Preclinical proof of principle for orally delivered Th17 antagonist miniproteins.

Interleukin (IL)-23 and IL-17 are well-validated therapeutic targets in autoinflammatory diseases. Antibodies targeting IL-23 and IL-17 have shown clinical efficacy but are limited by high costs, safety risks, lack of sustained efficacy, and poor patient convenience as they require parenteral administration. Here, we present designed miniproteins inhibiting IL-23R and IL-17 with antibody-like, low picomolar affinities at a fraction of the molecular size. The minibinders potently block cell signaling in vitro and are extremely stable, enabling oral administration and low-cost manufacturing. The orally administered IL-23R minibinder shows efficacy better than a clinical anti-IL-23 antibody in mouse colitis and has a favorable pharmacokinetics (PK) and biodistribution profile in rats. This work demonstrates that orally administered de novo-designed minibinders can reach a therapeutic target past the gut epithelial barrier. With high potency, gut stability, and straightforward manufacturability, de novo-designed minibinders are a promising modality for oral biologics.

Report from Health Professionals and Cancer Patients: Experiences and Wishes from Clinical Practice About the Integration of Quality of Life with a Health App.

Advanced cancer treatments increase survival rates and with that the importance of Quality of Life (QoL). QoL is well studied in trials, but the transition to standard care is little. For this reason, we identified the challenges for a regular integration to conceptualize an applicable solution together with patients and health professionals (HP). We conducted two meetings based on the design thinking method. Two Physicians, one employee of cancer counseling centers, one psycho-oncologists, and five patients were included. Based on the discussions a system was conceptualized to solve current thresholds. All participants had experience with the documentation of QoL, but none had shared it digitally from home. Therefore, the main threshold was the lack of system for data transition between agents, followed by lack of time for HP and acceptance of QoL for patients. HP were mainly interested in data on the trend of QoL whereas patients preferred information on their activity, energy level and social contacts. The conceptualized solution is based on a health app on the patients' side with a browser-based implementation for HP. Within the system, automatized data interpretation, alarm systems, support information, standardized input fields as an orientation for documentation with expandable options for specific restrictions as well as interinstitutional networking for HP to better refer patients to others was wished for. This article describes the concept of such a system developed with HP and patients. Implementation and transfer to clinical care has yet to be done.

Rapid Cycle Deliberate Practice Training for Simulated Cardiopulmonary Resuscitation in Resident Education.

Background: Simulation-based medical education has been used in medical training for decades. Rapid cycle deliberate practice (RCDP) is a novel simulation strategy that uses iterative practice and feedback to achieve skill mastery. To date, there has been minimal evaluation of RCDP vs standard immersive simulation (IS) for the teaching of cardiopulmonary resuscitation to graduate medical education (GME) learners. Our primary objective was to compare the time to performance of Advanced Cardiac Life Support (ACLS) actions between trainees who completed RCDP vs IS. Methods: This study was a prospective, randomized, controlled curriculum evaluation. A total of 55 postgraduate year-1 internal medicine and emergency medicine residents participated in the study. Residents were randomized to instruction by RCDP (28) or IS (27). Stress and ability were self-assessed before and after training using an anonymous survey that incorporated five-point Likert-type questions. We measured and compared times to initiate critical ACLS actions between the two groups during a subsequent IS. Results: Prior learner experience between RCDP and IS groups was similar. Times to completion of the first pulse check, chest compression initiation, backboard placement, pad placement, initial rhythm analysis, first defibrillation, epinephrine administration, and antiarrhythmic administration were similar between RCDP and IS groups. However, RCDP groups took less time to complete the pulse check between compression cycles (6.2 vs 14.2 seconds, P = 0.01). Following training, learners in the RCDP and IS groups scored their ability to lead and their levels of anticipated stress similarly (3.43 vs 3.30, (P = 0.77), 2.43 vs. 2.41, P = 0.98, respectively). However, RCDP groups rated their ability to participate in resuscitation more highly (4.50 vs 3.96, P = 0.01). The RCDP groups also reported their realized stress of participating in the event as lower than that of the IS groups (2.36 vs 2.85, P = 0.01). Conclusion: Rapid cycle deliberate practice learners demonstrated a shorter pulse check duration, reported lower stress levels associated with their experience, and rated their ability to participate in ACLS care more highly than their IS-trained peers. Our results support further investigation of RCDP in other simulation settings.

Performance of Febrile Infant Decision Tools on Hypothermic Infants Evaluated for Infection.

BACKGROUND: Given the lack of evidence-based guidelines for hypothermic infants, providers may be inclined to use febrile infant decision-making tools to guide management decisions. Our objective was to assess the diagnostic performance of febrile infant decision tools for identifying hypothermic infants at low risk of bacterial infection. METHODS: We conducted a secondary analysis of a retrospective cohort study of hypothermic (≤36.0 C) infants ≤90 days of age presenting to the emergency department or inpatient unit among 9 participating sites between September 1, 2016 and May 5, 2021. Well-appearing infants evaluated for bacterial infections via laboratory testing were included. Infants with complex chronic conditions or premature birth were excluded. Performance characteristics for detecting serious bacterial infection (SBI; urinary tract infection, bacteremia, bacterial meningitis) and invasive bacterial infection (IBI; bacteremia, bacterial meningitis) were calculated for each tool. RESULTS: Overall, 314 infants met the general inclusion criteria, including 14 cases of SBI (4.5%) and 7 cases of IBI (2.2%). The median age was 5 days, and 68.1% of the infants (214/314) underwent a full sepsis evaluation. The Philadelphia, Boston, IBI Score, and American Academy of Pediatrics Clinical Practice Guideline did not misclassify any SBI or IBI as low risk; however, they had low specificity and positive predictive value. Rochester and Pediatric Emergency Care Applied Research Network tools misclassified infants with bacterial infections. CONCLUSIONS: Several febrile infant decision tools were highly sensitive, minimizing missed SBIs and IBIs in hypothermic infants. However, the low specificity of these decision tools may lead to unnecessary testing, antimicrobial exposure, and hospitalization.