysiology.

Assessing knowledge, attitude, and practices of veterinarians towards antimicrobial use and stewardship as drivers of inappropriate use in Abuja, Nigeria

Introduction Antimicrobial resistance (AMR) has recently gained worldwide recognition, as the emergence of multi-drug resistant organisms has led to increased mortality and economic burden. This study aimed to assess knowledge, attitudes, and practices of veterinarians towards rational antimicrobial prescribing and identify factors influencing use. Methods We interviewed veterinary doctors in Abuja, Nigeria using a 50-point questionnaire distributed via WhatsApp mobile application. The questionnaire inquired about their experiences, knowledge, attitudes, and practices towards AMR and stewardship. We analyzed the data by calculating frequencies and proportions. Results Of 220 registered veterinarians, 144 (65.5%) participated in the survey. Most (52.8%) were within the age group 30 - 39 years; males (72.2%), with a Master’s degree (42.4%) and worked in public service (44.4%). Three-quarters (75.7%) had good knowledge of antimicrobials; 47.2% had received training on stewardship while 88.9% reported that they believed that overuse of antimicrobials was the major contributory factor towards AMR. Antimicrobial stewardship regulations are important in veterinary practice. Veterinarians were aware of the occurrence of resistant pathogens and agreed that restricting antimicrobial use in animal health care was necessary to reduce AMR. Conclusion Most respondents referred to the veterinary formulary (VF) when in doubt of the appropriate antimicrobial agent to administer. We recommend that the VF be updated following the WHO list of critically-important-antimicrobials (CIA) and veterinarians educated not to use these CIAs in the treatment of food animals.

Losartan Mitigates Oxidative Stress in the Brains of Aged IL10-/- Mice

Chronic inflammation has been linked to frailty and declined cognition in older adults. Activation of the renin-angiotensin system (RAS) through the angiotensin Type1 receptor (AT1R) has been suggested as a contributory factor that links both inflammation and aging. Here we examined the impact of 4 weeks of oral Losartan treatment on IL10-/- mice brains, a mouse model of chronic inflammation and frailty. Frontal cortex, cerebellar, and hippocampal tissue of aged (100 weeks old) male IL10-/- mice were studied. Western blot techniques were employed to quantify changes in brain AT1R, nitrotyrosine (NT) as an oxidative stress marker, and Tau proteins. Our data show that aged IL-10 mice have significantly higher levels of AT1R in the cortex tissue but not in cerebellar or hippocampal tissue compared to age and sex-matched WT mice (0.63 + 0.35 vs 1.5 + 0.54, WT vs IL10, respectively, P<0.004). When treated with LOS, brain cortical tissue of IL10 -/- mice showed significant decreases in levels of AT1R (1.5 + 0.54 vs 0.98 + 0.50, IL10 vs LOS treated IL10, respectively, P<0.04), NT (0.72 + 0.12 vs 0.42 + 0.10, IL10 vs LOS treated IL10, respectively, P<0.009), and Tau protein (1.3 + 0.31 vs 0.15 + 0.08, IL10 vs LOS treated IL10, respectively, P<0.004) as compared to control IL10-/- mice. Losartan treatment had no significant effect on hippocampal AT1R or NT levels. Our results highlight the impact of Losartan, a drug commonly prescribed for the treatment of high blood pressure, on the brain-specific angiotensin system and its downstream effects on brain oxidative stress and Tau pathology.

Acute and Chronic Graft-Versus-Host-Disease – A Focus on Pediatric Patients

Graft-versus-host disease (GVHD), either in its acute or chronic form, is the main contributory factor for morbidity and non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recent advancements in the classification of this disease, with better applicability and reproducibility of standardized criteria, coupled with improvements in the management of steroid-refractory or resistant cases, have led to promising results. In 2020, the Brazilian Group for Pediatric Bone Marrow Transplantation of the Brazilian Society for Blood and Marrow Transplantation and Cellular Therapy (SBTMO) convened a task force to provide updated, evidence-based guidance for the diagnosis, classification, staging, prophylaxis, and treatment of GVHD, with a focus on the pediatric population, the results of which are presented here.

Influence of upper level troughs and ridges on the formation of post-monsoon cyclones in the Bay of Bengal

The upper air conditions at the formative stages of several depressions and cyclones in the Indian seas were studied by Desai and Rao in the light of Riehl model for the formation of tropical cyclones. The recent introduction of twice daily radiosonde-rawin ascents at some stations in India provided additional facilities for similar studies in this area. The available upper air conditions associated with the formation of two post-monsoon cyclones of 1955 in the Bay of Bengal were accordingly studied with the idea of finding how far Riehl's theory of tropical cyclones could be applied in these cases. The present study of the post-monsoon cyclones of 1955 reveals that two radiosonde ascents a day from a reasonable network of stations should be minimum requirement for studies of this kind, Time cross-sections showing 24-hour changes of heights at intervals of 12 hours are presented to illustrate the sequence of movement of upper troughs and ridges. As postulated by Riehl, the formation of both the cyclones was apparently associated with the passage of troughs in the westerlies across northeast India, i.e., to the north of the area of cyclogenesis. But the upper air data from the available network of stations were too inadequate for drawing any definite conclusion as to whether the initial mass divergence at upper level was caused by the southward extension of the westerly trough and the superposition of its forward portion over the surface incipient low, or by the in-phase superposition of the upper trough in the westerlies with the upper tropospheric vortices moving across the Bay of pour Bengal, Dynamical development to the south of a confluent trough in the westerlies is suggested as a possible , contributory factor for the cyclogenesis in the south Bay of Bengal. The influence of the middle-latitude trough on the recurvature of one of the cyclones while out at sea and of 453474 another similar cyclone of October 1949 which had recurved only after crossing the coast, and the unexpected weakening of the former while out at sea, have been discussed.