Excitable dynamics of flares and relapses in autoimmune diseases.

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.

First-in-human study of the CAPTIS embolic protection system during transcatheter aortic valve replacement.

BACKGROUND: Stroke and other clinically significant embolic complications are well documented in the early period following transcatheter aortic valve replacement (TAVR). The CAPTIS device is an embolic protection system, designed to provide neurovascular and systemic protection by deflecting debris away from the brain's circulation, capturing the debris and thus avoiding systemic embolisation. AIMS: We aimed to study the safety and feasibility study of the CAPTIS complete cerebral and full-body embolic protection system during TAVR. METHODS: A first-in-human study investigated the safety, feasibility and debris capturing ability of CAPTIS during TAVR. Patients were followed for 30 days. The primary endpoints were device safety and cerebrovascular events at 72 hours. RESULTS: Twenty patients underwent TAVR using balloon-expandable or self-expanding valve systems. CAPTIS was successfully delivered, positioned, deployed, and retrieved in all cases, and TAVR was successfully completed without device-related complications. No cerebrovascular events were observed. High numbers of debris particles were captured in all patients. CONCLUSIONS: The use of the CAPTIS full-body embolic protection system during TAVR was safe, and it captured a substantial number of debris particles. No patient suffered from a cerebrovascular event. A randomised clinical trial is warranted to prove its efficacy.

Rules for body fat interventions based on an operating point mechanism.

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.

Dynamics of thyroid diseases and thyroid-axis gland masses.

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.

Hormone seasonality in medical records suggests circannual endocrine circuits.

Hormones control the major biological functions of stress response, growth, metabolism, and reproduction. In animals, these hormones show pronounced seasonality, with different set-points for different seasons. In humans, the seasonality of these hormones remains unclear, due to a lack of datasets large enough to discern common patterns and cover all hormones. Here, we analyze an Israeli health record on 46 million person-years, including millions of hormone blood tests. We find clear seasonal patterns: The effector hormones peak in winter-spring, whereas most of their upstream regulating pituitary hormones peak only months later, in summer. This delay of months is unexpected because known delays in the hormone circuits last hours. We explain the precise delays and amplitudes by proposing and testing a mechanism for the circannual clock: The gland masses grow with a timescale of months due to trophic effects of the hormones, generating a feedback circuit with a natural frequency of about a year that can entrain to the seasons. Thus, humans may show coordinated seasonal set-points with a winter-spring peak in the growth, stress, metabolism, and reproduction axes.

Immediate Pneumothorax Diagnosis by Surgical Residents Using Portable Ultrasound.

OBJECTIVE: Feasibility of diagnosis of pneumothorax using handheld ultrasound by non-radiologists shows inconsistent results. The aim of this study is to evaluate the feasibility and accuracy of portable ultrasound for immediate diagnosis of pneumothorax by general surgery residents who underwent short training. METHODS: Patients who presented to the emergency department of a university hospital with suspected pneumothorax between 10/2018 and 12/2019 were included in the study. Patients underwent ultrasound in 2 points of each hemithorax. Sensitivity and specificity for pneumothorax diagnosis by ultrasound and physical examination were calculated and compared with chest computed tomography (CT). Patients in whom a chest tube was placed prior to ultrasound examination and those who did not undergo a CT scan were excluded from the study. RESULTS: A total of 85 patients met the inclusion criteria. Mean age was 40.7 ± 20.2 years. Pneumothorax was found among 46 patients (54%) per chest CT, and of these, 21 (46%) underwent chest tube placement following imaging. Ultrasound showed the highest sensitivity and specificity (95.6% [95% confidence interval {CI} 85.16% to 99.47%] and 97.44% [95% CI 86.40% to 99.67%], respectively). Chest x-ray had the lowest sensitivity (47.8% [95% CI 32.89% to 63.05%]) for pneumothorax detection. Physical examination showed a moderate sensitivity and specificity (82.6% [95% CI 68.58% to 92.18%] and 77.89% [95% CI 60.67% to 88.87%], respectively) for the diagnosis of pneumothorax. CONCLUSIONS: We found high accuracy rates of 2-point ultrasound in immediate pneumothorax diagnosis when performed by surgical residents who underwent a short ultrasound training. This is a fast and repeatable test, and has the potential for successful implementation in prehospital and military scenarios as well, minimizing unnecessary chest tube placements.

A new model for the HPA axis explains dysregulation of stress hormones on the timescale of weeks.

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.

Clinical Course and Outcomes of Severe Covid-19: A National Scale Study.

Knowledge of the outcomes of critically ill patients is crucial for health and government officials who are planning how to address local outbreaks. The factors associated with outcomes of critically ill patients with coronavirus disease 2019 (Covid-19) who required treatment in an intensive care unit (ICU) are yet to be determined. METHODS: This was a retrospective registry-based case series of patients with laboratory-confirmed SARS-CoV-2 who were referred for ICU admission and treated in the ICUs of the 13 participating centers in Israel between 5 March and 27 April 2020. Demographic and clinical data including clinical management were collected and subjected to a multivariable analysis; primary outcome was mortality. RESULTS: This study included 156 patients (median age = 72 years (range = 22-97 years)); 69% (108 of 156) were male. Eighty-nine percent (139 of 156) of patients had at least one comorbidity. One hundred three patients (66%) required invasive mechanical ventilation. As of 8 May 2020, the median length of stay in the ICU was 10 days (range = 0-37 days). The overall mortality rate was 56%; a multivariable regression model revealed that increasing age (OR = 1.08 for each year of age, 95%CI = 1.03-1.13), the presence of sepsis (OR = 1.08 for each year of age, 95%CI = 1.03-1.13), and a shorter ICU stay(OR = 0.90 for each day, 95% CI = 0.84-0.96) were independent prognostic factors. CONCLUSIONS: In our case series, we found lower mortality rates than those in exhausted health systems. The results of our multivariable model suggest that further evaluation is needed of antiviral and antibacterial agents in the treatment of sepsis and secondary infection.