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Summary: Many autoimmune disorders exhibit flares in which symptoms erupt and then decline, as exemplified by multiple sclerosis (MS) in its relapsing-remitting form. Existing mathematical models of autoimmune flares often assume regular oscillations, failing to capture the stochastic and non-periodic nature of flare-ups. We suggest that autoimmune flares are driven by excitable dynamics triggered by stochastic events auch as stress, infection and other factors. Our minimal model, involving autoreactive and regulatory T-cells, demonstrates this concept. Autoimmune response initiates antigen-induced expansion through positive feedback, while regulatory cells counter the autoreactive cells through negative feedback. The model explains the decrease in MS relapses during pregnancy and the subsequent surge postpartum, based on lymphocyte dynamics. Additionally, it identifies potential therapeutic targets, predicting significant reduction in relapse rate from mild adjustments of regulatory T cell activity or production. These findings indicate that excitable dynamics may underlie flare-ups across various autoimmune disorders, potentially informing treatment strategies.

Abstract Thyroid disorders are common and often require lifelong hormone replacement. Treating thyroid disorders involves a fascinating and troublesome delay, in which it takes many weeks for serum thyroid‐stimulating hormone (TSH) concentration to normalize after thyroid hormones return to normal. This delay challenges attempts to stabilize thyroid hormones in millions of patients. Despite its importance, the physiological mechanism for the delay is unclear. Here, we present data on hormone delays from Israeli medical records spanning 46 million life‐years and develop a mathematical model for dynamic compensation in the thyroid axis, which explains the delays. The delays are due to a feedback mechanism in which peripheral thyroid hormones and TSH control the growth of the thyroid and pituitary glands; enlarged or atrophied glands take many weeks to recover upon treatment due to the slow turnover of the tissues. The model explains why thyroid disorders such as Hashimoto's thyroiditis and Graves' disease have both subclinical and clinical states and explains the complex inverse relation between TSH and thyroid hormones. The present model may guide approaches to dynamically adjust the treatment of thyroid disorders.

Background Maccabi-RED is a new service developed in Israel that allows primary care staff to direct urgent cases to specialists in the community for evaluation in their local clinics on the same day as an alternative to an emergency department (ED) visit. A primary care physician or a nurse can activate the service, and all nearby specialists receive "a call" and can decide if they are willing to accept it, thus allowing the patient to avoid an unnecessary visit to the ED. Aim To quantify and characterize the medical care provided by this service in a large national healthcare system. Design and Setting Multicenter, community-based, retrospective cohort study. Methods All Maccabi-RED visits recorded between September 2021 and August 2022 were included. Patient characteristics were compared to national demographics. Descriptive statistics were used to present data regarding recorded diagnoses, treating physicians, treatments or referrals provided, and subsequent emergency department admissions or hospitalizations. Results 31831 visits were recorded. Most frequent diagnoses were musculoskeletal pain (12.1%), otitis or otalgia (7.8%), contusions (7.6%), fractures (7.1%), foreign body (6.7%), pregnancy-related symptoms (6.3%), and upper-respiratory or unspecified viral infection (6.3%). The most common treatments reported were foreign body removal (5%) and cast application (3.5%). Only 7.8% of visits resulted in emergency department admission within seven days (any cause). The average time from patient request to physician treatment was 91 min. Conclusions Maccabi-RED is being widely used by patients nationwide. Additional studies are needed to investigate whether Maccabi-RED reduces emergency department visits and costs. [ABSTRACT FROM AUTHOR]

Summary: Interventions to reduce fat are important for human health. However, they can have opposing effects such as exercise that decreases fat but increases food intake, or coherent effects such as leptin resistance which raises both. Furthermore, some interventions show an overshoot in food intake, such as recovery from a diet, whereas others do not. To explain these properties we present a graphical framework called the operating point model, based on leptin control of feeding behavior. Steady-state fat and food intake is given by the intersection of two experimental curves – steady-state fat at a given food intake and ad libitum food intake at a given fat level. Depending on which curve an intervention shifts, it has opposing or coherent effects with or without overshoot, in excellent agreement with rodent data. The model also explains the quadratic relation between leptin and fat in humans. These concepts may guide the understanding of fat regulation disorders.

Abstract Stress activates a complex network of hormones known as the hypothalamic–pituitary–adrenal (HPA) axis. The HPA axis is dysregulated in chronic stress and psychiatric disorders, but the origin of this dysregulation is unclear and cannot be explained by current HPA models. To address this, we developed a mathematical model for the HPA axis that incorporates changes in the total functional mass of the HPA hormone‐secreting glands. The mass changes are caused by HPA hormones which act as growth factors for the glands in the axis. We find that the HPA axis shows the property of dynamical compensation, where gland masses adjust over weeks to buffer variation in physiological parameters. These mass changes explain the experimental findings on dysregulation of cortisol and ACTH dynamics in alcoholism, anorexia, and postpartum. Dysregulation occurs for a wide range of parameters and is exacerbated by impaired glucocorticoid receptor (GR) feedback, providing an explanation for the implication of GR in mood disorders. These findings suggest that gland‐mass dynamics may play an important role in the pathophysiology of stress‐related disorders.

Many distinct spaces surround our bodies. Most schematically, the key division is between peripersonal space (PPS), the close space surrounding our body, and an extrapersonal space, which is the space out of one’s reach. The PPS is considered as an action space, which allows us to interact with our environment by touching and grasping. In the current scientific literature, PPS’ visual representations are appearing as mere bubbles of even dimensions wrapped around the body. Although more recent investigations of PPS’ upper body (trunk, head, and hands) and lower body (legs and foot) have provided new representations, no investigation has been made yet concerning the estimation of PPS’s overall representation in 3D. Previous findings have demonstrated how the relationship between tactile processing and the location of sound sources in space is modified along a spatial continuum. These findings suggest that similar methods can be used to localize the boundaries of the subjective individual representation of PPS. Hence, we designed a behavioral paradigm in virtual reality based on audio-tactile interactions, which has enabled us to infer a detailed individual 3D audio-tactile representation of PPS. Considering that inadequate body-related multisensory integration processes can produce incoherent spatio–temporal perception, the development of a virtual reality setup and a method to estimate the representation of the subjective PPS volumetric boundaries will be a valuable addition for the comprehension of the mismatches occurring between body physical boundaries and body schema representations in 3D.

Aims: To evaluate the benefit of speckle tracking radial strain imaging (STRSI)-guided left ventricular (LV) lead (LVL) positioning in cardiac resynchronization therapy (CRT) in patients (pts) with ischaemic cardiomyopathy with CRT indication.Methods and Results: We conducted a prospective randomized controlled trial. Patients were enrolled in nine centres with 2:1 randomization into two groups (guided vs. control). Patients underwent STRSI to identify the optimal LV position from six LV segments at midventricular level. Implantation via STRSI was attempted for recommended segment in the guided group only. Follow-up included echocardiography (6 months) and clinical evaluation (6 and 12 months). The primary endpoint was comparison % reduction in LV end-systolic volume at 6 months with baseline. Secondary endpoints included hospitalizations for heart failure and death, and improvement in additional echocardiographic measurements and quality of life score. A total of 172 patients (115 guided vs. 57 control) were enrolled. In the guided group, 60% of the implanted LV leads were adjudicated to be successfully located at the recommended segment, whereas in the control group 44% reached the best STRSI determined segment. There was no difference between the groups in any of the primary or secondary endpoints at 6 and 12 months.Conclusion: Our findings suggest that echo-guided implantation of an LV lead using STRSI does not improve the clinical or echocardiographic response compared with conventional implantation. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the benefit of speckle tracking radial strain imaging (STRSI)-guided left ventricular (LV) lead (LVL) positioning in cardiac resynchronization therapy (CRT) in patients (pts) with ischaemic cardiomyopathy with CRT indication., Methods and Results: We conducted a prospective randomized controlled trial. Patients were enrolled in nine centres with 2:1 randomization into two groups (guided vs. control). Patients underwent STRSI to identify the optimal LV position from six LV segments at midventricular level. Implantation via STRSI was attempted for recommended segment in the guided group only. Follow-up included echocardiography (6 months) and clinical evaluation (6 and 12 months). The primary endpoint was comparison % reduction in LV end-systolic volume at 6 months with baseline. Secondary endpoints included hospitalizations for heart failure and death, and improvement in additional echocardiographic measurements and quality of life score. A total of 172 patients (115 guided vs. 57 control) were enrolled. In the guided group, 60% of the implanted LV leads were adjudicated to be successfully located at the recommended segment, whereas in the control group 44% reached the best STRSI determined segment. There was no difference between the groups in any of the primary or secondary endpoints at 6 and 12 months., Conclusion: Our findings suggest that echo-guided implantation of an LV lead using STRSI does not improve the clinical or echocardiographic response compared with conventional implantation., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)