Granzyme F: Exhaustion Marker and Modulator of Chimeric Antigen Receptor T Cell-Mediated Cytotoxicity.

Granzymes are a family of proteases used by CD8 T cells to mediate cytotoxicity and other less-defined activities. The substrate and mechanism of action of many granzymes are unknown, although they diverge among the family members. In this study, we show that mouse CD8+ tumor-infiltrating lymphocytes (TILs) express a unique array of granzymes relative to CD8 T cells outside the tumor microenvironment in multiple tumor models. Granzyme F was one of the most highly upregulated genes in TILs and was exclusively detected in PD1/TIM3 double-positive CD8 TILs. To determine the function of granzyme F and to improve the cytotoxic response to leukemia, we constructed chimeric Ag receptor T cells to overexpress a single granzyme, granzyme F or the better-characterized granzyme A or B. Using these doubly recombinant T cells, we demonstrated that granzyme F expression improved T cell-mediated cytotoxicity against target leukemia cells and induced a form of cell death other than chimeric Ag receptor T cells expressing only endogenous granzymes or exogenous granzyme A or B. However, increasing expression of granzyme F also had a detrimental impact on the viability of the host T cells, decreasing their persistence in circulation in vivo. These results suggest a unique role for granzyme F as a marker of terminally differentiated CD8 T cells with increased cytotoxicity, but also increased self-directed cytotoxicity, suggesting a potential mechanism for the end of the terminal exhaustion pathway.

[Pediatric orbital Rosai-Dorfman disease: An unusual case]. / Maladie de Rosai-Dorfman à localisation orbito-palpébrale de l'enfant : à propos d'une observation exceptionnelle.

INTRODUCTION: Rosai-Dorfman disease (RDD) is a sinus histiocytosis with massive lymphadenopathy. This rare condition is a benign disease of unknown etiology. Bilateral orbital localization of RDD is rare. OBSERVATION: The authors report the case of a 6-year-old child who presented with bilateral orbital-palpebral masses associated with chronic cervical lymphadenopathy. There were no laboratory signs of inflammation. Serological and tuberculosis screening tests were negative. Histopathological examination of a lymph node biopsy established a diagnosis of Rosai-Dorfman disease. The patient underwent surgical excision of the orbital lesions followed by long-term corticosteroid therapy. A favorable course was observed, with no sign of recurrence after one year of follow-up. CONCLUSION: Rosai-Dorfman disease is very rare in its bilateral orbital presentation. Histopathological diagnosis remains challenging. In Africa, the presence of chronic oculo-palpebral tumor associated with or without cervical lymphadenopathy must raise the suspicion of Rosai-Dorfman disease after ruling out tuberculosis and lymphoma.

Role of IFN-α in Rheumatoid Arthritis.

PURPOSE OF REVIEW: Type 1 interferons (IFN-I) are of increasing interest across a wide range of autoimmune rheumatic diseases. Historically, research into their role in rheumatoid arthritis (RA) has been relatively neglected, but recent work continues to highlight a potential contribution to RA pathophysiology. RECENT FINDINGS: We emphasise the importance of disease stage when examining IFN-I in RA and provide an overview on how IFN-I may have a direct role on a variety of relevant cellular functions. We explore how clinical trajectory may be influenced by increased IFN-I signalling, and also, the limitations of scores composed of interferon response genes. Relevant environmental triggers and inheritable RA genetic risk relating to IFN-I signalling are explored with emphasis on intriguing data potentially linking IFN-I exposure, epigenetic changes, and disease relevant processes. Whilst these data cumulatively illustrate a likely role for IFN-I in RA, they also highlight the knowledge gaps, particularly in populations at risk for RA, and suggest directions for future research to both better understand IFN-I biology and inform targeted therapeutic strategies.

Acquired haemophilia A diagnosed during pregnancy.

Pregnancy-associated haemophilia A is an uncommon, acquired bleeding disorder which usually presents post-partum; very rarely it may present during pregnancy. No consensus guidelines exist on the management of this condition in pregnancy and very few cases have been reported in the literature. Here we describe the case of a woman presenting with acquired haemophilia A during pregnancy and outline the management of her bleeding disorder. We contrast her case with that of two other women, presenting to the same tertiary referral centre, with acquired haemophilia A presenting post-partum. These cases highlight the heterogeneous management of this condition and how it may be successfully managed in pregnancy.

Association between nutrient intake from vegetables and BMI category of in-school adolescents in urban and rural areas in Davao City, Philippines.

Consumption of vegetables may contribute to alleviating the double burden of malnutrition, which is widespread among adolescents. However, the link between specific nutrient intakes from vegetables and the body mass index (BMI) of in-school adolescents is not widely studied. This study determined the association between the nutrient intakes from the vegetables consumed and the BMI category of in-school adolescents in urban and rural areas in Davao City, Philippines. Self-reported vegetable consumption was collected from the respondents, and the corresponding nutrient intakes were calculated using the USDA food composition tables. The BMI of the participating adolescents was also measured. The results show that being underweight or overweight is generally associated with lower macronutrient and micronutrient intakes from the vegetables consumed, namely, bell pepper, bitter gourd, cabbage, carrot, chayote, Chinese cabbage, cucumber, eggplant, Malabar spinach, moringa, mung bean, okra, potato, sponge gourd, squash, string beans, sweet potato, sweet potato tops, taro, tomato, water spinach (P < 0.05). The nutrient intakes from vegetables consumed by adolescents from urban households were generally higher. The findings highlight the contribution of vegetables to the nutrient intakes in the adolescent population. This study reinforces the need for targeted dietary guidelines and further promotion of vegetables, especially indigenous ones, to improve the nutritional status of adolescents in the Philippines.

Acute bronchiolitis: Experience of home oxygen therapy in "Hospital at Home" care from 2012 to 2014: Home oxygen therapy in "Hospital at Home" for bronchiolitis.

AIM: To describe the management of home oxygen therapy for infants with acute bronchiolitis through a home care network: Hospital at Home (HAH). METHODS: A retrospective observational study was carried out during two consecutive winters from 2012 to 2014. RESULTS: A total of 141 patients were eligible for home oxygen therapy, and 54 were discharged on home oxygen therapy through HAH. The median age of patients was 2.5 months (0.75-13 months). The average length of hospital stay before discharge was 4.9 days (1-17 days). In total, 73% of the children received oxygen at home. There was an average of five nurse visits per patient. Each child was seen by a pediatrician during the HAH care. There were no deaths or readmissions to an intensive care unit. There were two conventional readmissions for increased respiratory distress and two emergency department visits. The median length of HAH was 6 days (1-33 days). CONCLUSION: Home oxygen for infants with acute bronchiolitis is a promising and safe alternative to reduce conventional hospitalizations. It is necessary to evaluate the cost of this treatment and its impact on nosocomial infections.

Precision medicine: the precision gap in rheumatic disease.

For many oncological conditions, the application of timely and patient-tailored targeted therapies, or precision medicine, is a major therapeutic development that has provided considerable clinical benefit. However, despite the application of increasingly sophisticated technologies, alongside advanced bioinformatic and machine-learning algorithms, this success is yet to be replicated for the rheumatic diseases. In rheumatoid arthritis, for example, despite an array of targeted biologic and conventional therapeutics, treatment choice remains largely based on trial and error. The concept of the 'precision gap' for rheumatic disease can help us to identify factors that underpin the slow progress towards the discovery and adoption of precision-medicine approaches for rheumatic disease. In a rheumatic disease such as rheumatoid arthritis, it is possible to identify four themes that have slowed progress, solutions to which should help to close the precision gap. These themes relate to our fundamental understanding of disease pathogenesis, how we determine treatment response, confounders of treatment outcomes and trial design.

Antigens Expressed by Breast Cancer Cells Undergoing EMT Stimulate Cytotoxic CD8+ T Cell Immunity.

Antigenic differences formed by alterations in gene expression and alternative splicing are predicted in breast cancer cells undergoing epithelial to mesenchymal transition (EMT) and the reverse plasticity known as MET. How these antigenic differences impact immune interactions and the degree to which they can be exploited to enhance immune responses against mesenchymal cells is not fully understood. We utilized a master microRNA regulator of EMT to alter mesenchymal-like EO771 mammary carcinoma cells to a more epithelial phenotype. A computational approach was used to identify neoantigens derived from the resultant differentially expressed somatic variants (SNV) and alternative splicing events (neojunctions). Using whole cell vaccines and peptide-based vaccines, we find superior cytotoxicity against the more-epithelial cells and explore the potential of neojunction-derived antigens to elicit T cell responses through experiments designed to validate the computationally predicted neoantigens. Overall, results identify EMT-associated splicing factors common to both mouse and human breast cancer cells as well as immunogenic SNV- and neojunction-derived neoantigens in mammary carcinoma cells.

No adverse consequences associated with targeting clinical signs to initiate antimicrobial treatment of postoperative subclinical bacteriuria in dogs following surgical decompression of Hansen type I thoracolumbar disk herniation.

OBJECTIVE: To describe the prevalence of postoperative bacteriuria, clinical course of subclinical bacteriuria in the absence of antimicrobial intervention, clinical signs of bacteriuria that trigger antimicrobial treatment, and outcomes for dogs with subclinical bacteriuria following surgical decompression of acute intervertebral disc herniation (IVDH) Hansen type I. ANIMALS: Twenty client-owned dogs undergoing hemilaminectomy for acute (≤ 6 days) IVDH Hansen type I affecting the thoracolumbar spinal cord segments between August 2018 and January 2019. PROCEDURES: In this prospective study, dogs were serially evaluated at presentation, hospital discharge, 2 weeks postoperatively, and between 4 and 6 weeks postoperatively. Dogs were monitored for clinical signs of bacteriuria, underwent laboratory monitoring (CBC, biochemical analyses, urinalysis, urine bacterial culture), and were scored for neurologic and urinary status. In the absence of clinical signs, bacteriuria was not treated with antimicrobials. RESULTS: Four of the 18 dogs developed bacteriuria without clinical signs 4 days to 4 to 6 weeks after surgery. In all 4 dogs, bacteriuria resulted in lower urinary tract signs 13 to 26 weeks postoperatively. No dogs had evidence of systemic illness despite delaying antimicrobial treatment until clinical signs developed. New-onset incontinence was the only clinical sign in 3 dogs. All bacterial isolates had wide antimicrobial susceptibility. Bacteriuria and clinical signs resolved with beta-lactam antimicrobial treatment. CLINICAL RELEVANCE: Postoperative bacteriuria occurs in some dogs with IVDH Hansen type I and, when present, may lead to clinical signs over time. Clinical signs of bacteriuria may be limited to new-onset urinary incontinence, inappropriate urination, or both. Delaying antimicrobial treatment until clinical signs of bacteriuria developed did not result in adverse consequences or systemic illness.

A human model of bilateral pulmonary vein sampling to assess the effects of one-lung ventilation on neutrophil function.

BACKGROUND: Neutrophil activation drives lung complications after cardiopulmonary bypass (CPB). Evidence suggests the healthy, ventilated lung may beneficially re-condition pro-inflammatory neutrophils. However, evidence in humans is lacking, due to a paucity of good models. CPB with simultaneous central venous and bilateral pulmonary vein sampling provides an opportunity to model effects of one-lung ventilation. The study's primary objectives were to establish a model of intra-operative, bilateral pulmonary vein sampling and to determine whether neutrophil function differed after passing through inflated or deflated lungs. METHODS: Seventeen patients having "on pump" coronary artery bypass grafting (CABG) with one-lung ventilation (in two cohorts with tidal volume 2ml kg-1 and FiO2 0.21, or tidal volume 4 ml kg-1 and FiO2 0.5 respectively) were recruited. Cohort 1 consisted of 9 patients (7 male, median age 62.0 years) and Cohort 2 consisted of 8 male patients (median age 65.5 years). Recruitment was via prospective screening of scheduled elective and non-elective CABG procedures with cardiopulmonary bypass. Each patient had five blood samples taken-central venous blood pre-operatively; central venous blood pre-CPB; central venous blood post-CPB; pulmonary venous blood draining the ventilated lung post-CPB; and pulmonary venous blood draining the deflated lung post-CPB. Neutrophil phagocytosis and priming status were quantified. Plasma cytokines were measured. RESULTS: Phagocytosis and priming were not significantly different in neutrophils returning from the ventilated lung as compared to the non-ventilated lung. Plasma IL-6, IL-8 and IL-10 were significantly elevated by CPB. CONCLUSIONS: The intra-operative, bilateral pulmonary vein sampling model provides unique opportunities to assess biological effects of interventions to one lung, with the other lung acting as an internal control. Single-lung ventilation during CPB had no significant effects on neutrophil function.

Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming.

OBJECTIVES: An interferon (IFN) gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients where it has been shown to negatively impact initial response to treatment. We wished to validate this effect and explore potential mechanisms of action. METHODS: In a multicentre inception cohort of eRA patients (n=191), we examined the whole blood IGS (MxA, IFI44L, OAS1, IFI6, ISG15) with reference to circulating IFN proteins, clinical outcomes and epigenetic influences on circulating CD19+ B and CD4+ T lymphocytes. RESULTS: We reproduced our previous findings demonstrating a raised baseline IGS. We additionally showed, for the first time, that the IGS in eRA reflects circulating IFN-α protein. Paired longitudinal analysis demonstrated a significant reduction between baseline and 6-month IGS and IFN-α levels (p<0.0001 for both). Despite this fall, a raised baseline IGS predicted worse 6-month clinical outcomes such as increased disease activity score (DAS-28, p=0.025) and lower likelihood of a good EULAR clinical response (p=0.034), which was independent of other conventional predictors of disease activity and clinical response. Molecular analysis of CD4+ T cells and CD19+ B cells demonstrated differentially methylated CPG sites and dysregulated expression of disease relevant genes, including PARP9, STAT1, and EPSTI1, associated with baseline IGS/IFNα levels. Differentially methylated CPG sites implicated altered transcription factor binding in B cells (GATA3, ETSI, NFATC2, EZH2) and T cells (p300, HIF1α). CONCLUSIONS: Our data suggest that, in eRA, IFN-α can cause a sustained, epigenetically mediated, pathogenic increase in lymphocyte activation and proliferation, and that the IGS is, therefore, a robust prognostic biomarker. Its persistent harmful effects provide a rationale for the initial therapeutic targeting of IFN-α in selected patients with eRA.

Severe imported malaria involving hyperparasitemia (≥ 10%) in non-immune children: Assessment of French practices.

BACKGROUND: Plasmodium falciparum hyperparasitemia (over or equal to 10%), isolated or associated with other severity criteria, should be managed in a pediatric intensive care unit according to the French pediatric guidelines. The main objective of our study was to describe the management and course of these special cases. POPULATION AND METHODS: We conducted a retrospective study in eight French hospital facilities from January 2007 to December 2014. We reviewed the management of non-immune children aged 0-15 years, assessing the following: clinical and paraclinical data, type of care unit, treatment initiated, initial and long-term course. Data were analyzed for the whole population and for two groups according to the place of first-line management: group A (in pediatric intensive care unit), and group B (other places). RESULTS: A total of 61 children were included, 14 (23%) of whom were initially admitted to the intensive care unit (group A), all with neurological or hemodynamic disorders. Only 23 children (38%) overall received intravenous antimalarial treatment and the other patients received exclusively oral treatment. No deaths were reported. Median parasitemia was comparable in the two groups. In group B (n = 47/61, 77%), isolated hyperparasitemia, jaundice, and renal failure were predominant. The children who underwent initial intravenous treatment (n = 5/47, 11%) all progressed favorably, as did 92% of the children who received oral treatment (n = 42/47, 89%). CONCLUSION: A majority of children with Plasmodium falciparum hyperparasitemia were managed outside the pediatric intensive care unit via the oral route, against the French pediatric guidelines except when neurologic or hemodynamic disorders were present. Initial clinical evaluation and hospital supervision are essential for the best management of these patients.

Outcomes during delivery hospitalisations with inflammatory bowel disease.

OBJECTIVE: To characterise inflammatory bowel disease (IBD) trends and associated risk during delivery hospitalisations. DESIGN: Cross-sectional. SETTING: US delivery hospitalisations. POPULATION: Delivery hospitalisations in the 2000-2018 National Inpatient Sample. METHODS: This study analysed a nationally representative hospital discharge database based on the presence of IBD. Temporal trends in IBD were analysed using joinpoint regression to estimate the average annual percent change (AAPC). IBD severity was characterised by the presence of diagnoses such as penetrating and stricturing disease and history of bowel resection. Risks for adverse outcomes were analysed based on presence of IBD. Poisson regression models were performed with unadjusted and adjusted risk ratios (aRR) as measures of effect. MAIN OUTCOME MEASURE: Prevalence of IBD and associated adverse outcomes. RESULTS: Of 73 109 790 delivery hospitalisations, 89 965 had a diagnosis of IBD. IBD rose from 0.06% in 2000 to 0.21% in 2018 (AAPC 7.3%, 95% CI 6.7-7.9%). Among deliveries with IBD, IBD severity diagnoses increased from 4.1% to 8.1% from 2000 to 2018. In adjusted analysis, IBD was associated with increased risk for preterm delivery (aRR 1.50, 95% CI 1.47-1.53), severe maternal morbidity (aRR 1.93, 95% CI 1.83-2.04), venous thrombo-embolism (aRR 2.76, 95% CI 2.39-3.18) and surgical injury during caesarean delivery hospitalisation (aRR 5.03, 95% CI 4.76-5.31). In the presence of a severe IBD diagnosis, risk was further increased for all adverse outcomes. CONCLUSION: IBD is increasing in the obstetric population and is associated with adverse outcomes. Risk is increased in the presence of a severe IBD diagnosis. TWEETABLE ABSTRACT: Deliveries among women with inflammatory bowel disease are increasing. Disease severity is associated with adverse outcomes.

Direct targeting of amplified gene loci for proapoptotic anticancer therapy.

Gene amplification drives oncogenesis in a broad spectrum of cancers. A number of drugs have been developed to inhibit the protein products of amplified driver genes, but their clinical efficacy is often hampered by drug resistance. Here, we introduce a therapeutic strategy for targeting cancer-associated gene amplifications by activating the DNA damage response with triplex-forming oligonucleotides (TFOs), which drive the induction of apoptosis in tumors, whereas cells without amplifications process lower levels of DNA damage. Focusing on cancers driven by HER2 amplification, we find that TFOs targeting HER2 induce copy number-dependent DNA double-strand breaks (DSBs) and activate p53-independent apoptosis in HER2-positive cancer cells and human tumor xenografts via a mechanism that is independent of HER2 cellular function. This strategy has demonstrated in vivo efficacy comparable to that of current precision medicines and provided a feasible alternative to combat drug resistance in HER2-positive breast and ovarian cancer models. These findings offer a general strategy for targeting tumors with amplified genomic loci.

Increasing Nursing Student Success With Early Individual Remediation.

ABSTRACT: With the implementation of five remediation strategies immediately after the first failed exam in a pharmacology course, this quality improvement study demonstrated an increase in retention of at-risk associate degree nursing students. Unit exam scores and course failure rates were measured before and after implementation. Twelve of 14 students who completed the remediation demonstrated a statistically significant increase in scores from the first failed exam to the last exam taken. The mean increase was 17.3 percentage points (p < .0001, 95 percent confidence interval [13.3, 20.9]). Cohen's d, which equaled 0.604, indicated a significant increase in course pass rates.

Barriers to and Facilitators of Using mHealth Technology Among African-Americans Living with Hypertension.

MHealth provides a new way of promoting hypertension self-management behaviors. However, the acceptance, feasibility, and effectiveness of interventions incorporating mHealth technology have been understudied in African-Americans with hypertension. This study aimed to explore participants' (n = 30) experiences using a community and technology-based intervention to self-manage their hypertension (COACHMAN). Focus groups were conducted with African-Americans living with hypertension. Focus groups were audio-recorded, and the data were transcribed verbatim and analyzed qualitatively using thematic analysis. Regarding the use of mHealth-enabled self-management hypertension interventions to support hypertension control among African-Americans, the thematic analysis produced the following five barrier themes: (a) lack of knowledge regarding how to use technology, (b) resistance to learning new technology, (c) lack of access to technology, (d) privacy and security concerns, and (e) issues with the medication management support features. Facilitator themes that emerged from the thematic analysis were all related to the intervention components, which were: (a) reminders, (b) rewards, and (c) education modules. This study focused on mHealth barriers and facilitators as described by African-Americans living with hypertension. Results provide a starting point for developing a mHealth intervention for African-Americans that incorporates a self-management program.

The interferon gene signature as a clinically relevant biomarker in autoimmune rheumatic disease.

The interferon gene signature (IGS) is derived from the expression of interferon-regulated genes and is classically increased in response to type I interferon exposure. A raised whole blood IGS has increasingly been reported in rheumatic diseases as sequencing technology has advanced. Although its role remains unclear, we explore how a raised IGS can function as a clinically relevant biomarker, independent of whether it is a bystander effect or a key pathological process. For example, a raised IGS can act as a diagnostic biomarker when predicting rheumatoid arthritis in patients with arthralgia and anti-citrullinated protein antibodies, or predicting systemic lupus erythematous (SLE) in those with antinuclear antibodies; a theragnostic biomarker when predicting response for patients receiving disease modifying therapy, such as rituximab in rheumatoid arthritis; a biomarker of disease activity (early rheumatoid arthritis, dermatomyositis, systemic sclerosis, SLE); or finally a predictor of clinical characteristics, such as lupus nephritis in SLE or disease burden in primary Sjögren's syndrome. A high IGS does not uniformly predict worse clinical phenotypes across all diseases, as demonstrated by a reduced disease burden in primary Sjögren's syndrome, nor does it predict a universally poorer response to all therapies, as shown in rheumatoid arthritis. This dichotomy highlights both the complexity of type I interferon signalling in vivo and the current lack of standardisation when calculating the IGS. The IGS as a biomarker warrants further exploration, with beneficial clinical applications anticipated in multiple rheumatic diseases.

Medical check-up of newly arrived unaccompanied minors: A dedicated pediatric consultation service in a hospital.

BACKGROUND AND AIMS: Healthcare for the increasing number of migrants in Europe, and particularly of unaccompanied minors (UMs) seeking asylum, has become a major challenge. We aimed to describe the health issues of UMs managed in a dedicated pediatric consultation service in a care center in Paris. METHODS: All UMs attending a dedicated migrant medical consultation service in Robert Debré Hospital, Paris, France, were included in a single-center retrospective observational study from September 1, 2017, to September 30, 2018. RESULTS: Out of the 107 UMs who were included, 87% had a health problem (n=93) and 52% had an infectious disease (n=56). The main infectious diagnoses were schistosomiasis (22%), latent tuberculosis (22%), intestinal parasitosis (16%), and chronic hepatitis B (8%). Posttraumatic stress disorder (PTSD) and overweight were common (35% and 20%, respectively). The median age was 15 years old (IQR, 14-16), the male/female ratio was 95/12. Most of the children were from sub-Saharan Africa (n=67), 46% had crossed Libya (n=49) and, when compared to the other migration routes, faced an increasing risk of violence (69%, p=0.04), imprisonment (53%, p=0.03), and forced labor (48%, p=0.02). The median duration of the trip before reaching France was 6 months (IQR, 2-13), the median time to consultation was 2 months (0-5) and was not associated with an increased risk of health problems. A total of 43 UMs were lost to follow-up. CONCLUSION: Health problems, particularly infectious diseases and PTSD, are common among UMs and should prompt an early medical consultation with psychiatric evaluation. Follow-up is problematic and could be improved by an on-line health book.

Implications of Antigen Selection on T Cell-Based Immunotherapy.

Many immunotherapies rely on CD8+ effector T cells to recognize and kill cognate tumor cells. These T cell-based immunotherapies include adoptive cell therapy, such as CAR T cells or transgenic TCR T cells, and anti-cancer vaccines which expand endogenous T cell populations. Tumor mutation burden and the choice of antigen are among the most important aspects of T cell-based immunotherapies. Here, we highlight various classes of cancer antigens, including self, neojunction-derived, human endogenous retrovirus (HERV)-derived, and somatic nucleotide variant (SNV)-derived antigens, and consider their utility in T cell-based immunotherapies. We further discuss the respective anti-tumor/anti-self-properties that influence both the degree of immunotolerance and potential off-target effects associated with each antigen class.