Search

The potential increased risk of immune-related adverse events (irAEs) post-influenza vaccine is a concern in patients receiving immune checkpoint inhibitors (ICI). We conducted a systematic review with meta-analysis of studies reporting the effects of influenza vaccination in patients with cancer during ICI treatment. We searched five electronic databases until 01/2022. Two authors independently selected studies, appraised their quality, and collected data. The primary outcome was the determination of pooled irAE rates. Secondary outcomes included determination of immunogenicity and influenza infection rates and cancer-related outcomes. Nineteen studies (26 publications, n = 4705) were included; 89.5% were observational. Vaccinated patients reported slighter lower rates of irAEs compared to unvaccinated patients (32% versus 41%, respectively). Seroprotection for influenza type A was 78%–79%, and for type B was 75%. Influenza and irAE-related death rates were similar between groups. The pooled proportion of participants reporting a laboratory-confirmed infection was 2% (95% CI 0% to 6%), and influenza-like illness was 14% (95% CI 2% to 32%). No differences were reported on the rates of laboratory-confirmed infection between vaccinated and unvaccinated patients. Longer progression-free and overall survival was also observed in vaccinated compared with unvaccinated patients. Current evidence suggests that influenza vaccination is safe in patients receiving ICIs, does not increase the risk of irAEs, and may improve survival.

Background: The living-donor transplantation (LDT) is essential to provide patients with chronic kidney disease (CKD) a superior quality of life and improve their lifespan. Recent investigations prove that the living donors (LD) have a risk of developing CKD, without there being a way to anticipate it. The zero-time biopsies provide valuable information that may contribute to this objective since they report histopathologic findings of subclinical chronic damage. Methods: Retrospective, observational and analytical study. The information from the medical files and pathology department of LD attended at “Dr. Miguel Silva” general hospital from January 2006 to January 2018 was analyzed. The glomerular filtrate rate was obtained 24 hours and a year after nephrectomy and was estimated based on CDK-EPI. The comparison among groups was made through Mann-Whitney testing for continuous numeric. A value of p36 years, the dropping of the GFR >43%, the GFR and the creatinine levels after 24 hours of nephrectomy were associated with a reduction of the GFR the year after nephrectomy.

TPS12147 Background: Adjuvant therapy with immune checkpoint inhibitors (ICIs) is approved for melanoma, but immune-related adverse events (irAEs) remain a challenge. Although acute toxicities are well defined, long-term AEs and impact on quality of life (QOL) are undetermined. Available data derived from clinical trials involve highly selected populations and do not reflect real world experience. Additionally, trials measure outcomes only at predetermined endpoints, and symptoms may vary throughout the course of therapy. Moreover, the pathogenesis of irAEs and symptoms remains poorly understood. We hypothesize that AEs and sustained inflammation induced by adjuvant ICIs increase symptom burden and negatively impact function and QOL in a subset of patients (pts), and elevated expression of pro-inflammatory cytokines and T cell signatures during therapy correlate with toxicity and symptom burden. Our preliminary data identified i) interleukin-6/Th-17 pathway as a possible mediator of irAEs, ii) immune reactivity and increases in inflammatory cytokines are associated with symptom burden in cancer survivors, and iii) prioritized 30 genetic markers conferring risk for irAEs in ICI-treated melanoma pts. Methods: This is a prospective longitudinal cohort study to evaluate potential toxicity/symptom burden and immune correlates in melanoma pts receiving adjuvant ICIs (NCT04990726). A total of 240 pts will be enrolled. Eligibility criteria: age ≥18 years (yrs), surgically resected stage II, III, or IV melanoma, initiating adjuvant nivolumab or pembrolizumab, no prior systemic therapy for melanoma, and no prior autoimmune diseases. Patients will be assessed at baseline (before ICI infusion) and every 3 months (mos) up to 2 yrs or until attrition or death. The primary endpoint is the incidence rate of any irAEs at 12 mos. Demographics, personal/family history, comorbidities, tumor history/stage, prior therapies, performance status, concurrent medications, and other factors that play a role in pts perceptions of disease are collected. At each visit, pts undergo a clinical evaluation to assess potential irAEs, new comorbidities, and tumor recurrence. Patient-reported outcomes of fatigue, depression, sleep disturbance, and QOL are collected at each visit to assess changes from baseline up to 2 yrs. In addition to standard methods of data collection at pre-specified times, we leverage mobile technology to capture symptoms and AEs in real time. Longitudinal blood samples will characterize pts immune signatures from baseline up to 2 yrs to evaluate their association with irAEs, symptom burden, and QOL, and to compare the genotype of pts with and without irAEs. To characterize the effect of adjuvant ICI on bone health, eligible pts are evaluated by whole body dual-energy X-ray absorptiometry at baseline and at 12 mos as an exploratory aim. The study is currently active, and 27 pts are enrolled. Clinical trial information: NCT04990726.

Bone health education publicly available through the Internet, if evidence-based and unbiased, could help patients deal with issues such as decision-making, maintaining healthy lifestyles, using medications correctly, and improving their communication with health professionals. We performed an environmental scan and quality assessment of the currently available osteoporosis and bone health patient education information on the World Wide Web. The sample websites were identified by using three separate search tools: Google Advanced, Bing, and Ask.com . Two independent investigators collected data and appraised the quality of selected websites. We identified 48 websites. Most websites were focused on risks factors of osteoporosis, preventive measures, screening recommendations, and topics to discuss with the physician. All websites provided adequate information describing treatment options; however, only 36% had information addressing duration of treatment, what happens when treatment stops, and the benefits and risks of various treatments. A total of 55% of the websites had their content updated to 2019 and 68% cited their sources of information to support their content. Reading levels ranged from 7.5 to 15.2 (higher than the recommended 6-grade level). Websites with information about bone health and osteoporosis commonly present information about initial treatment choices, but most fail to address risk-benefit issues, and common barriers than can occur throughout the course of the disease. In addition, many websites did not update their content, did not cite their sources of information, or were written at a 9-grade level or above (rendering them unsuitable for low-literacy populations).

Aims Prediction of right heart failure (RHF) after left ventricular assist device (LVAD) implant remains a challenge. The EUROMACS right-sided heart failure (EUROMACS-RHF) risk score was proposed as a prediction tool for post-LVAD RHF but lacks from large external validation. The aim of our study was to externally validate the score. Methods and results From January 2007 to December 2017, 878 continuous-flow LVADs were implanted at three tertiary centres. We calculated the EUROMACS-RHF score in 662 patients with complete data. We evaluated its predictive performance for early RHF defined as either (i) need for short- or long-term right-sided circulatory support, (ii) continuous inotropic support for ≥14 days, or (iii) nitric oxide for ≥48 h post-operatively. Right heart failure occurred in 211 patients (32%). When compared with non-RHF patients, pre-operatively they had higher creatinine, bilirubin, right atrial pressure, and lower INTERMACS class (P Conclusion In an external cohort, the EUROMACS-RHF had limited discrimination predicting RHF. The clinical utility of this score remains to be determined.

As the use of cancer immunotherapy expands, a personalized benefit-risk profile of these agents needs to be considered in special populations at higher risk of experiencing adverse events with these agents. Cancer patients with preexisting autoimmune conditions or those who experience rheumatic adverse events with immunotherapy are faced with difficult decisions regarding their treatment. Often, therapeutic gains in survival need to be balanced with a deleterious impact on quality of life. Risk consideration should include types of potential benefits and harms, magnitude of effects, alternative therapeutic options, and, most importantly, patient values and preferences. Future research should aim to quantify risks in these special populations to ensure evidence-based decision-making that considers patient trade-offs between quality of life and survival.

Apicomplexan parasites are responsible for important livestock diseases that affect the production of much needed protein resources, and those transmissible to humans pose a public health risk. Vaccines, recognized as a cost-effective and environmentally friendly method for the prevention of infectious diseases in livestock, can avert losses in food production and decrease the exposure of humans to zoonotic pathogens. This review focuses on the need for and advances in vaccine development against the apicomplexan parasites Theileria spp., Babesia spp., Toxoplasma gondii , Neospora caninum , Eimeria spp., Besnoitia spp., Sarcocystis spp., and Cryptosporidium parvum . Together, the effect of these parasites on the cattle industry worldwide causes an enormous burden, yet they remain poorly controlled and very few effective and practical vaccines against them are available. Vaccine development is hampered by our scarce and limited knowledge of the biology and mechanisms of pathogenesis of these microorganisms, and the absence of correlates of host immune protection. More studies focused on these aspects as well as on the identification of parasite vulnerabilities that can be exploited for vaccine design are needed. Novel “omics” and gene editing approaches in understanding complex parasite biology together with advances in vaccinology will facilitate the development of effective, sustainable, and practical vaccines against cattle diseases caused by apicomplexan parasites. Such vaccines will help prevent animal and human diseases and allow production of enough animal protein to feed the growing human population in the twenty-first century and beyond.

Apical membrane antigen 1 is a microneme protein which plays an indispensable role during Apicomplexa parasite invasion. The detailed mechanism of AMA-1 molecular interaction with its receptor on bovine erythrocytes has not been completely defined in Babesia bovis. This study was focused on identifying the minimum B. bovis AMA-1-derived regions governing specific and high-affinity binding to its target cells. Different approaches were used for detecting ama-1 locus genetic variability and natural selection signatures. The binding properties of twelve highly conserved 20-residue-long peptides were evaluated using a sensitive and specific binding assay based on radio-iodination. B. bovis AMA-1 ectodomain structure was modelled and refined using molecular modelling software. NetMHCIIpan software was used for calculating B- and T-cell epitopes. The B. bovis ama-1 gene had regions under functional constraint, having the highest negative selective pressure intensity in the Domain I encoding region. Interestingly, B. bovis AMA-1-DI (100YMQKFDIPRNHGSGIYVDLG119 and 120GYESVGSKSYRMPVGKCPVV139) and DII (302CPMHPVRDAIFGKWSGGSCV321)-derived peptides had high specificity interaction with erythrocytes and bound to a chymotrypsin and neuraminidase-treatment sensitive receptor. DI-derived peptides appear to be exposed on the protein&rsquo, s surface and contain predicted B- and T-cell epitopes. These findings provide data (for the first-time) concerning B. bovis AMA-1 functional subunits which are important for establishing receptor-ligand interactions which could be used in synthetic vaccine development.

Summary Background Pain is an important and detrimental feature of systemic sclerosis but is often overlooked or deprioritised in research and clinical care. Raynaud's phenomenon, arthritis, and cutaneous ulcers are among the commonly reported disease manifestations of systemic sclerosis that could be associated with pain. We aimed to assess levels of pain intensity and interference and to evaluate disease factors associated with pain intensity and interference. Methods In this multicentre cross-sectional study, participants from the Scleroderma Patient-centered Intervention Network cohort who completed pain intensity and interference measures (Patient Reported Outcomes Information System-29 profile, version 2·0) as part of baseline assessments were included. Patients were recruited from 46 centres in Australia, Canada, France, Mexico, Spain, the UK, and the USA between April 15, 2014, and Jan 7, 2020. Eligible patients included those aged 18 years or older who met the criteria for systemic sclerosis devised by the American College of Rheumatology and the European League Against Rheumatism. Associations of pain intensity and pain interference with systemic sclerosis-related variables and overlap syndromes, controlling for sociodemographic variables, were assessed with multiple linear regression. Continuous independent variables were standardised. Findings Among 2157 participants with systemic sclerosis (268 [12%] males and 1889 [88%] females), 1870 (87%) reported mild, moderate, or severe pain (defined as ≥1 on a 0 to 10 scale), and 815 (38%) reported moderate or severe pain (defined as ≥5). Moreover, 757 (35%) participants reported moderate or severe pain interference. Greater pain intensity was independently associated with female sex (0·58 points [95% CI 0·26–0·90]), non-White race or ethnicity (0·50 points [0·21–0·79]), fewer years in formal education (0·30 points per SD [0·19–0·41]), country (reference: USA; Canada: 0·29 points [0·01–0·57] and UK: 0·58 points [0·21–0·95]), greater body-mass index (0·35 points per SD [0·24–0·45]); joint contractures (0·67 points [0·39–0·94]), digital ulcers (0·33 points [0·10–0·55]), gastrointestinal involvement (0·66 points [0·33–0·98]), skin involvement (measured using modified Rodnan skin score; 0·22 points per SD [0·10–0·35]), rheumatoid arthritis (0·96 points [0·50–1·43]), and Sjogren's syndrome (0·42 points [0·01–0·83]). Pain interference results were similar. Interpretation Pain is common among people with systemic sclerosis. Controlling for sociodemographic variables, greater pain was associated with multiple systemic sclerosis-related manifestations, including joint contractures, digital ulcers, gastrointestinal involvement, skin involvement, and the presence of overlap syndromes. Health-care providers should work with patients to address pain, including identifying and addressing systemic sclerosis manifestations associated with their pain, and supporting behavioural approaches to minimise impact on function and quality of life. Funding Canadian Institutes of Health Research, Arthritis Society, The Lady Davis Institute for Medical Research of the Jewish General Hospital, Jewish General Hospital Foundation, McGill University, Scleroderma Society of Ontario, Scleroderma Canada, Sclerodermie Quebec, Scleroderma Manitoba, Scleroderma Atlantic, Scleroderma Association of BC, Scleroderma SASK, Scleroderma Australia, Scleroderma New South Wales, Scleroderma Victoria, and Scleroderma Queensland.

Bovine babesiosis, caused by Babesia bovis and B. bigemina, is a major tick-borne disease of cattle with global economic impact. The disease can be prevented using integrated control measures including attenuated Babesia vaccines, babesicidal drugs, and tick control approaches. Vaccination of cattle with the Rhipicephalus microplus Bm86-based recombinant vaccine reduces the fitness of R. microplus and R. annulatus, but several booster inoculations are required to maintain protection. Herein, we generated a stable transfected strain of B. bovis expressing an enhanced GFP (eGFP) and a chimeric version of Bm86 (B. bovis/Bm86/eGFP). The eGFP was expressed in the parasite cytoplasm, whereas Bm86 was displayed on the surface of merozoites. Three splenectomized calves experimentally infected with B. bovis/Bm86/eGFP showed mild signs of acute disease and developed long-lasting antibody responses to B. bovis and native Bm86. No evidence of sequestration of parasites in the cerebral capillaries was found upon postmortem analysis, confirming attenuation of the strain. This is the first report of transfected B. bovis expressing the tick antigen Bm86 on the merozoite surface that elicits an antibody response to native Bm86. These results represent a proof of concept for a novel live, attenuated, tagged dual-vaccine approach to attempt simultaneous control of babesiosis and tick infestation.

Background Patients' information needs may differ from what their care providers may perceive to be the patients' needs. This discordance needs to be recognized and addressed. Objective We conducted a qualitative study to explore the perceptions of patients with selected musculoskeletal disorders and those of rheumatologists, on their preferred strategies for delivery of disease management information. Methods Fifty-two patients diagnosed with either rheumatoid arthritis, knee osteoarthritis, or osteoporosis took part in 6 focus groups and 18 individual semistructured interviews. In addition, 11 rheumatologists participated in 2 focus groups and 4 semistructured individual interviews. Data were explored by thematic content analysis. Perceived preferences were identified and compared between patients and rheumatologists regarding (a) media, (b) setting, (c) messengers, and (d) key message content. Results Patients' preferred media for disease management information were electronic (television and videos delivered as digital optical discs or the Internet), group instruction, and printed material. Patients preferred the information to be delivered in the setting of their homes, doctor's offices, or clinic waiting areas by the rheumatologists and patients with disease experience, addressing healthy lifestyle changes, medication adherence, and consequences of noncompliance. For rheumatologists, the perceived preference for information delivery was through printed material (brochures, booklets, and pamphlets) delivered in waiting areas by nurses and physicians, addressing nature of the disease, complications, and treatment adverse effects. Conclusions Provider perspectives on strategies for education may differ from those of patients. Our findings highlight the need for considering different stakeholder perspectives in designing educational tools and decision support materials for patients with chronic diseases. Take-home message Rheumatologists' preferences on strategies for education (mode of delivery, delivery setting, messengers, and topics) differ from those of patients. For example, patients want to learn about lifestyle changes and consequences of compliance versus noncompliance, whereas rheumatologists considered more important for patients to understand their disease, treatment adverse effects, and consequences of noncompliance.

Bovine babesiosis, caused by Babesia bovis and B. bigemina, is a major tick-borne disease of cattle with global economic impact. The disease can be prevented using integrated control measures including attenuated Babesia vaccines, babesicidal drugs, and tick control approaches. Vaccination of cattle with the Rhipicephalus microplus Bm86-based recombinant vaccine reduces the fitness of R. microplus and R. annulatus, but several booster inoculations are required to maintain protection. Herein, we generated a stable transfected strain of B. bovis expressing an enhanced GFP (eGFP) and a chimeric version of Bm86 (B. bovis/Bm86/eGFP). The eGFP was expressed in the parasite cytoplasm, whereas Bm86 was displayed on the surface of merozoites. Three splenectomized calves experimentally infected with B. bovis/Bm86/eGFP showed mild signs of acute disease and developed long-lasting antibody responses to B. bovis and native Bm86. No evidence of sequestration of parasites in the cerebral capillaries was found upon postmortem analysis, confirming attenuation of the strain. This is the first report of transfected B. bovis expressing the tick antigen Bm86 on the merozoite surface that elicits an antibody response to native Bm86. These results represent a proof of concept for a novel live, attenuated, tagged dual-vaccine approach to attempt simultaneous control of babesiosis and tick infestation.

Introduction: Post-operative right ventricular failure (RV failure) is the single largest contributor to short-term mortality in patients with left ventricular assist devices (LVAD); yet predicting which patient is at risk of developing this complication in the pre-operative setting has remained beyond the abilities of experts in the field. We hypothesized that deep artificial intelligence (AI) driven characterization of subtle pre-operative myocardial motion features, could predict post-operative RV failure in LVAD patients. Methods: We developed a novel echocardiography AI system using an improved dense trajectory algorithm that tracks motion vectors in an unsupervised fashion, and a 3-dimensional convolutional neural network that tracks spatiotemporal features from videos. We used pre-operative ECHO videos from a 536 patient multicenter echocardiographic and clinical dataset, and via a standard 10-fold cross validation, trained and validated the AI system to predict severe or higher grades of post-operative RV failure at the time of index hospitalization. Finally, we independently benchmarked our AI system against clinicians equipped with contemporary clinical risk scores to predict post-operative RV failure (Penn and CRITT score) and manually derived echocardiographic metrics of RV function. Results: 173 (32%) patients were adjudicated to have severe post-operative RV failure. The area under the receiver operator characteristic curve (AUC ROC) for the AI system was 0.86 (95% CI 0.824-0.896). The performance of our AI system exceeded that of both the best performing clinical risk score and manually derived echocardiographic metric by a significant margin (ΔAUC +0.30, 95% CI 0.27 - 0.33 and ΔAUC +0.24, 95% CI 0.21 - 0.27; both p &lt 0.0001). Conclusions: A novel ECHO AI system trained and validated on a multicenter dataset outperformed clinical experts equipped with both contemporary risk scores and manually calculated echocardiographic metrics.

Background: The most common apicomplexan parasites causing bovine babesiosis are Babesia bovis and B. bigemina, while B. caballi and Theileria equi are responsible for equine piroplasmosis. Treatment and control of these diseases are usually achieved using potentially toxic chemotherapeutics, such as imidocarb diproprionate, but drug-resistant parasites are emerging, and alternative effective and safer drugs are needed. Endochin-like quinolones (ELQ)-300 and ELQ-316 proved safe and efficacious against related apicomplexans, such as Plasmodium spp., and ELQ-316 was also effective against B. microti, without showing toxicity in mammals.Methods: Inhibitory effects of ELQ-300 and ELQ-316 were assessed on the growth of cultured B. bovis, B. bigemina, B. caballi and T. equi. Percentage of parasitized erythrocytes was measured by flow cytometry. Effect of the ELQ drugs on the viability of horse and bovine peripheral blood mononuclear cells (PBMC) was assessed by monitoring cell metabolic activity using a colorimetric assay.Results: We calculated IC50 ranging from 0.04 to 0.37 nM for ELQ-300, and from 0.002 to 0.1 nM for ELQ-316 at 72 h among all cultured parasites tested. None of the parasites tested were able to replicate in cultures in the presence of the ELQ-300 and ELQ-316 at IC100, which range from 1.3 to 5.7 nM for ELQ-300 and from 1.0 to 6.0 nM for ELQ-316 at 72 h. Neither ELQ-300 nor ELQ-316 altered the viability of equine and bovine PBMC at their IC100 in in vitro testing. Conclusions: ELQ-300 and ELQ-316 showed significant inhibitory activity on the main parasites responsible for bovine babesiosis and equine piroplasmosis at doses that are tolerable to host cells. These ELQ drugs may be viable candidates for developing alternative protocols for the treatment of bovine babesiosis and equine piroplasmosis.

Background Immune checkpoint inhibitors (ICIs) have resulted in unprecedented advances in the treatment of cancer. By disinhibiting the immune system, they enhance anti-tumor immunity, but provoke off-target inflammatory and immune-related adverse events (irAEs) which can seriously impact morbidity and mortality. The exact immunobiology of irAEs is not completely understood, but may involve specific immune pathways. To date, there is no validated biomarker test to predict the development of irAEs in patients treated with ICIs. Methods To identify possible biomarkers of irAEs, we performed in-depth proteomic profiling of blood samples obtained from cancer patients receiving ICIs. The plasmas were processed with Hu-14 immuno-depletion column (Agilent Technologies) and the samples were labeled with TMT (Thermo Scientific). The proteins were next pre-fractionated with HPLC, trypsin digested and analyzed by nanoAQUITY LC coupled Synapt G2-Si ion-mobility mass spectrometry (WATERS). Results A total of 12 patients were enrolled in the study; all were receiving anti-programmed cell death-1 (PD-1) agents. Cancer types included melanoma (n=9), renal cell carcinoma (n=2), and non-small cell lung cancer (n=1). Eight patients had irAEs with active toxicity symptoms at blood draw (4 with pneumonitis-irAE and 4 with arthritis-irAE); 6 of those patients were receiving corticosteroids (ranging from 5 to 60 mg/d), and 1 was receiving tocilizumab (an anti-IL-6 receptor antibody). Four patients who completed a minimum of one year of anti-PD1 treatments without irAEs were enrolled as control group. Median time from ICI initiation until blood draw was 16 months (range, 4–31) among patients with irAEs and 23 months (range, 17–28) among controls.We identified 925 protein gene products from 2.5 million mass spectra that can cover 107 dynamic range of plasma proteins. Among them, 19 proteins showed statistically significant differences between patients with and without irAEs (P Conclusions In-depth plasma proteome analysis identified possible biomarkers of adverse events modulated by ICI treatment. We plan a prospective validation cohort study of melanoma patients initiating treatment with ICIs to further evaluate the potential clinical utility of the identified biomarkers and their association with immune toxicity, and tumor response to ICI therapy. Ethics Approval The study was approved by The Institutional Review Board at The University of Texas MD Anderson Cancer Center, approval number PA16-0928 Consent Written informed consent was obtained from all patients who agreed to participate in the study

Babesia bovis is a hemoprotozoan parasite of cattle that has a complex life cycle within vertebrate and invertebrate hosts. In the mammalian host, B. bovis undergoes asexual reproduction while in the tick midgut, gametes are induced, fuse, and form zygotes. The zygote infects tick gut epithelial cells and transform into kinetes that are released into the hemolymph and invade other tick tissues such as the ovaries, resulting in transovarial transmission to tick offspring. To compare gene regulation between different B. bovis life stages, we collected parasites infecting bovine erythrocytes and tick hemolymph. Total RNA samples were isolated, and multiplexed libraries sequenced using paired-end 100 cycle reads of a HiSeq 2500. The data was normalized using the TMM method and analysed for significant differential expression using the generalized linear model likelihood ratio test (GLM LRT) in edgeR. To validate our datasets, ten genes were selected using NormFinder. Genes that had no significant fold change between the blood and tick stages in the RNA-Seq datasets were tested by quantitative PCR to determine their suitability as "housekeeping" genes. The normalized RNA-Seq data revealed genes upregulated during infection of the mammalian host or tick vector and six upregulated genes were validated by quantitative PCR. These datasets can help identify useful targets for controlling bovine babesiosis.

Background Autoimmunity is associated with increased risk of malignancy. However, patients with pre-existing autoimmune diseases (AIDs) were excluded from immune checkpoint inhibitor (ICI) trials as these agents can cause immune-related adverse events (irAEs). Data are limited on the safety and efficacy of combination immunotherapy in this at-risk population. Methods We conducted a multi-center retrospective study to evaluate the safety and efficacy of ICI therapy in patients with pre-existing AID treated at NYU and at MD Anderson Cancer Center. Primary endpoints were occurrence of irAEs and AID flares. Secondary endpoints were time to treatment failure (TTF) and overall survival (OS). Results Of 121 patients identified from our institutional databases, 53% received single-agent anti-PD-1 therapy, and 47% received ICI combination. Over half of malignancies were lung cancer (34%) and melanoma (20%). Preexisting AIDs included: rheumatologic (58%), gastrointestinal (12%), endocrine (16%) and neurologic (4%). Overall, 94% had asymptomatic AID, and 21% were receiving systemic immunomodulatory drugs at ICI initiation. Median duration of follow up after ICI initiation was 9 (0.4–41.9) months in patients receiving ICI combination and 8 (0.2–47.3) months in patients receiving anti-PD-1 monotherapy. Combination therapy was associated with higher rates of irAEs compared with anti-PD-1 monotherapy (56% versus 28%). Grade 3/4 irAEs were equivalent in both groups: combination (38%) and anti-PD-1 group (39%). Treatment related deaths were not observed in any group. AID flares occurred in 36% of the anti-PD-1 group versus 29% of combination group. Adverse events (irAEs and/or flares) required systemic immunomodulatory therapies more frequently in the combination group (84%) versus the anti-PD-1 group (59%), and permanent ICI discontinuation was reported in 19% of patients in the combination group versus 11% in the anti-PD-1 group. Tumor progression was observed in 49% of patients on combination ICI and TTF was 14.5 months (95% CI 0.000–31.5), while progression was observed in 64% of patients on anti-PD-1 monotherapy and TTF was 6.4 months (95% CI 4.01–8.9) (p=0.019). Median OS in the combination therapy group was not reached whereas it was 27.3 months in the anti-PD-1 monotherapy group. Conclusions Our novel findings suggest that high rates of adverse events were observed in patients with pre-existing AIDs treated with ICI combination therapy. However, they were manageable and rarely required permanent ICI discontinuation. Taken together, these data show that ICIs should be offered, albeit with caution in patients with AIDs, to achieve durable cancer remission. Prospective clinical data are needed to guide these complex decisions. Ethics Approval The study was approved by NYU Langone’s Ethics Board, approval number i18-01657 and MD Anderson’s Ethics Board, approval number PA19-0089

Introduction Microinvasive diseases of the cervix are conventionally treated with radical hysterectomy after confirmation of invasion depth and lymphovascular invasion in excisional biopsy. In some cases conization could be the definitive treatment in patients who wish to preserve fertility, it is essential to know the state of the section margins. The objective of this presentation is to demonstrate the risk of residual disease with cone positive margins. Methods Retrospective review of patients with microinvasive cervical cancer between December 2014 and February 2020. The contact of the lesion directly with the edge of the cone was taken as positive margin, we compared results of cone biopsies and hysterectomies. Results The study included 47 patients (median age 42.9). Diagnoses of microinvasive cervical cancer: insitu adenocarcinoma, (FIGO IA1 and IA2), histological: adenocarcinoma and squamous. 42 patients met the inclusion criteria (cone biopsy and hysterectomy). 30 (71%) with squamous cancer and 12 (29%) with adenocarcinoma. In 30 patients with squamous types, 14 cones had a positive margins, from which 10 (71%) surgical specimens resulted with residual disease, and 16 cones with negative margins, from which 1 (6.25%) specimen resulted with residual disease. In 12 patients with adenocarcinoma, there were 8 cones with positive margins, 6 (75%) surgical pieces were found with residual disease; 4 cones with negative margins, 3 (75%) surgical pieces were found with residual disease. Conclusions Patients with positive margins regardless of histologic type are at increased risk for residual disease and is clearly more risky in adenocarcinomas due to multifocality.

Introduction The objective of this presentation is to evaluate the reason for referral of patients with a diagnosis of cervical adenocarcinoma treated in the Cervical Pathology Unit of the Hospital San Borja Arriaran. Material and Method Retrospective analysis of records of patients treated for cervical adenocarcinoma, between the years 2008 to January 2019. Results Of 5353 positive cytologies studied between January 2008 and January 2019, a total of 105 adenocarcinoma were found, with a median age of 47 years (between 20 to 85 years). Out of these 105 patients: 15% were referred due to clinical suspicion, of which 5 patients (30%) had a visible tumor; and 89 patients (85%) were referred due to altered cytology, corresponding to 2% of the total. Analyzing the cytology that originated the referral of these 89 patients with abnormal results, 41.5% (37) had a PAP suggestive of adenocarcinoma, 6.7% (6) were suggestive of squamous carcinoma, 28% (25) had a PAP NIE II-III, and 23.5% (21) had an atypical in one of its three varieties [double non-specific atypical: 9.5% (2), glandular atypical: 47.6% (10) and atypical that does not exclude high-grade injury 42.8% (9)]. Conclusions Cervical adenocarcinoma is an emerging entity and it is difficult to diagnose. Screening programs do not necessarily decrease its incidence, on the contrary, they have become the main source of referral for cervical adenocarcinoma. In our review, it corresponded to 85% of the cases. Despite the difficulty of investigating an adenocarcinoma through PAP, this was the main cause of referral. The referral for clinical suspicion corresponded to 15%.

Background Management of certain immune mediated adverse events (irAEs) can be challenging and may require prolonged/chronic immune suppression with corticosteroids or other immunosuppressant which could compromise and even reverse the efficacy of immune checkpoint inhibitors (ICI). While the exact immunobiology of irAEs is not fully understood there is enough evidence that IL-6 induced Th-17 that may play critical role in the pathogenesis. Herein, we describe our clinical experience using interleukin-6 receptor (IL-6R) blockade in management of irAEs in melanoma patients. Methods We searched MD Anderson databases to identify cancer patients who had received ICIs between January 2004 and March 2020. Of 11,391 ICI-treated patients, 21 patients with melanoma who received IL-6R blockade after ICI infusion were identified and their medical records were reviewed. Results Median age was 61 years (41–82), 52% were females, 90% received anti-programmed cell death-1 antibodies. Fourteen patients (67%) had de novo onset irAEs (11 had arthritis, and 1 each with polymyalgia rheumatica, oral mucositis, and CNS vasculitis), and 7 patients (33%) had flare of their pre-existing autoimmune diseases (5 had had rheumatoid arthritis, and 1 each with myasthenia gravis and Crohn’s disease). Median time from ICI initiation to irAEs was 91 days (range, 1–496) and to initiation of IL-6R blockade was 6.6 months (range, 0.6–24.3). Median number of IL-6R blockade was 12 (range, 1–35), and 16 patients (76%) were concomitantly receiving corticosteroids of median dose of 10 mg (range, 5–20 mg). Of the 21 patients, irAEs improved in 14 (67%) (95% CI: 46%-87%). Of 13 evaluable patients with arthritis, 11 (85%) achieved remission or minimal disease activity as defined by the clinical disease activity index. Median time from initiation of IL-6R blockade till improvement of irAEs was 2.9 months (range, 1.5–36.9). Nineteen patients tolerated well IL-6R blockade, while two patients stopped treatment due to abdominal pain and sinus tachycardia. The median CRP levels at irAEs was 84 mg/L (0.6–187) and decreased to 1.9 mg/L (0.56–12) at 10 weeks after initiation of IL-6R blockade (P=0.02). Of the 17 evaluable patients, the overall tumor response rate by RECIST-1.1 criteria was similar before and after IL-6R blockade initiation (41% vs. 53%). Conclusions Our data demonstrated that IL-6R blockade could be an effective therapy for irAEs management without dampening the efficacy of ICIs. Prospective clinical trials with longitudinal blood, tumor, and inflamed tissue biopsies are planned to accurately validate these findings and better study the immunobiology of irAEs. Ethics Approval The study was approved by The University of Texas MD Anderson Cancer Center intuition’s Ethics Board, approval number PA19-0089

Hospital San Borja Arriaran, Chile Upon the publication of the LACC study, increasing evidence has emerged regarding the superiority of open versus minimally invasive surgery (MIS) in the treatment of cervical cancer. Introduction to report and compare the surgical results among woman undergoing surgery for cervical cancer with open versus MIS in San Borja Arriaran Hospital. Methods retrospective analysis, involving patients with stage IA1 (lymphovascular invasion), IA2, or IB1 cervical cancer undergoing open or MIS between 2015 to 2019. Data obtained from oncology committee registry. Analysis of demographic, histological and surgical variables. Data analyzed using the Chi2, Student’s t, and Fischer test with a 95% confidence interval and a P value of Results 42 patients analyzed, 20 in the open surgery and 22 MIS group. The mean age (46.2 ± 2.9 v/s 46.9 ± 2.37; P = 0.49). Surgical result, the number of nodes obtained in open surgery was significantly higher than in the MIS technique (27.4 ± 2.6 v/s 20.3 ± 2.04; P = 0.038), with no differences in the number of positive nodes, compromise of surgical margins, parametrial compromise, tumor size or in lymphovascular invasion. There was no significant difference in adjuvance treatment. Due to the short follow-up period in the open surgery group, no recurrence or survival analysis was performed. Conclusion Despite the small sample size, a significant difference in known variables of the oncological result, such as the number of lymph nodes obtained. This provides a first approach regarding oncological outcome. Survival analysis will be evaluated in future analysis.

Background The most common apicomplexan parasites causing bovine babesiosis are Babesia bovis and B. bigemina, while B. caballi and Theileria equi are responsible for equine piroplasmosis. Treatment and control of these diseases are usually achieved using potentially toxic chemotherapeutics, such as imidocarb diproprionate, but drug-resistant parasites are emerging, and alternative effective and safer drugs are needed. The endochin-like quinolones (ELQ)-300 and ELQ-316 have been proven to be safe and efficacious against related apicomplexans, such as Plasmodium spp., with ELQ-316 also being effective against Babesia microti, without showing toxicity in mammals. Methods The inhibitory effects of ELQ-300 and ELQ-316 were assessed on the growth of cultured B. bovis, B. bigemina, B. caballi and T. equi. The percentage of parasitized erythrocytes was measured by flow cytometry, and the effect of the ELQ compounds on the viability of horse and bovine peripheral blood mononuclear cells (PBMC) was assessed by monitoring cell metabolic activity using a colorimetric assay. Results We calculated the half maximal inhibitory concentration (IC50) at 72 h, which ranged from 0.04 to 0.37 nM for ELQ-300, and from 0.002 to 0.1 nM for ELQ-316 among all cultured parasites tested at 72 h. None of the parasites tested were able to replicate in cultures in the presence of ELQ-300 and ELQ-316 at the maximal inhibitory concentration (IC100), which ranged from 1.3 to 5.7 nM for ELQ-300 and from 1.0 to 6.0 nM for ELQ-316 at 72 h. Neither ELQ-300 nor ELQ-316 altered the viability of equine and bovine PBMC at their IC100 in in vitro testing. Conclusions The compounds ELQ-300 and ELQ-316 showed significant inhibitory activity on the main parasites responsible for bovine babesiosis and equine piroplasmosis at doses that are tolerable to host cells. These ELQ drugs may be viable candidates for developing alternative protocols for the treatment of bovine babesiosis and equine piroplasmosis. Graphical Abstract

Background: Thrombospondin-related anonymous protein (TRAP) has been described as a potential vaccine candidate for several diseases caused by apicomplexan parasites. However, this protein and members of this family have not yet been characterized in Babesia bigemina, one of the most prevalent species causing bovine babesiosis. Methods: The 3186-bp Babesia bigemina TRAP-1 (BbiTRAP-1) gene was identified by a bioinformatics search using the B. bovis TRAP-1 sequence. Members of the TRAP and TRAP-related protein families (TRP) were identified in Babesia and Theileria through a search of the TSP-1 adhesive domain, which is the hallmark motif in both proteins. Structural modeling and phylogenetic analysis were performed with the identified TRAP proteins. A truncated recombinant BbiTRAP-1 that migrates at approximately 107 kDa and specific antisera were produced and used in Western blot analysis and indirect fluorescent antibody tests (IFAT). B-cell epitopes with neutralizing activity in BbiTRAP-1 were defined by enzyme-linked immunosorbent assays (ELISA) and invasion assays. Results: Three members of the TRAP family of proteins were identified in B. bigemina (BbiTRAP-1 to -3). All are type 1 transmembrane proteins containing the von Willebrand factor A (vWFA), thrombospondin type 1 (TSP-1), and cytoplasmic C-terminus domains, as well as transmembrane regions. The BbiTRAP-1 predicted structure also contains a metal ion-dependent adhesion site for interaction with the host cell. The TRP family in Babesia and Theileria species contains the canonical TSP-1 domain but lacks the vWFA domain and together with TRAP define a novel gene superfamily. A variable number of tandem repeat units are present in BbiTRAP-1 and could be used for strain genotyping. Western blot and IFAT analysis confirmed the expression of BbiTRAP-1 by blood-stage parasites. Partial recognition by a panel of sera from B. bigemina-infected cattle in ELISAs using truncated BbiTRAP-1 suggests that this protein is not an immunodominant antigen. Additionally, bovine anti-recombinant BbiTRAP-1 antibodies were found to be capable of neutralizing merozoite invasion in vitro. Conclusions: We have identified the TRAP and TRP gene families in several Babesia and Theileria species and characterized BbiTRAP-1 as a novel antigen of B. bigemina. The functional relevance and presence of neutralization-sensitive B-cell epitopes suggest that BbiTRAP-1 could be included in tests for future vaccine candidates against B. bigemina. Fil: Montenegro, Valeria Noely. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación En Ciencias Veterinarias y Agronómicas. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Agrobiotecnología y Biología Molecular; Argentina Fil: Paoletta, Martina Soledad. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación En Ciencias Veterinarias y Agronómicas. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Agrobiotecnología y Biología Molecular; Argentina Fil: Jaramillo Ortiz, José Manuel. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación En Ciencias Veterinarias y Agronómicas. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Agrobiotecnología y Biología Molecular; Argentina Fil: Suarez, Carlos Esteban. Washington State University; Estados Unidos Fil: Wilkowsky, Silvina Elizabeth. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación En Ciencias Veterinarias y Agronómicas. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Agrobiotecnología y Biología Molecular; Argentina

Assess the association between digoxin use and gastrointestinal bleeding (GIB) in a multicenter continuous flow left ventricular assist device (LVAD) cohort.Patients implanted with continuous flow LVADs with data on GIB and digoxin use from two centers were included in the analysis (n = 649). GIB events were captured up to 2 years of follow-up. Digoxin use was defined as digoxin prescribed at discharge or within the first 3 months after LVAD implantation. A negative binomial regression model was performed to determine the association between digoxin use and number of GIB events over the follow-up period.Mean age of the cohort was 57 years (±14) and 45% (293/649) were bridge to transplant (BTT). Digoxin was prescribed in 33% of patients. Digoxin use was associated with an unadjusted 32% reduction in the incidence of rate of all cause GIB (IRR 0.68, 95% CI 0.46-0.99, p = 0.049). After adjusting for age, sex, Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile, renal function, and implanting center there was still a 34% reduction in the incidence rate (IRR 0.67, 95% CI 0.45-0.99, p = 0.048). When limiting the analysis to those with likely arteriovenous malformation associated GIB, the association strengthened (unadjusted: IRR 0.48, 95 % CI 0.26-0.89, p = 0.02, adjusted: IRR 0.47, 95 % CI 0.25-0.9, p = 0.022).In this multicenter study, inclusive of contemporary devices, digoxin use was associated with reduced GIB events. Prospective data will be required to confirm this association.

Introduction No studies have examined factors associated with fear in any group of people vulnerable during COVID-19 due to pre-existing medical conditions. Objective To investigate factors associated with fear of consequences of COVID-19 among people living with a pre-existing medical condition, the autoimmune disease systemic sclerosis (SSc; scleroderma), including country. Methods Pre-COVID-19 data from the Scleroderma Patient-centered Intervention Network (SPIN) Cohort were linked to COVID-19 data collected in April 2020. Multivariable linear regression was used to assess factors associated with continuous scores of the 10-item COVID-19 Fears Questionnaire for Chronic Medical Conditions, controlling for pre-COVID-19 anxiety symptoms. Results Compared to France (N = 156), COVID-19 Fear scores among participants from the United Kingdom (N = 50) were 0.12 SD (95% CI 0.03 to 0.21) higher; scores for Canada (N = 97) and the United States (N = 128) were higher, but not statistically significant. Greater interference of breathing problems was associated with higher fears due to COVID-19 (Standardized regression coefficient = 0.12, 95% CI 0.01 to 0.23). Participants with higher financial resources adequacy scores had lower COVID-19 Fear scores (Standardized coefficient = −0.18, 95% CI −0.28 to −0.09). Conclusions Fears due to COVID-19 were associated with clinical and functional vulnerabilities in this chronically ill population. This suggests that interventions may benefit from addressing specific clinical issues that apply to specific populations. Financial resources, health policies and political influences may also be important. The needs of people living with chronic illness during a pandemic may differ depending on the social and political context in which they live., Highlights • People with chronic diseases may experience high levels of fear due to COVID-19. • We examined factors associated with fears due to COVID-19 in an at-risk population. • We used the validated COVID-19 Fears Questionnaire for Chronic Medical Conditions. • Fears due to COVID-19 among people with SSc differed substantially by country. • Interference of breathing problems and financial adequacy were related to fears.

Support for obtaining the geochemical data in this paper was provided by funds to E.J.C. provided by the Jackson School of Geosciences at The University of Texas at Austin. This work was also funded by the Scottish Universities Environmental Research Centre. SIMS facilities at Heidelberg University acknowledge support through DFG Scientific Instrumentation and Information Technology programme. The Ludlow Bone Bed (Welsh Basin) is a critical stratigraphic horizon and contains a rich assemblage of fish scales. Units above provide insights into the early evolution of animal and plant life. The bed has not yet been radioisotopically dated. Here, we report 207 secondary ion mass spectrometry (SIMS) ages from 102 zircon (ZrSiO4 ) grains from the Ludlow (n = 2) and stratigraphically higher Downton (n = 1) bone beds. SIMS ages are middle Ordovician (471.6 ± 20.7 Ma) to late Devonian (375.7 ± 14.6 Ma,238 U–206 Pb, ±1σ analytical uncertainty). Cathodoluminescence images show that the youngest ages appear affected by alteration. Chemical abrasion isotope dilution thermal ionization mass spectrometry (CA-ID-TIMS) U–Pb geochronology was utilized to improve precision. Detrital zircon grains from Downton yield 424.91 ± 0.34/0.42/0.63 Ma and from Ludlow 424.85 ± 0.32/0.41/0.62 Ma (n = 5 each,238 U–206 Pb, ±2σ analytical, tracer or systematic uncertainty). These ages provide a maximum deposition age. Results overlap the basal Přídolí age (423.0 ± 2.3 Ma) in its stratotype (Požáry Section, Reporyje, Prague, Czech Republic). The Ludlow Bone Bed marks the base of the local Downton Group, which has previously been correlated with the base of the Přídolí Series. The CA-ID-TIMS ages are older than those for other land arthropod-bearing sediments, such as the Cowie Harbour Fish Bed and Rhynie Chert. Publisher PDF

Bone health education publicly available through the Internet, if evidence-based and unbiased, could help patients deal with issues such as decision-making, maintaining healthy lifestyles, using medications correctly, and improving their communication with health professionals.We performed an environmental scan and quality assessment of the currently available osteoporosis and bone health patient education information on the World Wide Web. The sample websites were identified by using three separate search tools: Google Advanced, Bing, and Ask.com . Two independent investigators collected data and appraised the quality of selected websites.We identified 48 websites. Most websites were focused on risks factors of osteoporosis, preventive measures, screening recommendations, and topics to discuss with the physician. All websites provided adequate information describing treatment options; however, only 36% had information addressing duration of treatment, what happens when treatment stops, and the benefits and risks of various treatments. A total of 55% of the websites had their content updated to 2019 and 68% cited their sources of information to support their content. Reading levels ranged from 7.5 to 15.2 (higher than the recommended 6-grade level).Websites with information about bone health and osteoporosis commonly present information about initial treatment choices, but most fail to address risk-benefit issues, and common barriers than can occur throughout the course of the disease. In addition, many websites did not update their content, did not cite their sources of information, or were written at a 9-grade level or above (rendering them unsuitable for low-literacy populations).

Phenomenon: Mental health problems among medical students are a worrisome issue; recent studies have shown that one-third may be suffering major depressive disorder and one out of ten had suicidal ...

Background Underreporting of harms in randomized controlled trials (RCTs) may lead to incomplete or erroneous assessments of the perceived benefit-to-harm profile of an intervention. To compare benefit with harm in clinical practice and future clinical studies, adverse event (AE) profiles including severity need to be understood. Even though patients report harm symptoms earlier and more frequently than clinicians, rheumatology RCTs currently do not provide a reporting framework from the patient's perspective regarding harms. Our objective for this meta-research project was to identify AEs in order to determine harm clusters and whether these could be self-reported by patients. Our other objective was to examine reported severity grading of the reported harms. Methods We considered primary publications of RCTs eligible if they were published between 2008 and 2018 evaluating pharmacological interventions in patients with a rheumatic or musculoskeletal condition and if they were included in Cochrane reviews. We extracted data on harms such as reported AE terms together with severity (if described), and categorized AE- and severity-terms into overall groups. We deemed all AEs with felt components appropriate for patient self-reporting. Results The literature search identified 187 possible Cochrane reviews, of which 94 were eligible for evaluation, comprising 1,297 articles on individual RCTs. Of these RCTs, 93 pharmacological trials met our inclusion criteria (including 31,023 patients; representing 20,844 accumulated patient years), which reported a total of 21,498 AEs, corresponding to 693 unique reported terms for AEs. We further sub-categorized these terms into 280 harm clusters (i.e., themes). AEs appropriate for patient self-reporting accounted for 58% of the AEs reported. Among the reported AEs, we identified medical terms for all of the 117 harm clusters appropriate for patient reporting and lay language terms for 86%. We intended to include severity grades of the reported AEs, but there was no evidence for systematic reporting of clinician- or patient-reported severity in the primary articles of the 93 trials. However, we identified 33 terms suggesting severity, but severity grading was discernible in only 9%, precluding a breakdown by severity in this systematic review. Conclusions Our results support the need for a standardized framework for patients’ reporting of harms in rheumatology trials. Reporting of AEs with severity should be included in future reporting of harms, both from the patients’ and investigators’ perspectives. Registration PROSPERO: CRD42018108393

Management of rheumatoid arthritis (RA) in patients with cancer is complex and requires a multidisciplinary approach. A few studies have examined the risk for recurrence in patients with RA receiving disease-modifying antirheumatic drugs, primarily tumor necrosis factor-α inhibitors. Although these agents seem to be safe in patients with a history of cancer and no evidence of disease, additional information is needed to determine their potential effects in patients with RA and active cancer. Patients with RA undergoing cancer therapy, including surgery, radiation, chemotherapy, and immunotherapy, need to be carefully monitored because they are at increased risk for adverse events.

Bovine babesiosis is a tick-borne disease caused by apicomplexan parasites of the Babesia genus that represents a major constraint to livestock production worldwide. Currently available vaccines are based on live parasites which have archetypal limitations. Our goal is to identify candidate antigens so that new and effective vaccines against Babesia may be developed. The perforin-like protein (PLP) family has been identified as a key player in cell traversal and egress in related apicomplexans and it was also identified in Babesia, but its function in this parasite remains unknown. The aim of this work was to define the PLP family in Babesia and functionally characterize PLP1, a representative member of the family in Babesia bovis. Bioinformatic analyses demonstrate a variable number of plp genes (four to eight) in the genomes of six different Babesia spp. and conservation of the family members at the secondary and tertiary structure levels. We demonstrate here that Babesia PLPs contain the critical domains present in other apicomplexan PLPs to display the lytic capacity. We then focused on the functional characterization of PLP1 of B. bovis, both in vitro and in vivo. PLP1 is expressed and exposed to the host immune system during infection and has high hemolytic capacity under a wide range of conditions in vitro. A B. bovis plp1 knockout line displayed a decreased growth rate in vitro compared with the wild type strain and a peculiar phenotype consisting of multiple parasites within a single red blood cell, although at low frequency. This phenotype suggests that the lack of PLP1 has a negative impact on the mechanism of egression of the parasite and, therefore, on its capacity to proliferate. It is possible that PLP1 is associated with other proteins in the processes of invasion and egress, which were found to have redundant mechanisms in related apicomplexans. Future work will be focused on unravelling the network of proteins involved in these essential parasite functions.

The effects of biologic disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) and cancer are largely unknown. We examined overall survival (OS) in patients with RA and solid malignancies receiving bDMARDs.We performed a retrospective cohort study of patients with RA and solid malignancies seen at MD Anderson Cancer Center between 2002 and 2014. Cox proportional hazard regression models, stratified by tumor type and stage, were fit evaluating use of bDMARDs as a time fixed and time varying covariate.We identified 431 RA patients with solid malignancies: 111 (26%) received bDMARDs after their cancer diagnosis. Median OS from cancer diagnosis was 16.1 years. Of the patients receiving bDMARDs, most had localized disease, and only 14 (13%) had advanced cancer. In the stratified Cox models no statistically significant differences were observed between patients who received tumor necrosis factor inhibitors (TNFi) or patients who received nonTNFi, compared with those who did not receive bDMARDs (hazard ratio (HR), 0.67; 95% confidence interval (CI), 0.31, 1.44; HR, 1.10; 95% CI, 0.26, 4.60 respectively). In breast cancer patients, those receiving TNFi or nonTNFi had a numerically higher but statistically nonsignificant HR compared with those who did not receive bDMARD: HR, 1.40 (95% CI, 0.42, 4.73), and HR, 1.37 (95% CI, 0.22, 8.42) respectively.No significant differences in OS were observed between patients who received bDMARDs and those who did not. Additional data is needed to evaluate other cancer outcomes such as recurrence and progression, and patients with advanced cancer. Key Points •We found no statistically significant differences in OS between patients with RA and concomitant solid malignancies who received bDMARDs and those who did not. •Most patients who received bDMARDs had been diagnosed with early stage cancer •As few patients with advanced cancer received bDMARDs safety for this group cannot be established •No significant differences were observed between TNFi and nonTNFi, but the sample size was small.

OBJECTIVE To determine rates of cervical cancer screening and associated abnormal results in women with systemic lupus erythematosus (SLE). METHODS We identified women with an initial diagnosis of SLE in the MarketScan Commercial Claims and Encounters Database from 2001 to 2014. Cervical cancer screening rates and associated diagnostic claims within 3 years of the initial claim were determined. Multivariable logistic regression was performed to evaluate the association of screening with lupus treatment. A matched logistic regression analysis was conducted to compare screening rates to those in age-matched women without connective tissue disease. RESULTS We included 4,316 women with SLE. Screening rates were higher in women with SLE than in general controls (73.4% versus 58.5%; P < 0.001). Factors associated with decreased screening included recent time (odds ratio [OR] 0.70 [95% confidence interval (95% CI)] 0.55-0.89) (2012-2014 compared to 2001-2005), age ≥61 years (OR 0.27 [95% CI 0.18-0.39]), comorbidity score ≥2 (OR 0.71 [95% CI 0.6-0.83]), corticosteroid use (OR 0.77 [95% CI 0.61-0.97]), and use of immunosuppressants (OR 0.80 [95% CI 0.69-0.94]). Abnormal pathology result claims were more common in women with SLE than in general controls (12.3% versus 9.8%; P < 0.001). CONCLUSION Though with higher rates than the general cohort, over 25% of the patients with SLE were not screened, and screening rates seem to be decreasing over time. Patients with SLE are at higher risk of abnormal cervical screening test results than controls, supporting the need for regular screening.

Background To date, there have not been any epidemiologic studies that have evaluated the association between swimming over a lifetime and knee health. Objective The study aimed to evaluate the relationship of a history of swimming with knee pain, radiographic knee OA (ROA), and symptomatic knee OA (SOA). Design Cross-sectional retrospective study. Setting Four academic centers in the United States. Participants Respondents to the historical physical activity survey within the Osteoarthritis Initiative with knee radiographs and symptom assessments. Methods In this retrospective study nested within the Osteoarthritis Initiative, researchers performed logistic regression with the predictor being swimming over a lifetime and over particular age ranges. Main outcome measurements Person-based definitions of frequent knee pain, ROA, and SOA. Results A total of 2637 participants were included, with a mean age of 64.3 years (SD 8.9), body mass index of 28.4 kg/m2 (SD 4.9), and 44.2% male. Over a lifetime, the adjusted prevalence measures for frequent knee pain, ROA, and SOA for any versus no history of swimming were 36.4% (33.4% - 39.5%) v. 39.9% (37.4% - 42.5%), 54.3% (51.0% - 57.6%) v. 61.1% (58.4% - 63.7%), and 21.9% (19.4% - 24.7%) v. 27.0% (24.7% - 29.4%) respectively. Conclusions This is the first epidemiologic study to indicate that swimming is potentially beneficial toward knee health, particularly when performed earlier in life (before age 35). Future prospective studies are needed to confirm these findings and to better scrutinize the associations in older age groups.

Background Identifying changes in pain score associated with clinically meaningful outcomes is necessary when using self-report measures to assess pain in children. We aimed to determine the changes in pain score associated with a minimum clinically significant difference (MCSD), ideal clinically significant difference (ICSD), and patient-perceived adequate analgesia (PPAA) and to evaluate for differences based on initial pain intensity and patient characteristics. Methods This was a cross-sectional study of children 6 to 17 and 4 to 17 years old who were assessed using the Verbal Numerical Rating Scale (VNRS) and Faces Pain Scale-Revised (FPS-R), respectively. Children qualitatively described any endorsed change in pain score; those who received an analgesic were asked if they wanted additional analgesics to decrease their pain intensity. We used a receiver operating characteristic curve-based methodology to identify changes in pain score associated with "a little less" and "much less" pain (MCSD and ICSD, respectively) and patients declining additional analgesics because of adequate analgesia (PPAA). Results We enrolled 431 children with painful conditions. For the VNRS, raw change and percent reductions in pain scores associated with MCSD, ICSD, and PPAA were 2/10 and 20%, 3/10 and 44%, and 2/10 and 29%, respectively, and for the FPS-R, 2/10 and 33%, 4/10 and 60%, and 4/10 and 40%, respectively. Raw change in pain scores increased with increasing initial pain intensity, but percent reductions remained stable. There were no significant differences based on patient characteristics such as age, sex, and race/ethnicity. Conclusion Our findings provide patient-centered outcomes in children that are suitable for designing trials and are generalizable across patient characteristics.

Objectives Immune checkpoint inhibitors (ICIs) can successfully treat cancer, but their use can be hindered by serious immune-related adverse events. We report six patients receiving ICIs who presented with de novo myositis. Methods We identified patients with myositis who were receiving ICIs between January 2004 and September 2016 at The University of Texas MD Anderson Cancer Center. Results Six patients developed de novo myositis. The mean age was 64.3 years and five patients were male. Cancer types included melanoma, urothelial carcinoma, renal cell carcinoma, and prostate cancer. ICI regimens included single-agent ipilimumab (n = 1), pembrolizumab (n = 1), or atezolizumab (n = 1); nivolumab and ipilimumab (n = 3). The median time to development of de novo myositis from first infusion was 5.4 weeks (range: 2.1–17.1 weeks). All patients with myositis had elevated levels of creatinine kinase, ranging from 514 to 13,710 U/L. Two of them developed rhabdomyolysis, one with concurrent myocarditis. Five patients were treated with 1–2 mg/kg corticosteroids, with variable response rates; one patient received nonsteroidal anti-inflammatory drugs. Two patients with myositis died as a result of cancer progression. Conclusion We found several occurrences of de novo myositis following ICI therapy. These preliminary data suggest that myositis can occur early after onset of ICI therapy with serious adverse outcomes.

Cancer immunotherapies have changed the landscape of cancer treatment during the past few decades. Among them, immune checkpoint inhibitors (ICIs), which target PD-1, PD-L1 and CTLA-4, are increasingly used for certain cancers; however, this increased use has resulted in an increased reports of immune-related adverse events (irAEs). These irAEs are unique and are different to those of traditional cancer therapies, and typically have a delayed onset and prolonged duration. IrAEs can involve any organ or system. These effects are frequently low-grade and are treatable and reversible; however, some adverse effects can be severe and lead to permanent disorders. Management is based primarily on corticosteroids and other immunomodulatory agents, which should be prescribed carefully to reduce the potential for short-term and long-term complications. Thoughtful management of irAEs is important in optimizing quality of life and long-term outcomes.

Rationale & Objective The approved therapeutic indication for immune checkpoint inhibitors (CPIs) are rapidly expanding including treatment in the adjuvant setting, the immune related toxicities associated with CPI can limit the efficacy of these agents. The literature on the nephrotoxicity of CPI is limited. Here, we present cases of biopsy proven acute tubulointerstitial nephritis (ATIN) and glomerulonephritis (GN) induced by CPIs and discuss potential mechanisms of these adverse effects. Study design, setting, & participants We retrospectively reviewed all cancer patients from 2008 to 2018 who were treated with a CPI and subsequently underwent a kidney biopsy at The University of Texas MD Anderson Cancer Center. Results We identified 16 cases diagnosed with advanced solid or hematologic malignancy; 12 patients were male, and the median age was 64 (range 38 to 77 years). The median time to developing acute kidney injury (AKI) from starting CPIs was 14 weeks (range 6–56 weeks). The average time from AKI diagnosis to obtaining renal biopsy was 16 days (range from 1 to 46 days). Fifteen cases occurred post anti-PD-1based therapy. ATIN was the most common pathologic finding on biopsy (14 of 16) and presented in almost all cases as either the major microscopic finding or as a mild form of interstitial inflammation in association with other glomerular pathologies (pauci-immune glomerulonephritis, membranous glomerulonephritis, C3 glomerulonephritis, immunoglobulin A (IgA) nephropathy, or amyloid A (AA) amyloidosis). CPIs were discontinued in 15 out of 16 cases. Steroids and further immunosuppression were used in most cases as indicated for treatment of ATIN and glomerulonephritis (14 of 16), with the majority achieving complete to partial renal recovery. Conclusions Our data demonstrate that CPI related AKI occurs relatively late after CPI therapy. Our biopsy data demonstrate that ATIN is the most common pathological finding; however it can frequently co-occur with other glomerular pathologies, which may require immune suppressive therapy beyond corticosteroids. In the lack of predictive blood or urine biomarker, we recommend obtaining kidney biopsy for CPI related AKI.

The immune checkpoints associated with the CTLA-4 and PD-1 pathways are critical modulators of immune activation. These pathways dampen the immune response by providing brakes on activated T cells, thereby ensuring more uniform and controlled immune reactions and avoiding immune hyper-responsiveness and autoimmunity. Cancer cells often exploit these regulatory controls through a variety of immune subversion mechanisms, which facilitate immune escape and tumor survival. Immune checkpoint inhibitors (ICI) effectively block negative regulatory signals, thereby augmenting immune attack and tumor killing. This process is a double-edged sword in which release of regulatory controls is felt to be responsible for both the therapeutic efficacy of ICI therapy and the driver of immune-related adverse events (IrAEs). These adverse immune reactions are common, typically low-grade and may affect virtually every organ system. In the early clinical trials, lung IrAEs were rarely described. However, with ever-expanding clinical applications and more complex ICI-containing regimens, lung events, in particular, pneumonitis, have become increasingly recognized. ICI-related lung injury is clinically distinct from other types of lung toxicity and may lead to death in advanced stage disease. Thus, knowledge regarding the key characteristics and optimal treatment of lung-IrAEs is critical to good outcomes. This review provides an overview of lung-IrAEs, including risk factors and epidemiology, as well as clinical, radiologic, and histopathologic features of ICI-related lung injury. Management principles for ICI-related lung injury, including current consensus on steroid refractory pneumonitis and the use of other immune modulating agents in this setting are also highlighted.

Nonprofit organizations often exist to serve vulnerable, marginalized, and underrepresented communities. Yet a lack of diversity and inclusion plagues the nonprofit sector. This chapter argues that when instructors engage in more ���critical��� perspectives, students of nonprofit management will not only be able to consider questions of power and privilege within nonprofit organizations, but will also be able to understand the impact of power and privilege imbalances within the communities that they serve. It provides a theoretical framework for critical pedagogies, and offers two exercise that instructors may use to provide examples of the way critical pedagogy can inform nonprofit management education (NME).

Immune checkpoint inhibitors (ICIs) have emerged as the newest pillar of cancer treatment. Immune-mediated toxicities, stemming from increased activity within the T cell lineage, range from asymptomatic or mild complications to those that are fulminant and potentially fatal. Although they are of variable occurrence, cardiovascular, rheumatic, and renal immune-mediated toxicities are among the most serious of these adverse events. We present MASCC recommendations with respect to the workup and management of cardiovascular, rheumatic, and renal immune-mediated toxicities with a focus on presentations that require treatment with immunomodulating agents.

There are not many direct comparisons of anxiety and depression symptoms between medicine students and the general population. This study aimed to determine the type of anxiety and depression symptoms at a medical school in Bogota (Colombia), and to compare the findings with population data. All students enrolled at a medical school were invited to participate in 2017. The Self-Reporting Questionnaire was applied to measure anxious and depressive symptoms. These findings were compared with data from the National Survey of Mental Health 2015 that were obtained with the same instrument in the same age range (18-25 years). A total of 554 students participated in the survey (70% response rate); 477 were between 18 and 25 years old. Anxiety symptoms (≥5) were reported by 44.9% of the medical students and 6.8% of the general population, and depression symptoms (≥7) were reported by 33.9% and 2.6%, respectively. The most prevalent symptoms reported by the medical students were fatigue, lack of sleep, and feeling tired all the time. In turn, the general population reported headaches, fear, nervousness, tension, and uneasiness. All comparisons showed p-values0.01. As prevalence is higher and symptom profile is different, specific policies are needed to reduce risk throughout medical degree programmes.

BACKGROUND. Optimal hepatitis C virus (HCV) screening strategies for cancer patients have not been established. We compared the performance of selective HCV screening strategies. METHODS. We surveyed patients presenting for first systemic anticancer therapy during 2013–2014 for HCV risk factors. We estimated the prevalence of positivity for HCV antibody (anti-HCV) and examined factors associated with anti-HCV status using Fisher’s exact test or Student’s t-test. Sensitivity was calculated for screening patients born during 1945–1965, patients with ≥1 other risk factor, or both cohorts (“combined screening”). RESULTS. We enrolled 2,122 participants. Median age was 59 years (range, 18–91); 1,138 participants were women. Race/ethnicity distribution was white non-Hispanic, 76% (n=1616); Hispanic, 11% (n=233); black non-Hispanic, 8% (n=160); Asian, 4% (n=78); other, 2% (n=35). Primary cancer distribution was non-liver solid tumor, 78% (n=1,664); hematologic cancer, 20% (n=422); liver cancer, 1% (n=28). Prevalence of anti-HCV was 1.93% (95% CI, 1.39%–2.61%). Over 28% of patients with detectable HCV RNA were unaware of infection. Factors significantly associated with anti-HCV positivity included less than a bachelor’s degree, birth in 1945–1965, chronic liver disease, injection drug use, and blood transfusion or organ transplant before 1992. A total of 1,315 participants (62%), including 39 of 41 with anti-HCV, reported ≥1 risk factor. Sensitivity was 80% (95% CI, 65–91%) for birth-cohort-based, 68% (95% CI, 52–82%) for other-risk-factor-based, and 95% (95% 83–99%) for combined screening. CONCLUSION. Combined screening still missed 5% of patients with anti-HCV. These findings favor universal HCV screening to identify all HCV-infected cancer patients.

Background: The NuPulseCV intravascular ventricular assist system (iVAS) provides extended duration ambulatory counterpulsation via a durable pump placed through the distal subclavian artery. Methods: We performed a prospective, single-arm, multicenter, US Food and Drug Administration-approved feasibility trial of iVAS therapy as a bridge to transplant or decision following the FIH (First-In-Human) trial. Results: Forty-seven patients were enrolled, and 45 patients (median 61 years old, 37 males, and 30 listed on United Network of Organ Sharing) received iVAS support for median 44 (25–87) days. There were no intraoperative complications. Success was defined as survival or transplant on iVAS therapy free from disabling stroke. Outcome success at 30 days (the primary end point of this study) and at 6 months was 89% and 80%, respectively. During 6 months of iVAS support, 2 patients died and 2 patients experienced disabling neurological dysfunction. Six-minute walk distance, 2-minute step test, and Kansas City Cardiomyopathy Questionnaire score improved during 4-week iVAS support. Conclusions: This feasibility trial demonstrated promising short-term outcomes of iVAS therapy with improved functional capacity and quality of life during the therapy. Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02645539.

Background Systemic sclerosis (SSc), or scleroderma, is a rare disease that often results in significant disruptions to activities of daily living and can negatively affect physical and psychological well-being. Because there is no known cure, SSc treatment focuses on reducing symptoms and disability and improving health-related quality of life (HRQoL). Self-management programs are known to increase self-efficacy for disease management in many chronic diseases. The Scleroderma Patient-centered Intervention Network (SPIN) developed a Web-based self-management program (SPIN self-management; SPIN-SELF) to increase self-efficacy for disease management and to improve HRQoL for patients with SSc. Objective The proposed study aims to assess the feasibility of conducting a full-scale randomized controlled trial (RCT) of the SPIN-SELF program by evaluating the trial implementation processes, required resources and management, scientific aspects, and participant acceptability and usage of the SPIN-SELF program. Methods The SPIN-SELF feasibility trial will be conducted via the SPIN Cohort. The SPIN Cohort was developed as a framework for embedded pragmatic trials using the cohort multiple RCT design. In total, 40 English-speaking SPIN Cohort participants with low disease management self-efficacy (Self-Efficacy for Managing Chronic Disease Scale score ≤7), who have indicated interest in using a Web-based self-management program, will be randomized with a 3:2 ratio into the SPIN-SELF program or usual care for 3 months. Feasibility outcomes include trial implementation processes, required resources and management, scientific aspects, and patient acceptability and usage of the SPIN-SELF program. Results Enrollment of the 40 participants occurred between July 5, 2019, and July 27, 2019. By November 25, 2019, data collection of trial outcomes was completed. Data analysis is underway, and results are expected to be published in 2020. Conclusions The SPIN-SELF program is a self-help tool that may improve disease-management self-efficacy and improve HRQoL in patients with SSc. The SPIN-SELF feasibility trial will ensure that trial methodology is robust, feasible, and consistent with trial participant expectations. The results will guide adjustments that need to be implemented before undertaking a full-scale RCT of the SPIN-SELF program. International Registered Report Identifier (IRRID) DERR1-10.2196/16799

OBJECTIVE The present study was undertaken to evaluate the efficacy of 2 educational tools for patients with rheumatoid arthritis (RA) by comparing a newly developed video tool, including storylines and testimonials, combined with a written booklet to the same written booklet alone. METHODS We conducted a randomized controlled trial. Our primary outcome was disease knowledge. Secondary outcomes were decisional conflict, self-efficacy, effective health care management, and satisfaction. Outcomes were measured before and after reviewing the materials, and 3 and 6 months later. Linear mixed-effects models were performed to evaluate changes over time. RESULTS In total, 221 participants received an educational video and booklet (n = 111) or a booklet alone (n = 110). The mean age was 50.8 years, mean disease duration was 4.8 years, 85% were female, and 24% had limited health literacy levels. Within groups, most outcomes improved between baseline and follow-up, but there were no statistically significant differences across groups. Patients receiving the video and booklet were more likely than those receiving the booklet alone to rate the presentation as excellent for providing information about the impact of RA, medication options, evidence about medications, benefits of medication, and self-care options. Factors significantly associated with greater improvements in knowledge and decisional conflict from baseline to 6 months included limited health literacy, lower educational level, and shorter disease duration. CONCLUSION Regardless of the delivery method, outcomes were improved up to 6 months after educational materials were delivered. Our findings support the implementation of self-administered educational materials in clinical settings, as they can result in sustained improvements in disease knowledge and decisional conflict.

Cytotoxic CD8 T cells (CTLs) play an important role in recovery from respiratory virus infection and provide protective immunity by targeting epitopes in well-conserved viral proteins that are shared by different strains of the virus. To provide immunity, CTLs migrate to different anatomical compartments in the lungs and destroy infected cells by injecting lytic molecules into the cytoplasm. Several adhesion molecules aid migration to the infected tissues and cytolysis. These molecules include killer lectin like receptor G1 (KLRG1), which is a membrane bound adhesion molecule that is expressed on terminally differentiated CD8 T effector (Teff) cells. Recently, several studies identified some long lived “terminal memory CD8 T cells (TTM)” that express KLRG1. The goal of our study is to determine the location of these TTM cells within the different compartments of the lungs during a respiratory infection. Our previous work showed that SMAD4 regulates several homing receptors on activated CTLs including KLRG1. We used transfer experiments to examine the distribution of WT cells that express SMAD4 and mutant CTLs that lack SMAD4 in the lungs. At 30 days after intranasal infection with Listeria monocytogenes, there were larger numbers of mutant CTLs in the airways (BAL fluid), while WT CTLs were primarily located in the lung tissue. Interestingly, the localization of the WT cells correlated with the expression of KLRG1. We are using in situ imaging to visualize these transferred CTLs during respiratory infection to better understand their role in protective immunity. Intravascular staining will be used to determine whether these CTLs remain in the blood vessels or enter the tissues of the infected recipient mice. This work was supported by NIH Grant AI123864.