HLA molecular mismatches and induced donor-specific tolerance in combined living donor kidney and hematopoietic stem cell transplantation.

Introduction: We investigated the potential role of HLA molecular mismatches (MM) in achieving stable chimerism, allowing for donor-specific tolerance in patients undergoing combined living donor kidney and hematopoietic stem cell transplantation (HSCT). Methods: All patients with available DNA samples (N=32) who participated in a phase 2 clinical trial (NCT00498160) where they received an HLA mismatched co-transplantation of living donor kidney and facilitating cell-enriched HSCT were included in this study. High-resolution HLA genotyping data were used to calculate HLA amino acid mismatches (AAMM), Eplet MM, three-dimensional electrostatic mismatch scores (EMS-3D), PIRCHE scores, HLA-DPB1 T-cell epitope group MM, HLA-B leader sequence MM, and KIR ligands MM between the donor and recipient in both directions. HLA MM were analyzed to test for correlation with the development of chimerism, graft vs. host disease (GvHD), de novo DSA, and graft rejection. Results: Follow-up time of this cohort was 6-13.5 years. Of the 32 patients, 26 developed high-level donor or mixed stable chimerism, followed by complete withdrawal of immunosuppression (IS) in 25 patients. The remaining six of the 32 patients had transient chimerism or no engraftment and were maintained on IS (On-IS). In host versus graft direction, a trend toward higher median number of HLA-DRB1 MM scores was seen in patients On-IS compared to patients with high-level donor/mixed chimerism, using any of the HLA MM modalities; however, initial statistical significance was observed only for the EMS-3D score (0.45 [IQR, 0.30-0.61] vs. 0.24 [IQR, 0.18-0.36], respectively; p=0.036), which was lost when applying the Bonferroni correction. No statistically significant differences between the two groups were observed for AAMM, EMS-3D, Eplet MM, and PIRCHE-II scores calculated in graft versus host direction. No associations were found between development of chimerism and GvHD and non-permissive HLA-DPB1 T-cell epitope group MM, HLA-B leader sequence, and KIR ligands MM. Conclusion: Our results suggest an association between HLA-DRB1 molecular mismatches and achieving stable chimerism, particularly when electrostatic quality of the mismatch is considered. The non-permissive HLA-DPB1 T-cell epitope group, HLA-B leader sequence, and KIR ligands MM do not predict chimerism and GvHD in this combined kidney/HSCT transplant patient cohort. Further work is needed to validate our findings. Clinical trial registration: https://clinicaltrials.gov/study/NCT00498160, identifier NCT00498160.

Annotating very high-resolution satellite imagery: A whale case study.

The use of very high-resolution (VHR) optical satellites is gaining momentum in the field of wildlife monitoring, particularly for whales, as this technology is showing potential for monitoring the less studied regions. However, surveying large areas using VHR optical satellite imagery requires the development of automated systems to detect targets. Machine learning approaches require large training datasets of annotated images. Here we propose a standardised workflow to annotate VHR optical satellite imagery using ESRI ArcMap 10.8, and ESRI ArcGIS Pro 2.5., using cetaceans as a case study, to develop AI-ready annotations.•A step-by-step protocol to review VHR optical satellite images and annotate the features of interest.•A step-by-step protocol to create bounding boxes encompassing the features of interest.•A step-by-step guide to clip the satellite image using bounding boxes to create image chips.

Association of HLA Mismatches and Histology Suggestive of Antibody-Mediated Injury in the Absence of Donor-Specific Anti-HLA Antibodies.

BACKGROUND AND OBJECTIVES: The histology of antibody-mediated rejection after kidney transplantation is observed frequently in the absence of detectable donor-specific anti-HLA antibodies. Although there is an active interest in the role of non-HLA antibodies in this phenotype, it remains unknown whether HLA mismatches play an antibody-independent role in this phenotype of microcirculation inflammation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: To study this, we used the tools HLAMatchmaker, three-dimensional electrostatic mismatch score, HLA solvent accessible amino acid mismatches, and mismatched donor HLA-derived T cell epitope targets to determine the degree of HLA molecular mismatches in 893 kidney transplant recipients with available biopsy follow-up. Multivariable Cox proportional hazards models were applied to quantify the cause-specific hazard ratios of the different types of HLA mismatch scores for developing antibody-mediated rejection or histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies. In all survival analyses, the patients were censored at the time of the last biopsy. RESULTS: In total, 121 (14%) patients developed histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies, of which 44 (36%) patients had concomitant T cell-mediated rejection. In multivariable Cox analysis, all different calculations of the degree of HLA mismatch associated with developing histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies. This association was dependent neither on the presence of missing self (potentially related to natural killer cell activation) nor on the formation of de novo HLA antibodies. Also, glomerulitis and complement C4d deposition in peritubular capillaries associated with the degree of HLA mismatch in the absence of anti-HLA antibodies. CONCLUSIONS: The histology of antibody-mediated rejection and its defining lesions are also observed in patients without circulating anti-HLA antibodies and relate to the degree of HLA mismatch.

Impact of sports on temporomandibular dysfunction: a comparison of competitive and recreational female athletes as well as female non-athletes.

OBJECTIVES: The present study was conducted to investigate the correlation between (competitive) sports and the occurrence of temporomandibular dysfunctions (TMD) by comparing the prevalences in competitive, recreational, and non-athletic women. MATERIALS AND METHODS: A total of 138 women between the ages of 18 and 45 were interviewed about symptoms of TMD by means of a questionnaire. Based on their athletic performance level, the participating women were classified as competitive athletes, recreational athletes, or non-athletes (each group n = 46). RESULTS: Symptoms of TMD were notably less frequent in competitive female athletes (52.2%) than in recreational female athletes (63.0%) and female non-athletes (60.9%). With increasing training load, the prevalence of TMD decreased in both the competitive and recreational female athlete groups. CONCLUSIONS: Athletic activity in general seems to have a positive effect on the occurrence of TMD. Competitive female athletes appear less likely to suffer from symptoms of TMD than recreational athletes and non-athletes. One possible explanation for this could be the better supervision by qualified trainers and physiotherapists in competitive sports. CLINICAL RELEVANCE: Patients should be motivated to engage in sports as a protective measure against symptoms of TMD. However, it is important to ensure that they are properly instructed by experienced personnel in order to avoid unphysiological strain and negative consequences.

Effects of competitive sports on temporomandibular dysfunction: a literature review.

OBJECTIVES: The German Society of Craniomandibular Function and Disorders recommends that patients suffering from temporomandibular dysfunctions should practice sports in order to compensate for everyday stress. This raises the question as to what extent competitive athletes develop temporomandibular dysfunctions or whether their athletic activities protect them. With the present literature review, the authors intend to give an overview of the currently available publications on this topic. MATERIALS AND METHODS: A literature research in the PubMed and Google Scholar databases was performed to filter out the currently available publications on the topic 'sports, and temporomandibular dysfunction. RESULTS: Out of 114 available articles, seven met the inclusion criteria. Two other relevant articles were found in the list of references, so that in total, nine publications were picked for the review. In case numbers ranging from eight to 347 subjects, a temporomandibular dysfunction was detected with a prevalence between 11.7% and 100% for athletes and between 11.11% and 14.3% for non-athletes. Different kinds of sports were evaluated, all of them contact sports: basketball, handball, wrestling, boxing, karate, mixed martial arts, field hockey, water polo, and soccer. One study compared athletes with and without consumption of anabolic steroids, regardless of the type of sport. The level of athletic performance varied across the different studies. CONCLUSIONS: Currently, studies dealing with the effect of competitive sports on temporomandibular dysfunction are scarce. Inconsistent methodological procedures permit only limited comparability. CLINICAL RELEVANCE: A general trend, however, can already be discerned: professional athletes suffer from temporomandibular dysfunctions more frequently than non-athletes.

Influence of HLA class II polymorphism on predicted cellular immunity against SARS-CoV-2 at the population and individual level

Development of effective adaptive immune responses after coronavirus disease 2019 (COVID-19) and after vaccination against SARS-CoV-2 is predicated on recognition of viral peptides, presented in the context of HLA class II molecules, by CD4+ T-cells. We capitalised on extensive high resolution HLA data deposited in the National Marrow Donor Program registry to obtain detailed information on human HLA haplotype frequencies of twenty five human populations and used a bioinformatics approach to investigate the role of HLA polymorphism on SARS-CoV-2 immunogenicity at the population and at the individual level. Within populations, we identify wide inter-individual variability in predicted CD4+ T-cell reactivity against structural, non-structural and accessory SARS-CoV-2 proteins, according to expressed HLA genotype. However, we find similar potential for anti-SARS-CoV-2 cellular immunity at the population level, across all ethnic groups examined, suggesting that HLA polymorphism is unlikely to account for observed disparities in clinical outcomes after COVID-19 among different race and ethnic groups. We predict robust immune reactivity against SARS-CoV-2 Spike protein, the basis for the majority of current vaccination efforts, both at the population and individual level, despite significant variation in Spike-derived peptide presentation by individual HLA genotypes. Finally, we provide comprehensive maps of SARS-CoV-2 proteome immunogenicity accounting for population coverage in major ethnic groups. Our findings provide important insight on the potential role of HLA polymorphism on development of protective immunity after SARS-CoV-2 infection and after vaccination and a firm basis for further experimental studies in this field.

A computational model of pedestrian road safety: The long way round is the safe way home.

We propose a novel linear model of pedestrian safety in urban areas with respect to road traffic crashes that considers a single independent variable of pedestrian path safety. This variable is estimated for a given urban area by sampling pedestrian paths from the population of such paths in that area and in turn estimating the mean safety of these paths. We argue that this independent variable directly models the factors contributing to pedestrian safety. This contrasts previous approaches, which, by considering multiple independent variables describing the environment, traffic and pedestrians themselves, indirectly model these factors. Using data about 15 UK cities, we demonstrate that the proposed model accurately estimates numbers of pedestrian casualties.

Efficacy of antiplatelet therapy in secondary prevention following lacunar stroke: pooled analysis of randomized trials.

BACKGROUND AND PURPOSE: Lacunar stroke accounts for ≈25% of ischemic stroke, but optimal antiplatelet regimen to prevent stroke recurrence remains unclear. We aimed to evaluate the efficacy of antiplatelet agents in secondary stroke prevention after a lacunar stroke. METHODS: We searched MEDLINE, Embase, and the Cochrane library for randomized controlled trials that reported risk of recurrent stroke or death with antiplatelet therapy in patients with lacunar stroke. We used random effects meta-analysis and evaluated heterogeneity with I(2). RESULTS: We included 17 trials with 42,234 participants (mean age 64.4 years, 65% male) and follow up ranging from 4 weeks to 3.5 years. Compared with placebo, any single antiplatelet agent was associated with a significant reduction in recurrence of any stroke (risk ratio [RR] 0.77, 0.62-0.97, 2 studies) and ischemic stroke (RR 0.48, 0.30-0.78, 2 studies), but not for the composite outcome of any stroke, myocardial infarction, or death (RR 0.89, 0.75-1.05, 2 studies). When other antiplatelet agents (ticlodipine, cilostazol, and dipyridamole) were compared with aspirin, there was no consistent reduction in stroke recurrence (RR 0.91, 0.75-1.10, 3 studies). Dual antiplatelet therapy did not confer clear benefit over monotherapy (any stroke RR 0.83, 0.68-1.00, 3 studies; ischemic stroke RR 0.80, 0.62-1.02, 3 studies; composite outcome RR 0.90, 0.80-1.02, 3 studies). CONCLUSIONS: Our results suggest that any of the single antiplatelet agents compared with placebo in the included trials is adequate for secondary stroke prevention after lacunar stroke. Dual antiplatelet therapy should not be used for long-term stroke prevention in this stroke subtype.

Acquired haemophilia A associated with autoimmune thyroiditis: a case report.

INTRODUCTION: Acquired haemophilia A is a rare life- and limb-threatening bleeding disorder if left untreated. Autoimmune thyroiditis is an autoimmune disorder that can be rarely associated with acquired haemophilia. Here we report a case of a 60-year-old woman presenting with cutaneous and muscle haematomas secondary to acquired haemophilia A in association with autoimmune thyroiditis, who was successfully treated with recombinant activated factor VII and immunosuppression. CASE PRESENTATION: A 60-year-old Sri Lankan woman with a background of longstanding hypothyroidism, diabetes mellitus, hypertension, hyperlipidaemia and bronchial asthma developed spontaneous cutaneous purpura and a limb-threatening intramuscular haematoma. Initial coagulation screening revealed prolonged activated partial thromboplastin time of 66.4 seconds (normal range 26 to -36 seconds) and time-dependent inhibitors against factor VIII. She had positive antinuclear antibody and antithyroid peroxidase (microsomal) antibody titre of over 1/80 and 1000IU/mL respectively. The diagnosis was therefore made of acquired haemophilia A in association with autoimmune thyroiditis. Acute limb-threatening bleeding was managed with recombinant activated factor VII (NovoSeven®). Immunosuppressive treatment consisting of oral prednisone 60mg/day and cyclophosphamide 100mg/day was administered in order to remove the factor VIII inhibitor. This treatment led to normalisation of her haemostatic parameters. This case illustrates a very rare association of acquired haemophilia and autoimmune thyroiditis as well as the importance of considering acquired haemophilia as a differential diagnosis of spontaneous bleeding. CONCLUSIONS: Acquired haemophilia should be considered in the differential diagnosis of unexplained bleeding in adults. Treatment of the acute coagulopathy with recombinant activated factor VII and immunosuppressive therapy was successful in this case.