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Babesia bovis natural field strains are composed of several geno-phenotypically distinct subpopulations. This feature, together with possible epigenetic modifications, may facilitate adaptation to variable environmental conditions. In this study we compare geno-phenotypical features among long-term (more than 12 years) (LTCP) and short-term cultured B. bovis parasites (STCP) derived from the B. bovis S74-T3Bo strain. LTCPs intraerythrocytic forms are smaller in size than STCPs and have faster in vitro growth rate. In contrast to its parental strain, the LTCP lack expression of the sexual stage specific 6cysA and 6cysB proteins and are unable to develop sexual forms upon in vitro sexual stage induction. Consistently, in contrast to its parental strain, LTCPs have reduced virulence and are not transmissible to cattle by vector competent Rhipicephalus microplus (R. microplus). Similar to previous comparisons among attenuated and virulent B. bovis strains, the LTCP line has decreased genomic diversity compared to the STCP line. Thus, LTCP may contribute to our understanding of adaptive mechanisms used by the parasites in response to environmental changes, protective immunity, virulence, and transmission by ticks. In addition, LTCPs may be considered as candidates for a non-tick transmissible vaccine against bovine babesiosis.

Bovine babesiosis, caused by Babesia bovis, is an economically significant tick-borne disease that imposes restrictions to livestock production worldwide. Current methods to control bovine babesiosis have severe limitations and novel approaches, including transmission-blocking vaccines, are needed. Members of the widely conserved CCp family are multidomain adhesion proteins containing LCCL motifs, which are differentially expressed on gametocytes of apicomplexans, including Babesia spp. and Plasmodium spp. While Plasmodium parasites contain 6 distinct CCp genes, only three members (CCp 1-3) were previously identified in B. bovis. In this study, we describe the identification and characterization of two novel non-canonical members of the CCp gene family in B. bovis, named CCp5 and FNPA. The genes were identified in silico by TBLASTN using P. falciparum CCp family domains as queries. Unlike CCp1-3, the B. bovis CCp5 and FNPA proteins lack the LCCL canonical domain but contain other typical multidomain adhesion motifs which are present in classical CCp proteins. In addition, the B. bovis CCp5 and FNPA are in synteny with known CCp genes in related apicomplexans. Sequence analysis of these two proteins demonstrated high sequence conservation among B. bovis different isolates. Transcription, immunoblot, and immunofluorescence analyses demonstrated expression of CCp5 and FNPA in blood and in vitro induced sexual stages of B. bovis. The FNPA, in contrast to CCp5, has a predicted transmembrane domain, suggesting that it might be expressed in the surface of sexual stage parasites. Altogether, finding of this study support FNPA as a possible target of a transmission-blocking vaccine against B. bovis.

Transforming growth factor β (TGFβ) is an important differentiation factor for cytotoxic T lymphocytes (CTLs) and alters the expression levels of several of homing receptors during infection. SMAD4 is part of the canonical signaling network used by members of the transforming growth factor family. For this study, genetically modified mice were used to determine how SMAD4 and TGFβ receptor II (TGFβRII) participate in transcriptional programming of pathogen-specific CTLs. We show that these molecules are essential components of opposing signaling mechanisms, and cooperatively regulate a collection of genes that determine whether specialized populations of pathogen-specific CTLs circulate around the body, or settle in peripheral tissues. TGFβ uses a canonical SMAD-dependent signaling pathway to downregulate Eomesodermin (EOMES), KLRG1, and CD62L, while CD103 is induced. Conversely, in vivo and in vitro data show that EOMES, KLRG1, CX3CR1, and CD62L are positively regulated via SMAD4, while CD103 and Hobit are downregulated. Intravascular staining also shows that signaling via SMAD4 promotes formation of long-lived terminally differentiated CTLs that localize in the vasculature. Our data show that inflammatory molecules play a key role in lineage determination of pathogen-specific CTLs, and use SMAD-dependent signaling to alter the expression levels of multiple homing receptors and transcription factors with known functions during memory formation.

Bovine babesiosis, caused by

BackgroundImmune checkpoint inhibitors (ICI) can cause off-target inflammatory and immune-related adverse events (irAE). Conceivably, COVID-19 vaccination could trigger an inflammatory and immune response that could induce or aggravate irAE.MethodsThe objective of this systematic review is to appraise the efficacy and safety of COVID-19 vaccination in patients with cancer treated with ICI. The literature search was performed in PubMed and Embase in English from December 2019 to February 2022. The review included clinical trials, observational cohort studies, case series, and case reports reporting on the clinical efficacy and safety of COVID-19 vaccines on patients with cancer treated with ICI. Outcomes of interest included seroconversion, SARS-CoV-2 infection rate, severe COVID-19, COVID-19 mortality rate. Incidence of ICI irAEs was also ascertained as well as vaccine adverse events. A meta-analysis was conducted to estimate the pooled effect sizes of the outcomes when possible, using random effects models.ResultsOverall, 19 studies were included for the analysis (n=10 865 with 2477 receiving ICI). We analyzed 15 cohort studies, 1 cross-sectional study, and 3 case reports. There were no statistically significant differences in seroconversion rates after the second dose of the vaccine when comparing patients with cancer receiving ICI with patients without cancer (risk ratio, RR 0.97, 95% CI 0.92 to 1.03) or with patients with cancer without active treatment (RR 1.00, 95% CI 0.96 to 1.04). There was a higher probability of seroconversion in patients with cancer treated with ICI compared with patients with cancer treated with chemotherapy (RR 1.09, 95% CI 1.00 to 1.18). In a single study in patients receiving ICI, no differences were observed in risk of irAE between those receiving inactivated vaccine and those unvaccinated (pneumonitis RR 0.88, 95% CI 0.33 to 2.3; rash RR 1.03, 95% CI 0.66 to 1.62; arthralgia RR 0.94, 95% CI 0.51 to 1.75). There were no studies for other types of vaccines comparing vaccinated vs not vaccinated in patients treated with ICI. The most common vaccine-related adverse events were local pain or fatigue. Overall, the quality of evidence was rated as very low.ConclusionCOVID-19 vaccination appears to be effective and safe in patients with cancer receiving ICI.

Objective Smoking rates among patients with rheumatoid arthritis (RA) exceed those in the general population. This study identified smoking cessation strategies used in patients with RA and synthesized data on their effects. Methods We conducted a systematic review of studies that reported effects of interventions for smoking cessation in patients with RA. We searched 5 electronic databases until March 2022. Screening, quality appraisal, and data collection were done independently by 2 reviewers. Results We included 18 studies reporting interventions for patients or providers: 14 evaluated strategies for patients (5 education on cardiovascular risk factors including smoking, 3 educational interventions on smoking cessation alone, 3 education with nicotine replacement and counseling, and 1 study each: education with nicotine replacement, counseling sessions alone, and a social marketing campaign). Smoking cessation rates ranged from 4% (95% CI: 2%-6%, 24 to 48 weeks) for cardiovascular risk education to 43% (95% CI: 21%-67%, 104 weeks) for counseling sessions alone. The pooled cessation rate for all interventions was 22% (95% CI: 8%-41%, 4 weeks to 104 weeks; 9 studies). Four interventions trained providers to ascertain smoking status and provide referrals for smoking cessation. The pooled rates of referrals to quit services increased from 5% in pre-implementation populations to 70% in post-implementation populations. Conclusion Studies varied in patient characteristics, the interventions used, and their implementation structure. Only 3 studies were controlled clinical trials. Additional controlled studies are needed to determine best practices for smoking cessation for patients with RA.

Babesiosis is a disease caused by tickborne hemoprotozoan apicomplexan parasites of the genus Babesia that negatively impacts public health and food security worldwide. Development of effective and sustainable vaccines against babesiosis is currently hindered in part by the absence of definitive host correlates of protection. Despite that, studies in Babesia microti and Babesia bovis, major causative agents of human and bovine babesiosis, respectively, suggest that early activation of innate immune responses is crucial for vertebrates to survive acute infection. Trained immunity (TI) is defined as the development of memory in vertebrate innate immune cells, allowing more efficient responses to subsequent specific and non-specific challenges. Considering that Mycobacterium bovis bacillus Calmette-Guerin (BCG), a widely used anti-tuberculosis attenuated vaccine, induces strong TI pro-inflammatory responses, we hypothesize that BCG TI may protect vertebrates against acute babesiosis. This premise is supported by early investigations demonstrating that BCG inoculation protects mice against experimental B. microti infection and recent observations that BCG vaccination decreases the severity of malaria in children infected with Plasmodium falciparum, a Babesia-related parasite. We also discuss the potential use of TI in conjunction with recombinant BCG vaccines expressing Babesia immunogens. In conclusion, by concentrating on human and bovine babesiosis, herein we intend to raise awareness of BCG TI as a strategy to efficiently control Babesia infection.

PURPOSE To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with chimeric antigen receptor (CAR) T-cell therapy. METHODS A multidisciplinary panel of medical oncology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to develop the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 to 2021. RESULTS The systematic review identified 35 eligible publications. Because of the paucity of high-quality evidence, recommendations are based on expert consensus. RECOMMENDATIONS The multidisciplinary team issued recommendations to aid in the recognition, workup, evaluation, and management of the most common CAR T-cell–related toxicities, including cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, B-cell aplasia, cytopenias, and infections. Management of short-term toxicities associated with CAR T cells begins with supportive care for most patients, but may require pharmacologic interventions for those without adequate response. Management of patients with prolonged or severe CAR T-cell–associated cytokine release syndrome includes treatment with tocilizumab with or without a corticosteroid. On the basis of the potential for rapid decline, patients with moderate to severe immune effector cell–associated neurotoxicity syndrome should be managed with corticosteroids and supportive care. Additional information is available at www.asco.org/supportive-care-guidelines .

PURPOSE To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitor (ICPi) therapy. METHODS A multidisciplinary panel of medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to update the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 through 2021. RESULTS A total of 175 studies met the eligibility criteria of the systematic review and were pertinent to the development of the recommendations. Because of the paucity of high-quality evidence, recommendations are based on expert consensus. RECOMMENDATIONS Recommendations for specific organ system–based toxicity diagnosis and management are presented. While management varies according to the organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, except for some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert ≤ grade 1. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids. Corticosteroids should be tapered over the course of at least 4-6 weeks. Some refractory cases may require other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, except for endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines .

Human babesiosis caused by the intraerythrocytic apicomplexan Babesia microti is an expanding tick-borne zoonotic disease that may cause severe symptoms and death in elderly or immunocompromised individuals. In light of an increasing resistance of B. microti to drugs, there is a lack of therapeutic alternatives. Species-specific proteases are essential for parasite survival and possible chemotherapeutic targets. However, the repertoire of proteases in B. microti remains poorly investigated. Herein, we employed several combined bioinformatics tools and strategies to organize and identify genes encoding for the full repertoire of proteases in the B. microti genome. We identified 64 active proteases and 25 nonactive protease homologs. These proteases can be classified into cysteine (n = 28), serine (n = 21), threonine (n = 14), asparagine (n = 7), and metallopeptidases (n = 19), which, in turn, are assigned to a total of 38 peptidase families. Comparative studies between the repertoire of B. bovis and B. microti proteases revealed differences among sensu stricto and sensu lato Babesia parasites that reflect their distinct evolutionary history. Overall, this data may help direct future research towards our understanding of the biology and pathogenicity of Babesia parasites and to explore proteases as targets for developing novel therapeutic interventions. Instituto de Patobiología Fil: Florin-Christensen, Monica. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Patobiología; Argentina Fil: Florin-Christensen, Monica. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Wieser, Sarah Nathaly. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Patobiología; Argentina. Fil: Wieser, Sarah Nathaly. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Suarez, Carlos E. USDA-ARS. Animal Disease Research Unit; Estados Unidos Fil: Suarez, Carlos E. Washington State University. Department of Veterinary Microbiology and Pathology; Estados Unidos Fil: Schnittger, Leonhard. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Patobiología; Argentina Fil: Schnittger, Leonhard. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Theileria equi is an obligate intracellular protozoan parasite that causes severe hemolytic anaemia in most equid species. Similar to other apicomplexan parasites, T. equi contains rhoptries whose contents have been implicated in host cell invasion and formation of the parasitophorous vacuole that is crucial for survival of the species within cells. Despite their importance, the composition of T. equi rhoptries and their role(s) in host cell invasion remain unexplored. To gain insight into these issues, we evaluated the expression, immunogenicity, and functional roles of two T. equi rhoptry-associated proteins abbreviated as RAP-1a and RAP-1b. The full-length RAP-1a protein was expressed to perform the analysis but our efforts to express the full-length RAP-1b protein failed due to an unknown reason. We therefore generated synthetic immunogenic peptides that map onto the N- and C-termini of the RAP-1b protein as an alternative approach. Our findings show that both proteins are expressed in the extracellular and intra-erythrocytic merozoite stages of T. equi. Serological analyses show that T. equi-infected horses mount antibody responses that recognise both proteins and correlate with a decrease in T. equi load in both acutely and persistently infected horses. In vitro neutralisation studies show that the T. equi RAP-1a protein contains neutralisation-sensitive epitopes as antibodies developed against the protein significantly inhibited the parasites from invading equine erythrocytes. Conversely, antibodies developed against the RAP-1b synthetic peptides did not neutralise parasite invasion, showing that the protein regions on which the peptides were based are not required for T. equi invasion. Overall, the data shows that T. equi rhoptries and their contents are involved in invasion of host cells and supports T. equi RAP-1 proteins as candidates for developing novel serodiagnosis tools and vaccines.

To identify patient-centered domains with long-term relevance to people with rheumatoid arthritis (RA).We conducted semi-structured individual cognitive interviews of patients with RA with at least five years of disease duration, sampled from five different countries (United States, Italy, Spain, Mexico, and Argentina). Participants were encouraged to discuss their long-term concerns regarding RA. Interviews were transcribed and analyzed using qualitative content analysis within a constructivist/interpretivist theoretical framework.Twenty-eight participants were interviewed, 24 were women. Six main themes, representing important aspects of the daily life of people with RA were generated: (i) Living with symptoms and functional limitations, (ii) Lack of participation, (iii) Partner and family issues, (iv) Risk of damage to vital organs, (v) Coping strategies, and (vi) Healthcare concerns, primarily expressed by participants from non-European countries lacking universal healthcare coverage. In addition, participants discussed the importance of contextual factors and how they impact long-term outcomes. These included attitudes towards disease, social support, or financial burdens.We identified six domains of importance to people with RA that are seldom measured in longitudinal registries and should be considered in patient-centered longitudinal studies.

Babesia, Cytauxzoon and Theileria are tick-borne apicomplexan parasites of the order Piroplasmida, responsible for diseases in humans and animals. Members of the piroplasmid rhoptry-associated protein-1 (pRAP-1) family have a signature cysteine-rich domain and are important for parasite development. We propose that the closely linked B. microti genes annotated as BMR1_03g00947 and BMR1_03g00960 encode two paralogue pRAP-1-like proteins named BmIPA48 and Bm960. The two genes are tandemly arranged head to tail, highly expressed in blood stage parasites, syntenic to rap-1 genes of other piroplasmids, and share large portions of an almost identical ~225 bp sequence located in their 5′ putative regulatory regions. BmIPA48 and Bm960 proteins contain a N-terminal signal peptide, share very low sequence identity (&lt, 13%) with pRAP-1 from other species, and harbor one or more transmembrane domains. Diversification of the piroplasmid-confined prap-1 family is characterized by amplification of genes, protein domains, and a high sequence polymorphism. This suggests a functional involvement of pRAP-1 at the parasite-host interface, possibly in parasite adhesion, attachment, and/or evasion of the host immune defenses. Both BmIPA48 and Bm960 are recognized by antibodies in sera from humans infected with B. microti and might be promising candidates for developing novel serodiagnosis and vaccines.

Human babesiosis caused by the intraerythrocytic apicomplexan Babesia microti is an expanding tick-borne zoonotic disease that may cause severe symptoms and death in elderly or immunocompromised individuals. In light of an increasing resistance of B. microti to drugs, there is a lack of therapeutic alternatives. Species-specific proteases are essential for parasite survival and possible chemotherapeutic targets. However, the repertoire of proteases in B. microti remains poorly investigated. Herein, we employed several combined bioinformatics tools and strategies to organize and identify genes encoding for the full repertoire of proteases in the B. microti genome. We identified 64 active proteases and 25 nonactive protease homologs. These proteases can be classified into cysteine (n = 28), serine (n = 21), threonine (n = 14), asparagine (n = 7), and metallopeptidases (n = 19), which, in turn, are assigned to a total of 38 peptidase families. Comparative studies between the repertoire of B. bovis and B. microti proteases revealed differences among sensu stricto and sensu lato Babesia parasites that reflect their distinct evolutionary history. Overall, this data may help direct future research towards our understanding of the biology and pathogenicity of Babesia parasites and to explore proteases as targets for developing novel therapeutic interventions.

Babesiosis is a tick-borne disease with global impact caused by parasites of the phylum Apicomplexa, genus Babesia. Typically, acute bovine babesiosis (BB) is characterized by fever, anemia, hemoglobinuria, and high mortality. Surviving animals remain persistently infected and become reservoirs for parasite transmission. Bovids in China can be infected by one or more Babesia species endemic to the country, including B. bovis, B. bigemina, B. orientalis, B. ovata, B. major, B. motasi, B. U sp. Kashi and B. venatorum. The latter may pose a zoonotic risk. Occurrence of this wide diversity of Babesia species in China may be due to a combination of favorable ecological factors, such as the presence of multiple tick vectors, including Rhipicephalus and Hyalomma, the coexistence of susceptible bovid species, such as domestic cattle, yaks, and water buffalo, and the lack of efficient measures of tick control. BB is currently widespread in several regions of the country and a limiting factor for cattle production. While some areas appear to have enzootic stability, others have considerable cattle mortality. Research is needed to devise solutions to the challenges posed by uncontrolled BB. Critical research gaps include risk assessment for cattle residing in endemic areas, understanding factors involved in endemic stability, evaluation of parasite diversity and pathogenicity of regional Babesia species, and estimation of whether and how BB should be controlled in China. Research should allow the design of comprehensive interventions to improve cattle production, diminish the risk of human infections, and increase the availability of affordable animal protein for human consumption in China and worldwide. In this review, we describe the current state of BB with reference to the diversity of hosts, vectors, and parasite species in China. We also discuss the unique risks and knowledge gaps that should be taken into consideration for future Babesia research and control strategies.

Objective To evaluate consensus recommendations regarding management of rheumatoid arthritis (RA) in patients with cancer. Methods We searched electronic databases, guideline registries, and relevant web sites for cancer-specific recommendations on RA management. Reviewers independently selected and appraised the recommendations according to the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. We identified similarities and discrepancies among recommendations. Results Of 4,077 unique citations, 39 recommendations were identified, of which half described their consensus process. Average scores for the AGREE II domains ranged from 33% to 87%. Cancer risk in RA was addressed in 79% of recommendations, with acknowledgement of increased overall cancer risk. Recommendations did not agree on the safety of using disease-modifying antirheumatic drugs (DMARDs) in RA patients with cancer, except for the contraindication of tumor necrosis factor inhibitors in patients at risk for lymphoma. Most recommendations agreed that RA treatment should be stopped and re-evaluated with a new diagnosis of cancer. Recommendations for patients with a history of cancer differed depending on the drug, cancer type, and time since cancer diagnosis. Few recommendations addressed all issues. Conclusion Recommendations for the treatment of RA in patients with cancer often fail to meet expected methodologic criteria. There was agreement on the need for caution when prescribing DMARDs to these patients. However, several areas continue to lack consensus, and given the paucity of evidence, there is an urgent need for research and expert opinion to guide and standardize the management of RA in patients with cancer.

To reduce costs associated to ex vitro adaptation of arrow cane (Gynerium sagitatum Aubl.) plants Cv “Criolla”, the effect of three substrate mixes (Peat, peat + river sand and peat + rice husk) on survival, plant height and substrate associated plant cost were evaluated. Plants were micropropagated in semisolid MS medium supplied with 0,5 mg L-1 BAP. After medium removal, plants were transferred on 72-plug plastic trays filled with the respective substrate treatment. Trays were covered with translucent plastic covers during three days. Thereafter, plants were maintained in a 50% light shade house, fog irrigated twice a day for 1 minute each during 8 weeks. Treatments were distributed with a block randomized design. Data were analyzed with ANOVA and means were separated with Tukey´s mean separation test. Results allowed to evidence that peat + sand resulted in significant increase in survival, plant height and >35 decrease in substrate associated plant cost during adaptation to ex vitro conditions.

Biologic disease-modifying anti-rheumatic drugs (bDMARDs) interfere with the immune system and could theoretically increase risk of malignancies. However, recent evidence has not substantiated such concerns and physicians are less reluctant in treating patients with underlying cancer with such bDMARDs. We aimed to understand the current utilization patterns of bDMARDs for the treatment of rheumatoid arthritis (RA) in cancer patients.We performed a retrospective cohort study of patients with prevalent RA and cancer initially seen at MD Anderson Cancer Center between 2002 and 2014. A cohort of cancer patients was identified from the tumor registry, and patients with RA were identified through ICD-9 codes, followed by review of electronic medical records. We included patients 18 years and older, with a cancer diagnosis, and a diagnosis of RA by a rheumatologist. Patients were followed until 2016.We identified 431 patients with RA and cancer that met our inclusion criteria. Overall, 111 (26%) received bDMARDs after their cancer diagnosis; of these, 60 (54%) had received bDMARDs prior to their cancer diagnosis and continued to receive this therapy following their diagnosis. Thirteen (22%) switched to a different bDMARD, and the rest continued to receive the same agent after their cancer diagnosis. Of all patients on a bDMARD, 91 (82%) received tumor necrosis factor inhibitors (TNFi).The treatment landscape of patients with a history of cancer and RA is changing. Future studies evaluating the safety of bDMARDs in patients with a recent history of cancer or with active cancer are needed. Part of the data of this project was presented as a poster at the 2016 American College of Rheumatology annual meeting. Zamora NV, Siddhanamatha H, Barbo A, Tayar J, Lin H, Suarez-Almazor M. Utilization of Biologic Therapy in Patients with Rheumatoid Arthritis and Cancer [abstract].Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/utilization-of-biologic-therapy-in-patients-with-rheumatoid-arthritis-and-cancer/. Accessed September 30, 2019. Key Points • One in four patients with RA and concomitant cancer received bDMARDs, including TNFi, after their cancer diagnosis, at our institution. • Half of the patients with RA and cancer who received bDMARDs had initiated therapy prior to the cancer diagnosis, continuing thereafter.

Objective To assess methotrexate (MTX) adherence using the Medication Event Monitoring System (MEMS) and characterize associations with adherence in patients with rheumatoid arthritis (RA). Methods Eligible patients participated in Forward, the National Databank for Rheumatic Diseases, and recently (12 months or sooner) initiated oral MTX. MEMS was used to compile MTX weekly dosing over 24 weeks. The Beliefs about Medicines Questionnaire (BMQ) was completed, and baseline demographics and disease characteristics obtained. MTX adherence (percentage of weeks dose taken correctly), implementation (percentage of weeks dose taken correctly from initiation until last dose), and persistence (duration from initiation to last dose) were calculated. Analyses measured associations between patient characteristics and adherence, modeled using logistic generalized estimating equations and censored Poisson regression, and persistence modeled using Cox regression. Results Overall, 60 of 119 eligible patients were included in the analysis. MTX adherence, implementation, and persistence were 75%, 80%, and 83%, respectively, at 24 weeks. Demographics and disease characteristics were generally similar between patients with 1 week or less and 2 weeks or more of missed MTX. Unemployment, less disability, higher Patient Global scores, and no prior disease-modifying antirheumatic drug (DMARD) use were associated with correct dosing. No significant differences in adherence were observed between patients receiving concomitant MTX versus MTX monotherapy, and biologic DMARD-experienced versus biologic DMARD-naive patients. Higher scores in BMQ Specific Necessity (indicating a greater belief in the necessity of the medication) was associated with a decreased likelihood of dosing at an interval shorter than prescribed (odds ratio 0.89). Conclusion Even in a participatory group over a short period, MTX adherence was suboptimal and associated with certain demographics, medication experience, and beliefs about medicines. This suggests a need for screening and alternative treatment opportunities in nonadherent MTX patients with RA.

Objective.The Outcome Measures in Rheumatology (OMERACT) Shared Decision Making (SDM) Working Group aims to determine the core outcome domain set for measuring the effectiveness of SDM interventions in rheumatology trials.Methods.A white paper was developed to clarify the draft core domain set. It was then used to prepare for interviews to investigate reasons for lack of consensus on it and to suggest further improvements.Results.OMERACT scientists/clinicians (n = 13) and patients (n = 10) suggested limiting the core domain set to outcome domains, removing process domains, and clarifying remaining domains.Conclusion.A revised core domain set will undergo further consensus-building.

The incidence and prevalence of babesiosis in animals and humans is increasing, yet prevention, control, or treatment measures remain limited and ineffective. Despite a growing body of new knowledge of the biology, pathogenicity, and virulence of Babesia parasites, there is still no well-defined, adequately effective and easily deployable vaccine. While numerous published studies suggest that the development of such anti-Babesia vaccines should be feasible, many others identify significant challenges that need to be overcome in order to succeed. Here, we review historic and recent attempts in babesiosis vaccine discovery to avoid past pitfalls, learn new lessons, and provide a roadmap to guide the development of next-generation babesiosis vaccines.

Background: Despite their efficacy, immune checkpoint inhibitors (ICIs) can cause significant immune-related adverse events (irAEs). Rheumatic and musculoskeletal irAEs can be serious and adversely affect the quality of life. The full spectrum of irAEs is still emerging, and to represent and better understand their scope, we evaluated the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods: We used AERSMine, an open-access web application to mine FAERS data across 11,919,342 patients from 2011 (first quarter) to 2018 (fourth quarter). Measures of disproportionality were calculated using well-established pharmacovigilance metrics, proportional reporting ratios, and safety signals (information component), in patients receiving ICI. Results: We analyzed 63,979 cancer patients for reports of ICI-associated AEs. Eighty-two percent of these reports were in relation with anti-PD-1 inhibitors. Rates of rheumatic and musculoskeletal AEs were higher in men and in patients >65 years of age. Several statistically significant AEs were identified, most in relation with PD-1 inhibitors. AEs with the highest number of reports included arthralgia (n = 1062), followed by myalgia (n = 532), myositis (n = 438), arthritis (n = 403), and rhabdomyolysis (n = 230). Novel AEs affecting the skeleton included compression fractures, fractures at various skeletal sites (rib, thoracic vertebral, and humerus), osteonecrosis of the jaw, osteitis, and osteomyelitis. Conclusion: A wide spectrum of rheumatic and musculoskeletal AE signals were detected within the FAERS data which may signify the emerging trends of irAEs post approval of ICI. Additional research to explore mechanisms and identify optimal management strategies of these AEs is warranted.

Background Postoperative bleeding complications are associated with less favorable outcomes in cardiac surgery and contribute to excessive overall healthcare costs. HEMOBLAST (Biom'up, Lyon, France) (HB) is a novel ready-to-use hemostatic powder that consists of porcine collagen, bovine chondroitin sulfate, and human pooled plasma thrombin that may help reduce surgical bleeding. Aims The aim of this study was to describe the techniques of application for this new combination powder-based hemostat, HB, and demonstrate its use employing photographs of application methods during cardiac procedures. Materials and methods The initial 24 procedures in which HB was used at our institution included: left ventricular assist device (LVAD) insertions, lung transplants, heart transplants, aortic valve replacements, coronary artery bypass grafting, and mitral valve repair. Results Hemostasis was achieved in all cases and there were no instances of mediastinitis, sternal infections, allergic reactions, or 30-day mortality. Discussion This report describes the best methods of application of HB including use for treatment of mediastinal bleeding in a re-operative procedure in a patient on antiplatelet agents and sternal bleeding during an LVAD insertion. Proper application can facilitate excellent hemostasis using this powder. Conclusion HB is a novel powder-based multiple component hemostatic agent that promotes focal or large area hemostasis. We have presented the techniques of use that are important to the successful application of HB to facilitate hemostasis.

New technologies can do more than just digitize health information; they can support multimedia platforms for patient education and health decision support. Technology can simplify the way health decisions are made by offering quick access to a vast amount of information that can be tailored to specific populations. Digital tools can increase knowledge and assist consumers in comparing health care alternatives. They are well received by patients because of the myriad features that render them visually appealing and entertaining, including audiovisual and interactive elements. To be effective, however, digital tools must be evidence based and developed following quality standards.

This study examined the association between the degree of religiosity, combined with cultural beliefs, social stigmas, and attitudes towards mental-health treatment in two groups, who, despite having similar cultural and religious affiliation, have experienced different socio-political contexts: Palestinian Muslim college students living in the Occupied Palestinian Territory (OPT) and Israel. The study was guided by Tanhan and Young’s (2021) conceptual framework. Methods: A snowball recruitment strategy was applied, using a cross-sectional survey. A total sample size was 214 students, 105 from the OPT and 109 from Israel. Results indicate that students from the OPT (n = 105) did not differ from those living in Israel (n = 109) on religiosity using the Islamic Belief scale, or Attitudes Towards Mental Health treatment (F(1, 189) = 1.07, p = 0.30). However, students from the OPT had higher confidence in mental-health professionals (M = 15.33) than their counterparts (M = 14.59), and women had higher confidence (M = 16.03) than men (M = 13.90). The reliance on traditions for Muslim students over Western mental-health approaches is a critical factor in predicting the attitudes towards students’ mental problems and their chosen treatment. Sociopolitical context played a significant role in shaping attitudes toward mental-health providers.

Acute kidney injury; Immune checkpoint inhibitors; Immune-related hepatitis Lesión renal aguda; Inhibidores del punto de control inmunitario; Hepatitis relacionada con el sistema inmunitario Lesió renal aguda; Inhibidors del punt de control immunitari; Hepatitis associada a la immunitat There are differences in recommendations for the management of immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs). To assess the real-world management of irAEs, three surveys regarding ICI-induced hepatitis (IIH), renal irAEs, and myositis were developed and sent to experts in each area. Fifty-six surveys were completed (17 IIH, 20 renal irAEs, and 19 myositis). All experts agreed on performing imaging in every suspected case of severe IIH. Sixty-five percent agreed on performing a liver biopsy in patients not responding to corticosteroids. The most common indication for corticosteroid use (59%) was for severe IIH not improving after discontinuation of ICIs. Additionally, 60% of the experts agreed on performing a biopsy for stage 2/3 acute kidney injury (AKI), and 70% recommended imaging for any stage of AKI. Thirty-five percent favored corticosteroids in AKI patients with creatinine levels 2–3-fold above baseline. For myositis, 58% would recommend a muscle biopsy in a patient with weakness and creatine kinase levels of 5000 U/L; 47% would also opt for an endomyocardial biopsy when the troponin levels are increased. Fifty-eight percent recommended oral corticosteroids for myositis, and 37% recommended additional therapy, mainly immunoglobulins. These results show substantial differences in expert practice patterns for the management of severe liver, kidney, and muscular irAEs. This research was funded by ISCIIII-FEDER and ISCIII-RETICS REDinREN (grant numbers PI17/00257, PI21/01292, RD16/0009/0030, and RICORS RD21/0005/0016) and Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR) enfermedades glomerulares complejas. Supported in part by the University of Texas MD Anderson’s Cancer Center Support Grant from the National Cancer Institute (NCI P30 CA016672).

Social networking has been shown to improve health outcomes in certain patient populations. While patients with rheumatoid arthritis (RA) increasingly use social networking to communicate with peers, the effects of these interactions are largely unknown.In a randomized controlled trial, we compared RA patients who participated in a social networking group moderated by peer leaders and who had access to a static website offering RA materials with a control group, who only had access to the website. The primary outcomes were patients' RA knowledge, self-efficacy and empowerment. Secondary outcomes included participation in desired health behaviors, and satisfaction with peer support, among others. Follow-up assessments were conducted at 3 and 6 months. Participants who never signed in were excluded from the primary analysis.105 participants were randomized to each group. Mean age was 52 (±12.4) and 92.4% were females. Knowledge scores improved in both groups, but only in the control group the differences observed at 3 and 6 months were significant (p≤0.02). Self-efficacy scores also improved in both groups, but only the differences observed at 6 months in the Facebook group were significant (p=0.02). When comparing groups, at 3 months the knowledge improvements observed in the control group were greater compared with those observed in the Facebook group (mean difference 0.4 versus 0.1; respectively, p=0.03). No other differences were observed in secondary outcomes between the 2 groups, except in peer support satisfaction. The Facebook® group reported greater peer support satisfaction in 3 out 5 subscales compared with the control group (p≤0.04).Peer support satisfaction was higher in participants using an online social network, but this was not translated into greater disease knowledge or empowerment.

Patients with cancer and systemic lupus erythematosus (SLE) may have worse outcomes than those without SLE, given their comorbidities. We examined survival in elderly women with breast cancer (BC) and SLE and hypothesized that survival would be decreased compared with women with BC but without SLE.We identified patients with BC and SLE and patients with BC without SLE in the Texas Cancer Registry and Surveillance, Epidemiology, and End Results, linked to Medicare claims. Overall survival (OS) was estimated after matching (age and cancer stage) and in multivariable Cox proportional hazards models adjusting for other cancer characteristics, treatment, and comorbidities. Two additional cohorts of women without cancer with and without SLE were also studied.We identified 494 BC SLE cases and 145,517 BC non-SLE cases, of whom we matched 9,708. Women with SLE were less likely to receive radiation, breast conserving surgery, or endocrine therapy. The 8-year OS estimate for women with early BC (stages 0-II) with and without SLE was 52% (95% confidence interval [95% CI] 45%-59%) and 74% (95% CI 73%-75%), respectively. In the Cox multivariable model, BC and SLE had increased risk of death (hazard ratio [HR] 1.65, 95% CI 1.38-1.98). Women with BC and SLE also had increased risk of death compared with women with SLE but without cancer (HR 1.42, 95% CI 1.05-1.92) after adjusting for SLE severity. Women with SLE and BC received less glucocorticoids, antimalarials, and immunosuppressants after cancer diagnosis than those without cancer.Systemic lupus is a risk factor for increased mortality in women with early BC.

Background Babesia bovis is one of the most significant tick-transmitted pathogens of cattle worldwide. Babesia bovis parasites have a complex lifecycle, including development within the mammalian host and tick vector. Each life stage has developmental forms that differ in morphology and metabolism. Differentiation between these forms is highly regulated in response to changes in the parasite’s environment. Understanding the mechanisms by which Babesia parasites respond to environmental changes and the transmission cycle through the biological vector is critically important for developing bovine babesiosis control strategies. Results In this study, we induced B. bovis sexual stages in vitro using xanthurenic acid and documented changes in morphology and gene expression. In vitro induced B. bovis sexual stages displayed distinctive protrusive structures and surface ruffles. We also demonstrated the upregulation of B. bovis calcium-dependent protein kinase 4 (cdpk4), tubulin-tyrosine ligase (ttl), and methyltransferase (mt) genes by in vitro induced sexual stages and during parasite development within tick midguts. Conclusions Similar to other apicomplexan parasites, it is likely that B. bovis upregulated genes play a vital role in sexual reproduction and parasite transmission. Herein, we document the upregulation of cdpk4, ttl, and mt genes by both B. bovis in vitro induced sexual stages and parasites developing in the tick vector. Understanding the parasite's biology and identifying target genes essential for sexual reproduction will enable the production of non-transmissible live vaccines to control bovine babesiosis. Graphical abstract

PURPOSE: Readmissions for the medical treatment of cancer have traditionally been excluded from readmission measures under the Hospital Readmissions Reduction Program. Patients with cancer often have higher readmission rates and may need heightened support to ensure effective care transitions after hospitalization. Estimating readmission risk before discharge may assist in discharge planning efforts and help promote care coordination at time of discharge. PATIENTS AND METHODS: We developed and validated a readmission risk scoring system among a cohort of adult cancer patients with solid tumor admitted at a comprehensive cancer center. Multivariate logistic regression analysis was used to develop the model. The model's discriminative capacity was evaluated through a receiver operating characteristic curve analysis. We further compared the performance of the developed score with existing risk scores for 30-day readmission. RESULTS: The 30-day unplanned readmission rate in the total cohort was 16.0% (n = 1,078 of 6,720). After multivariate analysis, Cancer site, Recent emergency room visit within 30 days, non-English primary language, Anemia defined as hemoglobin < 10 g/dL, > 4 Days length of stay during the index admission, unmarried Marital status, Increased white blood cell count > 11 × 109/L, and distant Tumor spread were significantly associated with risk of unplanned 30-day readmission. The derived score, which we call the Cancer READMIT score, had modest discriminatory performance in predicting readmissions (area under the curve for the model receiver operating characteristic curve = 0.647). CONCLUSION: The Cancer READMIT score was able to predict 30-day unplanned readmissions to our institution with fairly modest performance. External validation of our derived risk scoring system is recommended.

Vaccines against bovine babesiosis must, ideally, induce a humoral immune response characterized by neutralizing antibodies against conserved epitopes and a cellular Th1 immune response. In Babesia bovis, proteins such as AMA-1, MSA-2c, and RAP-1 have been characterized and antibodies against these proteins have shown a neutralizing effect, demonstrating the implication of B and T-cell epitopes in the immune response. There is evidence of the existence of B and T-cell epitopes in these proteins, however, it remains to be defined, the presence of conserved peptides in strains from around the world containing B and T-cell epitopes, and their role in the generation of a long-lasting immunity. The aim in this paper was to identify peptides of Babesia bovis AMA-1, MSA-2c, and RAP-1 that elicit a neutralizing and long-lasting Th1 immune response. Peptides containing B-cell epitopes of AMA-1, MSA-2c and RAP-1, were identified. The immune response generated by each peptide was characterized in cattle. All peptides tested induced antibodies that recognized intraerythrocytic parasites, however, only 5 peptides generated neutralizing antibodies in vitro: P2AMA-1 (6.28%), P3MSA-2c (10.27%), P4MSA-2c (10.42%), P1RAP-1 (32.45%), and P4RAP-1 (36.98%). When these neutralizing antibodies were evaluated as a pool, the inhibition percentage of invasion increased to 52.37%. When the T cellular response was evaluated, two peptides: P3MSA2c and P2AMA1 induced a higher percentage (70%) of activated CD4 +/CD45RO+ T cells than unstimulated cells. Additionally, both peptides induced the production of gamma interferon (IFN-) in PBMCs from vaccinated cattle after one year proving the implication of a long-lasting Th1 immune response. In conclusion, we identified conserved peptides containing B and T-cell epitopes in antigens of B. bovis that elicit a Th1 immune response and showed evidence that peptides from the same protein elicit different immune responses, which has implication for vaccine development in bovine babesiosis.

Objective: To gain consensus on the Outcome Measures in Rheumatology (OMERACT) core domain set for rheumatology trials of shared decision making (SDM) interventions.Methods: The process followed the OMERACT Filter 2.1 methodology, and used consensus-building methods, with patients involved since the inception. After developing the draft core domain set in previous research, we conducted five steps: (i) improving the draft core domain set; (ii) developing and disseminating whiteboard videos to promote its understanding; (iii) conducting an electronic survey to gather feedback on the draft core domain set; (iv) finalizing the core domain set and developing summaries, a plenary session video and discussion boards to promote its understanding; and (v) conducting virtual workshops with voting to endorse the core domain set.Results: A total of 167 participants from 28 countries answered the survey (62% were patients/caregivers). Most participants rated domains as relevant (81%-95%) and clear (82%-93%). A total of 149 participants (n = 48 patients/caregivers, 101 clinicians/researchers) participated in virtual workshops and voted on the proposed core domain set which received endorsement by 95%. Endorsed domains are: 1-Knowledge of options, their potential benefits and harms; 2-Chosen option aligned with each patient's values and preferences; 3-Confidence in the chosen option; 4-Satisfaction with the decision-making process; 5-Adherence to the chosen option and 6-Potential negative consequences of the SDM intervention.Conclusion: We achieved consensus among an international group of stakeholders on the OMERACT core domain set for rheumatology trials of SDM interventions. Future research will develop the Core Outcome Measurement Set.Clinical significance: Prior to this study, there had been no consensus on the OMERACT core domain set for SDM interventions. The current study shows that the OMERACT core domain set achieved a high level of endorsement by key stakeholders, including patients/caregivers, clinicians and researchers.(c) 2021 Elsevier Inc. All rights reserved.

Purpose The risks and benefits of remote corticosteroid weaning in heart transplant recipients more than 2 years post-transplant are unknown. We compared outcomes in patients undergoing early and remote steroid weaning after heart transplantation. Methods We performed a retrospective study (range 09, 1991-04, 2017). Primary outcomes included short-term and long-term mortality, allograft dysfunction, and burden of rejection. Secondary outcomes included impact on hemoglobin A1c, lipid panel, bone scan T-score, and body mass index. Results 63 patients underwent corticosteroid weaning between 2012 and 2017. Outcomes of patients weaned early (n = 34; median time from transplant = 1.1 years) were compared with those weaned late (n = 29; median time from transplant = 4.4 years). 52 (82.5%) patients were successfully weaned off corticosteroids. No statistically significant difference in outcomes was found between the early and late weaning groups (p = .20). There were no differences in allograft function (p-value = .16), incidence of rejection (p = .46), or mortality (p = .15). Improvement in metabolic profile was seen in both groups but was not statistically significant. Conclusions In heart transplant recipients, remote vs early weaning of corticosteroids is not associated with significant differences in graft function or the incidence of rejection after 1-year follow-up. Moreover, there were no significant differences in survival up to 3 years between the two groups.

This study aimed to develop a definition of vasoplegia that reliably predicts clinical outcomes. Vasoplegia was evaluated using data from the electronic health record for each 15-minute interval for 72 hours following cardiopulmonary bypass. Standardized definitions considered clinical features (systemic vascular resistance [SVR], mean arterial pressure [MAP], cardiac index [CI], norepinephrine equivalents [NEE]), threshold strategy (criteria occurring in any versus all measurements in an interval), and duration (criteria occurring over multiple consecutive versus separated intervals). Minor vasoplegia was MAP 60 mm Hg or SVR 800 dynes⋅sec⋅cm-5 with CI 2.2 L/min/m2 and NEE ≥ 0.1 µg/kg/min. Major vasoplegia was MAP 60 mm Hg or SVR 700 dynes⋅sec⋅cm-5 with CI 2.5 L/min/m2 and NEE ≥ 0.2 µg/kg/min. The primary outcome was incidence of vasoplegia for eight definitions developed utilizing combinations of these criteria. Secondary outcomes were associations between vasoplegia definitions and three clinical outcomes: time to extubation, time to intensive care unit discharge, and nonfavorable discharge. Minor vasoplegia detected anytime within a 15-minute period (MINOR_ANY_15) predicted the highest incidence of vasoplegia (61%) and was associated with two of three clinical outcomes: 1 day delay to first extubation (95% CI: 0.2 to 2) and 7 day delay to first intensive care unit discharge (95% CI: 1 to 13). The MINOR_ANY_15 definition should be externally validated as an optimal definition of vasoplegia.

Rationale: Growing literature on the coronavirus disease 2019 (COVID-19) suggests that obesity (BMI > 30 kg/m2) is a strong risk factor for increasing disease severity, hospitalization and admission to the intensive care unit (ICU). In such critically ill patients with acute respiratory distress syndrome (ARDS), the use of extracorporeal membrane oxygenation (ECMO) can serve as salvage therapy. The Extracorporeal Life Support Organization (ELSO) COVID-19 ECMO registry reports that 49% of its patients were classified as obese as of 12/01/2020. However, the morbidity and mortality outcomes of this subgroup remains unclear. As such, this high-risk population merits further examination. Methods: We identified adult COVID-19 ARDS patients who were candidates for either veno-venous ECMO or veno-arterial ECMO between March 13, 2020 and August 31, 2020. The eligibility for ECMO was selected based on our institutional algorithm and the EOLIA Trial criteria (except for high BMI cutoff). Patients were divided into two groups, obese (BMI > 30 kg/m2) and non-obese (BMI < 29.9 kg/m2). We compared the pre-cannulation characteristics including time elapsed between admission to ECMO, intubation to ECMO and respiratory indices. We then examined length on ECMO, ICU or hospital length of stay and disposition. Fisher's exact and Mann-Whitney U tests were used to analyze categorical and continuous data. Results: We identified a total of 41 patients, 33 (80.5%) were obese and 8 (19.5%) were non-obese [Table 1]. The average age of the obese and non-obese groups was 47.8 years and 55.5 years respectively. The median BMI was 39.85 kg/m2 (IQR: 35.63, 43.00) in the obese group and 29.05 kg/m2 (IQR: 25.35, 29.39) in the non-obese group (p

Theileria equi is a widely distributed apicomplexan parasite that causes severe hemolytic anemia in equid species. There is currently no effective vaccine for control of the parasite and understanding the mechanism that T. equi utilizes to invade host cells may be crucial for vaccine development. Unlike most apicomplexan species studied to date, the role of micronemes in T. equi invasion of host cells is unknown. We therefore assessed the role of the T. equi claudin-like apicomplexan microneme protein (CLAMP) in the invasion of equine erythrocytes as a first step towards understanding the role of this organelle in the parasite. Our findings show that CLAMP is expressed in the merozoite and intra-erythrocytic developmental stages of T. equi and in vitro neutralization experiments suggest that the protein is involved in erythrocyte invasion. Proteomic analyses indicate that CLAMP interacts with the equine erythrocyte α-and β- spectrin chains in the initial stages of T. equi invasion and maintains these interactions while also associating with the anion-exchange protein, tropomyosin 3, band 4.1 and cytoplasmic actin 1 after invasion. Additionally, serological analyses show that T. equi-infected horses mount robust antibody responses against CLAMP indicating that the protein is immunogenic and therefore represents a potential vaccine candidate.

Natural disasters are typically associated with the emergence of infectious diseases. On 15 June 2010, severe storms caused flooding in the Var department (France). A rumour about increased risk of Staphylococcusaureus skin infections after bathing in the sea began to circulate on Internet a few days after the floods. The aim of this study was to compare the rumour with the true incidence of cases of infection.Since 1999, we have been conducting a prospective survey of S. aureus skin infections in our hospital to study their clinical, laboratory and epidemiologic features. We compared data on cases of Staphylococcus skin infection recorded in our institution from 2008 to 2012.We found that there was no increase in S. aureus skin infections after the floods compared to the previous and subsequent years.We had a unique opportunity to check the rumoured increase in incidence of infectious disease with the true incidence. In our study, the fear of S. aureus skin infections following flooding proved to be unfounded.

Objectives To identify patient-centered core domains for prospective longitudinal observational studies (LOS) in rheumatoid arthritis. Methods Our working group held a virtual meeting in November 2020 to review data from a literature review and patient qualitative interviews, and to discuss strategies to move forward on domain identification and selection using the OMERACT 2.1 domain selection process. Results Important candidate domains and subdomains were identified including in the areas of life impact. Consensus was reached on moving forward with a Delphi process. Conclusions The meeting provided future directions to identify and select a core set of domains for use in LOS.

Regardless of workspace or class setting, group work has gotten a reputation for being less than pleasant. However, when individuals have the opportunity to prepare for group work via understanding their personal strengths, expectations, and perspectives, the not-so-popular group work can often turn into pleasant, productive, and collaborative engagement. Because group dynamics shift and vary from group to group, there is a constant learning opportunity to understand how to work in groups successfully. This new 2-page publication of the UF/IFAS Department of Agricultural Education and Communication will identify simple yet effective strategies that can serve as foundational building blocks whenever preparing oneself or others for group work. Written by Cecilia E. Suarez and Jarred A. Shellhouse.https://edis.ifas.ufl.edu/wc389

Immune checkpoint inhibitors are associated with immune-related adverse events (irAEs), including arthritis (arthritis-irAE). Management of arthritis-irAE is challenging because immunomodulatory therapy for arthritis should not impede antitumor immunity. Understanding of the mechanisms of arthritis-irAE is critical to overcome this challenge, but the pathophysiology remains unknown. Here, we comprehensively analyze peripheral blood and/or synovial fluid samples from 20 patients with arthritis-irAE, and unmask a prominent Th1-CD8+ T cell axis in both blood and inflamed joints. CX3CR1hi CD8+ T cells in blood and CXCR3hi CD8+ T cells in synovial fluid, the most clonally expanded T cells, significantly share TCR repertoires. The migration of blood CX3CR1hi CD8+ T cells into joints is possibly mediated by CXCL9/10/11/16 expressed by myeloid cells. Furthermore, arthritis after combined CTLA-4 and PD-1 inhibitor therapy preferentially has enhanced Th17 and transient Th1/Th17 cell signatures. Our data provide insights into the mechanisms, predictive biomarkers, and therapeutic targets for arthritis-irAE.

Background Babesia bovis reproduces sexually in the gut of its tick vector Rhipicephalus microplus, which involves expression of 6cys A and 6cys B proteins. Members of the widely conserved 6cys superfamily are candidates for transmission blocking vaccines (TBV), but intricacies in the immunogenicity of the 6cys proteins in the related Plasmodium parasites required the identification of transmission blocking domains in these molecules for vaccine design. Hereby, the immunogenic efficacy of recombinant (r) B. bovis 6cys A and B proteins as a TBV formulation was studied. Methods The immunogenicity of r6cys A and 6cys B proteins expressed in a eukaryotic system was evaluated in a cattle immunization trial (3 immunized and 3 control calves). A B. bovis sexual stage induction in vitro inhibition assay to assess the ability of antibodies to block the production of sexual forms by the parasite was developed. Results Immunized cattle generated antibodies against r6cys A and r6cys B that were unable to block sexual reproduction of the parasite in ticks. Additionally, these antibodies also failed in recognizing native 6cys A and 6cys B and peptides representing 6cys A and 6cys B functional domains and in inhibiting the development of sexual forms in an in vitro induction system. In contrast, rabbit antibodies generated against synthetic peptides representing predicted B-cell epitopes of 6cys A and 6cys B recognized recombinant and native forms of both 6cys proteins as well as peptides representing 6cys A and 6cys B functional domains and were able to neutralize development of sexual forms of the parasite in vitro. Conclusions These data, combined with similar work performed on Plasmodium 6cys proteins, indicate that an effective 6cys protein-based TBV against B. bovis will require identifying and targeting selected regions of proteins containing epitopes able to reduce transmission. Graphical abstract