Immune response evolution in peanut epicutaneous immunotherapy for peanut-allergic children.

BACKGROUND: Epicutaneous immunotherapy with investigational Viaskin™ Peanut 250 µg (DBV712) has demonstrated statistically superior desensitization versus placebo in peanut-allergic children in clinical trials. It is unclear whether serologic biomarkers predict response. METHODS: Serum-specific IgG4 and IgE (whole peanut and components) from subjects enrolled in the phase 3 Efficacy and Safety of Viaskin Peanut in Children With IgE-Mediated Peanut Allergy study were examined by exploratory univariate and multivariate analyses to determine trajectories and predictors of treatment response, based upon peanut protein eliciting dose (ED) at Month (M) 12 double-blind placebo-controlled food challenge. RESULTS: Among Viaskin Peanut-treated subjects, peanut sIgG4 significantly increased from baseline through M12 and peanut sIgE peaked at M3 and fell below baseline by M12, with sIgG4 and sIgE peanut components mirroring these trajectories. Placebo subjects had no significant changes. By univariate analysis, M12 peanut sIgG4/sIgE was higher in treatment responders (p < 0.001) and had highest area under the curve (AUC) for predicting ED ≥300 mg and ≥1000 mg (AUC 69.5% and 69.9%, respectively). M12 peanut sIgG4/sIgE >20.1 predicted M12 ED ≥300 mg (80% positive predictive value). The best performing component was Ara h 1 sIgE <15.7 kUA /L (AUC 66.5%). A multivariate model combining Ara h 1 and peanut sIgG4/sIgE had an AUC of 68.2% (ED ≥300 mg) and 67.8% (ED ≥1000 mg). CONCLUSIONS: Peanut sIgG4 rise most clearly differentiated Viaskin Peanut versus placebo subjects. sIgG4/sIgE ratios >20.1 and the combination of Ara h 1 and peanut sIgG4/sIgE had moderate ability to predict treatment response and could potentially be useful for clinical monitoring. Additional data are needed to confirm these relationships.

The impact of orthostatic intolerance on early ambulation following abdominal surgery in an enhanced recovery programme.

BACKGROUND: The prevalence of orthostatic intolerance on the day of surgery is more than 50% after abdominal surgery. The impact of orthostatic intolerance on ambulation on the day of surgery has been little studied. We investigated orthostatic intolerance and walking ability after colorectal and bariatric surgery in an enhanced recovery programme. METHODS: Eighty-two patients (colorectal: n = 46, bariatric n = 36) were included and analysed in this prospective study. Walk tests for 2 min (2-MWT) and 6 min (6-MWT) were performed before and 24 h after surgery, and 3 h after surgery for 2-MWT. Orthostatic intolerance characterised by presyncopal symptoms when rising was recorded at the same time points. Multivariate binary logistic regressions modelling the probability of orthostatic intolerance and walking inability were performed taking into account potential risk factors. RESULTS: Prevalence of orthostatic intolerance and walking inability was, respectively, 65% and 18% 3-hour after surgery. The day after surgery, patients' performance had greatly improved: approximately 20% of the patients experienced orthostatic intolerance, whilst only 5% of the patients were unable to walk. Adjusted binary logistic regressions demonstrated that age (p = .37), sex (p = .39), BMI (p = .74), duration of anaesthesia (p = .71) and type of surgery (p = .71) did not significantly influence walking ability. CONCLUSION: Our study confirms that orthostatic intolerance was frequent (~ 60%) 3-hour after abdominal surgery but prevented a 2-MWT only in ~20% of patients. No risk factors for orthostatic intolerance and walking inability were evidenced.

Characteristics of insulinopenic and non insulinopenic diabetes related to immune checkpoint inhibitors: A French pharmacovigilance study.

INTRODUCTION: Immune checkpoint inhibitor-induced diabetes mellitus (ICI-DM) is an immune-related adverse drug reaction (irADR). Hyperglycemia can be linked to endogenous insulin deficiency with ketoacidosis or associated with preserved beta-cell function. OBJECTIVES: We aimed to identify the characteristics of both types of ICI-DM (type 1 and type 2 DM), to improve our understanding of this irADR and its management. METHODS: Data for ICI-DM recorded in the French Pharmacovigilance Database from 2015 to October 2019 were analyzed according to the French causality assessment. RESULTS: In total, 60 subjects were included. Anti-PD1/PDL1 pathway blockade therapy (nivolumab: 61.7%+3.3% in association with ipilimumab pembrolizumab: 28.3%) was most frequently implicated in ICI-DM, but some reports involved anti-CTLA4 drug (ipilimumab: 6.7%+3.3% in association with nivolumab). One third of reports occurred within one month of the initiation of immunotherapy. Decreased insulin secretion (defined by the presence of ketone bodies) were confirmed in 80% of reports. Among them, 54% of patients met the diagnostic criteria for fulminant diabetes. Overall, 17.7% of the reports had pre-existing type 2 diabetes T2D. Four deaths due to hyperglycemia were declared, with altered insulin secretion in only two of these reports. BMI was lower in the insulinopenic group (23.4±0.7 vs. 27.9±1.6, P=0.004) and other irADRs were more frequently observed in patients with persistent insulin secretion (66.7 vs. 18.8%, P=0.02). We found no difference in age, indication or cumulative ICI dose between the two groups (with and without insulinopenia). The presence of GAD antibodies was associated with a shorter time to diabetes onset (42.6±6.1 vs. 208.1±41.6 days, P=0.029). CONCLUSIONS: ICI-DM is a rare but serious irADR triggered by all classes of immunotherapy. The observation period for ICI-DM can be shortened for patients positive for anti-GAD antibodies. Endogenous insulin deficiency did not appear to be the only mechanism involved in ICI-DM, as beta-cell function was preserved in 20% of reports. Improvements in our understanding of this complication will be required for its prevention.

Feedback Adaptation to Unpredictable Force Fields in 250 ms.

Motor learning and adaptation are important functions of the nervous system. Classical studies have characterized how humans adapt to changes in the environment during tasks such as reaching, and have documented improvements in behavior across movements. However, little is known about how quickly the nervous system adapts to such disturbances. In particular, recent work has suggested that adaptation could be sufficiently fast to alter the control strategies of an ongoing movement. To further address the possibility that learning occurred within a single movement, we designed a series of human reaching experiments to extract from muscles recordings the latency of feedback adaptation. Our results confirmed that participants adapted their feedback responses to unanticipated force fields applied randomly. In addition, our analyses revealed that the feedback response was specifically and finely tuned to the ongoing perturbation not only across trials with the same force field, but also across different kinds of force fields. Finally, changes in muscle activity consistent with feedback adaptation occurred in ∼250 ms following reach onset. The adaptation that we observed across trials presented in a random context was similar to the one observed when the force fields could be anticipated, suggesting that these two adaptive processes may be closely linked to each other. In such case, our measurement of 250 ms may correspond to the latency of motor adaptation in the nervous system.

Dual GIP-GLP1-Receptor Agonists In The Treatment Of Type 2 Diabetes: A Short Review On Emerging Data And Therapeutic Potential.

The need for efficient and safe therapy to improve such metabolic diseases as obesity and type 2 diabetes mellitus is currently unmet. The development of dual GIPR-GLP1R coagonists that bind to either one or the other receptor (sequence-mixed dual agonists) has emerged as an innovative therapeutic strategy for obesity and type 2 diabetes. Combined activation of both receptors may act synergistically providing additive effects on glucose and body weight in comparison of GLP1 analogues alone. Preclinical studies have confirmed that GIPR-GLP1R coagonists improve several hallmarks of metabolic syndrome, such as obesity, hyperglycemia, and dyslipidemia. These metabolic benefits have been translated from mice to nonhuman primates and humans. Recent clinical trials have shown that coagonists induce significant benefits on body weight, fasting, and postprandial glucose levels, insulin sensitivity, and total cholesterol. Combined GIP- and GLP1R activators have the potential to become a treatment option for patients with type 2 diabetes.

Diabetes Mellitus, Extreme Insulin Resistance, and Hypothalamic-Pituitary Langerhans Cells Histiocytosis.

BACKGROUND: Langerhans Cell Histiocytosis (LCH) is a rare inflammatory neoplasm characterized by an infiltration of organs by Langerin + (CD207+) and CD1a+ histiocytes. Diabetes insipidus is a frequent manifestation of the disease, while diabetes mellitus is very rare. We report the first case of a 20-year-old man suffering from hypothalamopituitary histiocytosis and diabetes mellitus with serum anti-insulin receptor antibodies. CASE PRESENTATION: A 20-year-old patient was admitted for the evaluation of growth delay and hyperphagia. HbA1c level and fasting blood glucose were in the normal range. The diagnosis of hypothalamopituitary histiocytosis was based on histological features after biopsy of a large suprachiasmatic lesion identified on magnetic resonance imaging (MRI). Association of vinblastine and purinethol was started followed by a second-line therapy by cladribine. During the follow-up, the patient was admitted for recurrence of hyperglycemic states and extreme insulin resistance. The screening for serum anti-insulin receptor antibodies was positive. Each episode of hyperglycemia appeared to be correlated with tumoral activity and increase in serum anti-insulin receptor antibodies and appeared to be improved when the disease was controlled by chemotherapy. CONCLUSION: We report the first description of a hypothalamopituitary histiocytosis associated with serum anti-insulin receptor antibodies, extreme insulin resistance, and diabetes. Parallel evolution of glucose levels and serum anti-insulin receptor antibodies seemed to be the consequence of immune suppressive properties of cladribine.

Community-Based Assessment to Inform a Chlamydia Screening Program for Women in a Rural American Indian Community.

BACKGROUND: Rates of chlamydial infection in American Indian/Alaska Native women in the United States are approximately 4-fold those in non-Hispanic white women. We conducted a community-based survey of self-identified American Indian/Alaska Native women 14 to 25 years of age on a reservation in the Northwestern United States to inform a chlamydia screening strategy. METHODS: The anonymous survey assessed respondents' knowledge, perceptions, and preferences related to chlamydia screening, results receipt, and partner notification. We recruited women using respondent-driven sampling, school-based sampling, and direct recruitment through social media and fliers. Participants in schools completed the survey as a paper-based, self-administered survey. Other participants could complete the survey in person, by phone as an interviewer-administered survey, or online. RESULTS: We recruited 162 participants, most in schools (n = 83; 51%) or by peer referral (n = 55; 34%). Only 1 woman completed the survey online. Thirty-one respondents (19%) reported a history of an unplanned first pregnancy, and 19 (12%) reported a history of a diagnosed sexually transmitted disease. Most women (n = 98; 63%) recognized the potential impact of Chlamydia trachomatis on fertility. The preferred site for chlamydia screening was the Indian Health Service Clinic (n = 114; 70%), but 79 women (41%) would accept a C. trachomatis test at a nonclinical testing site. Of the 56 women (35%) who would accept home testing, most preferred to get the test kit from a clinic. CONCLUSIONS: Our results suggest that Indian Health Service efforts to increase chlamydia screening in the clinic and through outreach may be more successful than promotion of home testing in this population.