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Aims: The influence of human factors on safety in healthcare settings is well established, with targeted interventions reducing risk and enhancing team performance. In experimental and early phase clinical research participant safety is paramount and safeguarded by guidelines, protocolized care and staff training; however, the real‐world interaction and implementation of these risk‐mitigating measures has never been subjected to formal system‐based assessment. Methods: Independent structured observations, systematic review of study documents, and interviews and focus groups were used to collate data on three key tasks undertaken in a clinical research facility (CRF) during a SARS CoV‐2 controlled human infection model (CHIM) study. The Systems Engineering Initiative for Patient Safety (SEIPS) was employed to analyse and categorize findings, and develop recommendations for safety interventions. Results: High levels of team functioning and a clear focus on participant safety were evident throughout the study. Despite this, latent risks in both study‐specific and CRF work systems were identified in all four SEIPS domains (people, environment, tasks and tools). Fourteen actionable recommendations were generated collaboratively. These included inter‐organization and inter‐study standardization, optimized checklists for safety critical tasks, and use of simulation for team training and exploration of work systems. Conclusions: This pioneering application of human factors techniques to analyse work systems during the conduct of research in a CRF revealed risks unidentified by routine review and appraisal, and despite international guideline adherence. SEIPS may aid categorization of system problems and the formulation of recommendations that reduce risk and mitigate potential harm applicable across a trials portfolio. [ABSTRACT FROM AUTHOR]

Alcoholic liver disease (ALD) is characterized by high morbidity and mortality, and mainly results from prolonged and excessive alcohol use. Amomum villosum Lour. (A. villosum), a well‐known traditional Chinese medicine (TCM), has hepatoprotective properties. However, its ability to combat alcohol‐induced liver injury has not been fully explored. The objective of this study was to investigate the hepatoprotective effects of A. villosum in a rat model of alcohol‐induced liver disease, thereby establishing a scientific foundation for the potential preventive use of A. villosum in ALD. We established a Chinese liquor (Baijiu)‐induced liver injury model in rats. Hematoxylin and eosin (HE) staining, in combination with biochemical tests, was used to evaluate the protective effects of A. villosum on the liver. The integration of network medicine analysis with experimental validation was used to explore the hepatoprotective effects and potential mechanisms of A. villosum in rats. Our findings showed that A. villosum ameliorated alcohol‐induced changes in body weight, liver index, hepatic steatosis, inflammation, blood lipid metabolism, and liver function in rats. Network proximity analysis was employed to identify 18 potentially active ingredients of A. villosum for ALD treatment. These potentially active ingredients in the blood were further identified using mass spectrometry (MS). Our results showed that A. villosum plays a hepatoprotective role by modulating the protein levels of estrogen receptor 1 (ESR1), anti‐nuclear receptor subfamily 3 group C member 1 (NR3C1), interleukin 6 (IL‐6), and tumor necrosis factor‐α (TNF‐α). In conclusion, the results of the current study suggested that A. villosum potentially exerts hepatoprotective effects on ALD in rats, possibly through regulating the protein levels of ESR1, NR3C1, IL‐6, and TNF‐α. [ABSTRACT FROM AUTHOR]

Background: Our aim was to develop a validated Patient Reported Experience Measure (PREM) to capture patient and carer experience during participation in experimental cancer medicine trials (ECM): called PREM-ECM. Methods: Mixed method design, consisting of four stages. Questionnaire items were produced for both patients and carers using interviews, focus groups, and cognitive interviews with patients and carers separately. For both patient and carer PREMs, a cross-sectional questionnaire study was conducted to identify final items for inclusion using hierarchical item reduction and Rasch analysis. Questionnaire validity and reliability were assessed, including administration feasibility. Results: Initial interview participants suggested the need for three PREMs, two specific to patients: (i) a 'prior' questionnaire that captured experiences of trial introduction, screening, consenting, and early trial experience (< 6 weeks post consent); and (ii) 'on-trial' that captured experiences of ongoing consent and trial participation; and (iii) a PREM specific for carers. The draft 25-item 'prior' questionnaire was completed by 162 patients and 162 patients completed the draft 35-item 'on-trial' questionnaire. Hierarchical and Rasch analysis produced a 14-item 'prior' list and a 15-item list for 'on-trial'. Both patient PREM's demonstrated a good fit to the Rasch model following Bonferroni correction (X2p = 0.008). The carer 34-draft item questionnaire was completed by 102 participants. Hierarchical and Rasch analysis produced a 13-item list for PREM-ECM-Carer, with good fit to the Rasch model (X2p = 0.62). The pilot testing demonstrated the feasibility of all the PREMs in capturing patient and caregiver experiences in routine clinical settings. Conclusions: The three PREM-ECM questionnaires will be the first validated experience measures for ECM trial patients and their carers. These questionnaires may be used to assess patients' and their carers' experiences of ECM and enable robust comparisons across cancer trial units highlighting areas for service improvement. [ABSTRACT FROM AUTHOR]

Background: Accidental hypothermia is common in all trauma patients and contributes to the lethal diamond, increasing both morbidity and mortality. In hypotensive shock, fluid resuscitation is recommended using fluids with a temperature of 37–42°, as fluid temperature can decrease the patient's body temperature. In Sweden, virtually all prehospital services use preheated fluids. The aim of the present study was to investigate how the temperature of preheated infusion fluids is affected by the ambient temperatures and flow rates relevant for prehospital emergency care. Methods: In this experimental simulation study, temperature changes in crystalloids preheated to 39 °C were evaluated. The fluid temperature changes were measured both in the infusion bag and at the patient end of the infusion system. Measurements were conducted in conditions relevant to prehospital emergency care, with ambient temperatures varying between − 4 and 28 °C and flow rates of 1000 ml/h and 6000 ml/h, through an uninsulated infusion set at a length of 175 cm. Results: The flow rate and ambient temperature affected the temperature in the infusion fluid both in the infusion bag and at the patient end of the system. A lower ambient temperature and lower flow rate were both associated with a greater temperature loss in the infusion fluid. Conclusion: This study shows that both a high infusion rate and a high ambient temperature are needed if an infusion fluid preheated to 39 °C is to remain above 37 °C when it reaches the patient using a 175-cm-long uninsulated infusion set. It is apparent that the lower the ambient temperature, the higher the flow rate needs to be to limit temperature loss of the fluid. [ABSTRACT FROM AUTHOR]

Hyaluronic acid (HA), a major glycosaminoglycan of the brain extracellular matrix, modulates cell behaviors through binding its receptor, Cd44. In this study, we assessed the influence of HA on high-grade brain tumors in vitro. The model comprised cell cultures derived from six rodent carcinogen-induced brain tumors, forming 3D spheroids prone to spontaneous fusion. Supplementation of the standard culture medium with 0.25% HA significantly inhibited the fusion rates, preserving the shape and size uniformity of spheroids. The 3D cultures were assigned to two groups; a Cd44lo group had a tenfold decreased relative expression of Cd44 than another (Cd44hi) group. In addition, these two groups differed by expression levels of Sox2 transcription factor; the correlation analysis revealed a tight negative association for Cd44 and Sox2. Transcriptomic responses of spheroids to HA exposure also depended on Cd44 expression levels, from subtle in Cd44lo to more pronounced and specific in Cd44hi, involving cell cycle progression, PI3K/AKT/mTOR pathway activation, and multidrug resistance genes. The potential HA-induced increase in brain tumor 3D models' resistance to anticancer drug therapy should be taken into account when designing preclinical studies using HA scaffold-based models. The property of HA to prevent the fusion of brain-derived spheroids can be employed in CNS regenerative medicine and experimental oncology to ensure the production of uniform, controllably fusing neurospheres when creating more accurate in vitro brain models. [ABSTRACT FROM AUTHOR]

On 15–16 June 2023, healthcare professionals and breast cancer patients and advocates from across Canada met in Toronto, Ontario, for the 2023 Canadian Breast Cancer Symposium (CBSC.). The CBSC. is a national, multidisciplinary event that occurs every 2 years with the goal of developing a personalized approach to the management of breast cancer in Canada. Experts provided state-of-the-art information to help optimally manage breast cancer patients, including etiology, prevention, diagnosis, experimental biology, and therapy of breast cancer and premalignant breast disease. The symposium also had the objectives of increasing communication and collaboration among breast cancer healthcare providers nationwide and providing a comprehensive and real-life review of the many facets of breast cancer. The sessions covered the patient voice, the top breast cancer papers from different disciplines in 2022, artificial intelligence in breast cancer, systemic therapy updates, the management of central nervous system metastases, multidisciplinary management of ductal carcinoma in situ, special populations, optimization-based individual prognostic factors, toxicity management of novel therapeutics, survivorship, and updates in surgical oncology. The key takeaways of these sessions have been summarized in this conference report. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is a type of cancer that originates from the mucosal lining of the nasopharynx and can invade and spread. Although contemporary chemoradiotherapy effectively manages the disease locally, there are still challenges with locoregional recurrence and distant failure. Therefore, it is crucial to have a deeper understanding of the molecular basis of NPC cell movement in order to develop a more effective treatment and to improve patient survival rates. Cancer cell line models are invaluable in studying health and disease and it is not surprising that they play a critical role in NPC research. Consequently, scientists have established around 80 immortalized human NPC lines that are commonly used as in vitro models. However, over the years, it has been observed that many cell lines are misidentified or contaminated by other cells. This cross-contamination leads to the creation of false cell lines that no longer match the original donor. In this commentary, we discuss the impact of misidentified NPC cell lines on the scientific literature. We found 1159 articles from 2000 to 2023 that used NPC cell lines contaminated with HeLa cells. Alarmingly, the number of publications and citations using these contaminated cell lines continued to increase, even after information about the contamination was officially published. These articles were most commonly published in the fields of oncology, pharmacology, and experimental medicine research. These findings highlight the importance of science policy and support the need for journals to require authentication testing before publication. [ABSTRACT FROM AUTHOR]

Experimental studies devoted to the study of the mechanisms of the pathogenesis of acute peritonitis and the development of new methods of medical and surgical treatment are becoming increasingly relevant. Today, experimental medicine knows many different ways to modeling septic peritonitis and eliminate it, but the role of the local immune system is underestimated, whereas it takes a direct part in inflammation. The objective of our work to study morphological features of results of experimental modeling of septic peritonitis in white rats. The study included 15 sexually mature white male rats weighing 276.75±6.56 grams. A simulation of septic peritonitis was performed by perforating the upper part of the cecum with four punctures with a G16 injection needle. As a result of the experiment, after examination of the peritoneal cavity, all 15 animals were diagnosed with omentum tamponade of perforated damage to the caecum. In 11 cases, the perforated wall of the caecum was covered by the greater omentum (73.34 %), and in the other 4 animals, tamponade was performed by one of the epididymal omentum (26.66 %). The initial stage of tamponade with the greater or epididymal omentums of a perforated caecum begins on the first day of the experiment and consists of tight interstitial consolidation between them, as well as in the invasion of blood vessels from the omentum side to the focus of infection, which ensure the delivery of the appropriate immunocompetent cells. As a result of this process, intensive lymphoid infiltrates are formed in this area, as well as the growth of adipose tissue, which isolates the inflammatory focus from the peritoneal cavity with a thick layer. [ABSTRACT FROM AUTHOR]

Strategies to separately manufacture arterial-scale tissue engineered vascular grafts and microvascular networks have been well-established, but efforts to bridge these two length scales to create hierarchical vasculature capable of supporting parenchymal cell functions or restoring perfusion to ischemic tissues have been limited. This work aimed to create multiscale vascular constructs by assessing the capability of macroscopic vessels isolated from mice to form functional connections to engineered capillary networks ex vivo. Vessels of venous and arterial origins from both thoracic and femoral locations were isolated from mice, and then evaluated for their abilities to sprout endothelial cells (EC) capable of inosculating with surrounding human cell-derived microvasculature within bulk fibrin hydrogels. Comparing aortae, vena cavae, and femoral vessel bundles, we identified the thoracic aorta as the rodent macrovessel that yielded the greatest degree of sprouting and interconnection to surrounding capillaries. The presence of cells undergoing vascular morphogenesis in the surrounding hydrogel attenuated EC sprouting from the macrovessel compared to sprouting into acellular hydrogels, but ultimately sprouted mouse EC interacted with human cell-derived capillary networks in the bulk, yielding chimeric vessels. We then integrated micromolded mesovessels into the constructs to engineer a primitive 3-scale vascular hierarchy comprising capillaries, mesovessels, and macrovessels. Overall, this study yielded a primitive hierarchical vasculature suitable as proof-of-concept for regenerative medicine applications and as an experimental model to better understand the spontaneous formation of host-graft vessel anastomoses. [ABSTRACT FROM AUTHOR]

Strategies to separately manufacture arterial-scale tissue engineered vascular grafts and microvascular networks have been well-established, but efforts to bridge these two length scales to create hierarchical vasculature capable of supporting parenchymal cell functions or restoring perfusion to ischemic tissues have been limited. This work aimed to create multiscale vascular constructs by assessing the capability of macroscopic vessels isolated from mice to form functional connections to engineered capillary networks ex vivo. Vessels of venous and arterial origins from both thoracic and femoral locations were isolated from mice, and then evaluated for their abilities to sprout endothelial cells (EC) capable of inosculating with surrounding human cell-derived microvasculature within bulk fibrin hydrogels. Comparing aortae, vena cavae, and femoral vessel bundles, we identified the thoracic aorta as the rodent macrovessel that yielded the greatest degree of sprouting and interconnection to surrounding capillaries. The presence of cells undergoing vascular morphogenesis in the surrounding hydrogel attenuated EC sprouting from the macrovessel compared to sprouting into acellular hydrogels, but ultimately sprouted mouse EC interacted with human cell-derived capillary networks in the bulk, yielding chimeric vessels. We then integrated micromolded mesovessels into the constructs to engineer a primitive 3-scale vascular hierarchy comprising capillaries, mesovessels, and macrovessels. Overall, this study yielded a primitive hierarchical vasculature suitable as proof-of-concept for regenerative medicine applications and as an experimental model to better understand the spontaneous formation of host-graft vessel anastomoses. [ABSTRACT FROM AUTHOR]

Introduction: Receptor-interacting protein kinase 1 (RIPK1), a key mediator of inflammation through necroptosis and proinflammatory cytokine production, may play a role in the pathogenesis of immune-mediated inflammatory diseases such as chronic plaque psoriasis. An experimental medicine study of RIPK1 inhibition with GSK2982772 immediate-release formulation at doses up to 60 mg three times daily in mild to moderate plaque psoriasis indicated that efficacy may be improved with higher trough concentrations of GSK2982772. Methods: This multicenter, randomized, double-blind, placebo-controlled, repeat-dose study (NCT04316585) assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of 960 mg GSK2982772 (once-daily modified-release formulation) in patients with moderate to severe plaque psoriasis. Twenty-nine patients were randomized 2:1 to GSK2982772 (N = 19) or placebo (N = 10) for 12 weeks. Results: GSK2982772 was well tolerated with trough concentrations greater than tenfold higher than the previous phase 1 study with immediate release. Despite near complete RIPK1 target engagement in blood and modest reduction in circulating inflammatory cytokines, the proportion of patients achieving 75% improvement from baseline in Psoriasis Area Severity Index score at week 12 was similar between GSK2982772 and placebo (posterior median 1.8% vs 4.9%, respectively), with an estimated median treatment difference of − 2.3%. This analysis incorporated historical placebo data through the use of an informative prior distribution on the placebo arm. Week 4 changes in skin biopsy gene expression suggested sufficient local drug exposure to elicit a pharmacodynamic response. Conclusion: Administration of the RIPK1 inhibitor GSK2982772 to patients with moderate to severe plaque psoriasis did not translate into meaningful clinical improvements. Plain Language Summary: Psoriasis is thought to be caused by problems with the immune system, including possibly receptor-interacting protein kinase 1 (RIPK1), which plays an important role in the development of inflammation. A previous study suggested that the drug, GSK2982772, which interferes with RIPK1, might improve symptoms in patients with psoriasis. This study examined whether higher doses of GSK2982772 than previously studied would be beneficial for patients with psoriasis. The study found that the severity of psoriasis was similar in patients treated with GSK2982772 for 12 weeks as in those who did not receive the drug, indicating that GSK298772 did not improve psoriasis. [ABSTRACT FROM AUTHOR]

The article discusses the prevalence and evaluation of postoperative pain following root canal treatment. It highlights the increase in clinical trials focusing on postoperative pain as a primary outcome, but questions the relevance of short-term pain studies in determining the efficacy of different irrigation protocols. The article emphasizes the subjective nature of pain and the presence of confounding factors that make it challenging to attribute pain solely to irrigation. It suggests that longer-term follow-up or the control of various variables is necessary for more meaningful results. The article concludes by suggesting the consideration of objective surrogate outcomes, such as inflammatory markers, in future studies. [Extracted from the article]

BACKGROUND. Phase 1 study of ATR inhibition alone or with radiation therapy (PATRIOT) was a first-in-human phase I study of the oral ATR (ataxia telangiectasia and Rad3-related) inhibitor ceralasertib (AZD6738) in advanced solid tumors. METHODS. The primary objective was safety. Secondary objectives included assessment of antitumor responses and pharmacokinetic (PK) and pharmacodynamic (PD) studies. Sixty-seven patients received 20--240 mg ceralasertib BD continuously or intermittently (14 of a 28-day cycle). RESULTS. Intermittent dosing was better tolerated than continuous, which was associated with dose-limiting hematological toxicity. The recommended phase 2 dose of ceralasertib was 160 mg twice daily for 2 weeks in a 4-weekly cycle. Modulation of target and increased DNA damage were identified in tumor and surrogate PD. There were 5 (8%) confirmed partial responses (PRs) (40--240 mg BD), 34 (52%) stable disease (SD), including 1 unconfirmed PR, and 27 (41%) progressive disease. Durable responses were seen in tumors with loss of AT-rich interactive domain-containing protein 1A (ARID1A) and DNA damage-- response defects. Treatment-modulated tumor and systemic immune markers and responding tumors were more immune inflamed than nonresponding. CONCLUSION. Ceralasertib monotherapy was tolerated at 160 mg BD intermittently and associated with antitumor activity. TRIAL REGISTRATION. Clinicaltrials.gov: NCT02223923, EudraCT: 2013-003994-84. FUNDING. Cancer Research UK, AstraZeneca, UK Department of Health (National Institute for Health Research), Rosetrees Trust, Experimental Cancer Medicine Centre. [ABSTRACT FROM AUTHOR]

Objectives: Bee venom is used for medicinal purposes, including the treatment of neurological and liver diseases, but its use as a primary health care approach for preventive purposes requires further exploration. The aim of this study was to provide the first investigation into the possible protective effects of bee venom against hepatic encephalopathy, a serious neurodegenerative disease. Materials and Methods: An experimental animal study was conducted in which healthy albino Sprague–Dawley rats were randomized into three groups: healthy, control and bee venom groups. All rats were tested for locomotor activity at the beginning and end of the study. No intervention was made in the healthy group, whereas hepatic encephalopathy was induced in the control and bee venom groups by the administration of thioacetamide (TAA) (200 mg/kg/day). The bee venom group also received bee venom (5 mg/kg/day) subcutaneously every day for 14 days prior to the TAA administration. Results: The results for the final locomotor activity tests were statistically better in the bee venom group than in the control group, supporting a beneficial effect of prophylactic bee venom application. Blood ammonia levels and liver weights, determined as indicators of inflammation, were lower in the bee venom group than in the control group and were close to levels in the healthy group, but not statistically significant. Conclusions: Bee venom administration has protective effects against the development of hepatic encephalopathy and offers a promising therapeutic opportunity in preventive medicine. [ABSTRACT FROM AUTHOR]

The number of retracted papers from Chinese university-affiliated hospitals is increasing, which has raised much concern. The aim of this study is to analyze the retracted papers from university-affiliated hospitals in mainland China from 2000 to 2021. Data for 1,031 retracted papers were identified from the Web of Science Core collection database. The information of the hospitals involved was obtained from their official websites. We analyzed the chronological changes, journal distribution, discipline distribution and retraction reasons for the retracted papers. The grade and geographic locations of the hospitals involved were explored as well. We found a rapid increase in the number of retracted papers, while the retraction time interval is decreasing. The main reasons for retraction are plagiarism/self-plagiarism (n=255), invalid data/images/conclusions (n=212), fake peer review (n=175) and honesty error(n=163). The disciplines are mainly distributed in oncology (n=320), pharmacology & pharmacy (n=198) and research & experimental medicine (n=166). About 43.8% of the retracted papers were from hospitals affiliated with prestigious universities. This study fails to differentiate between retractions due to honest error and retractions due to research misconduct. We believe that there is a fundamental difference between honest error retractions and misconduct retractions. Another limitation is that authors of the retracted papers have not been analyzed in this study. This study provides a reference for addressing research misconduct in Chinese university-affiliated hospitals. It is our recommendation that universities and hospitals should educate all their staff about the basic norms of research integrity, punish authors of scientific misconduct retracted papers, and reform the unreasonable evaluation system. Based on the analysis of retracted papers, this study further analyzes the characteristics of institutions of retracted papers, which may deepen the research on retracted papers and provide a new perspective to understand the retraction phenomenon. [ABSTRACT FROM AUTHOR]

Introduction Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that requires multidisciplinary care. Evidence-based practice indicates that early intervention may improve long-term ASD outcomes. The Autism Resource Clinic (ARC) provides an educational session for guardians empowering them to build a personalized ASD team for their child. We examined the impact of guardian attendance of an ARC at a Military Treatment Facility on time to initiation of patient services and guardian stress level. Materials and Methods A quasi-experimental controlled study was conducted comparing a group of guardians attending the ARC with a group of guardians not attending the ARC following a child's initial ASD diagnosis. ARC speakers included medical, county/state, community/military, and advocacy experts. Surveys were completed at diagnosis, 1, 2, and 3 mo postdiagnosis. Initiation of patient services and Parental Stress Scale scores were compared between groups using independent samples t -test, chi-square tests, or nonparametric tests, as appropriate. Results Use of Applied Behavioral Analysis was significantly higher among ARC attendees vs. nonattendees (73.3% vs. 33.3%, P  = 0.028). County early intervention was more frequent among ARC attendees versus nonattendees (40% vs. 13.3%, P  = 0.09). Of borderline significance, median time to initiation of genetics services was greater in ARC attendees vs. nonattendees (106 vs. 65.5, P  = 0.10). The two groups did not differ on changes in Parental Stress Scale score from baseline to follow-up months 1, 2, or 3. Conclusions Although ARC did not influence time to initiation of patient services or guardian stress level, attendance of ARC was associated with more frequent use of Applied Behavioral Analysis services and county early intervention services. This pilot study is unique as it targets guardians of ASD patients within military treatment facilities. Study limitations include data collection during the coronavirus disease 2019 pandemic, sequential evaluation of experimental and control groups, sample size and generalizability. A large, multicenter, randomized controlled trial is required to better assess the impact of this educational opportunity among military populations. [ABSTRACT FROM AUTHOR]

This article presents the findings of a study conducted in Uruguay to determine the prevalence and endoscopic-histological correlation of premalignant gastric lesions. The study included 102 patients who underwent upper endoscopy and gastric biopsies. The prevalence of chronic atrophic gastritis (CAG) was found to be 38.2%, while intestinal metaplasia (IM) had a prevalence of 31.4%. The endoscopic-histological correlation for CAG and IM was low, indicating the need for biopsy for diagnosis in all cases. The study also identified a low proportion of high-risk stages of premalignant lesions. [Extracted from the article]

The global burden of respiratory diseases is very high and still on the rise, prompting the need for accurate models for basic and translational research. Several model systems are currently available ranging from simple airway cell cultures to complex tissue-engineered lungs. In recent years, human lung organoids have been established as highly transferrable three-dimensional in vitro model systems for lung research. For acute infectious and chronic inflammatory diseases as well as lung cancer, human lung organoids have opened possibilities for precise in vitro research and a deeper understanding of mechanisms underlying lung injury and regeneration. Human lung organoids from induced pluripotent stem cells or from adult stem cells of patients' samples introduce tools for understanding developmental processes and personalized medicine approaches. When further state-of-the-art technologies and protocols come into use, the full potential of human lung organoids can be harnessed. High-throughput assays in drug development, gene therapy, and organoid transplantation are current applications of organoids in translational research. In this review, we emphasize novel approaches in translational and personalized medicine in lung research focusing on the use of human lung organoids. [ABSTRACT FROM AUTHOR]

• SOBC tools aid behavioral interventionists using the experimental medicine approach. • SOBC emphasizes mechanistic insights about malleable behavioral processes. • SOBC intervention development requires measurement of target engagement. • CLIMBR enhances SOBC open science resources and health behavior change research. The National Institutes of Health established the Science of Behavior Change (SOBC) program to promote basic research on the initiation, personalization, and maintenance of health behavior change. The SOBC Resource and Coordinating Center now leads and supports activities to maximize the creativity, productivity, scientific rigor, and dissemination of the experimental medicine approach and experimental design resources. Here, we highlight those resources, including the Checklist for Investigating Mechanisms in Behavior-change Research (CLIMBR) guidelines introduced in this special section. We describe the ways in which SOBC can be applied across a range of domains and contexts, and end by considering ways to extend SOBC's perspective and reach, so as to best promote behavior change linked with health, quality of life, and well-being. [ABSTRACT FROM AUTHOR]

• This is the introductory article for a special section on mechanistic science. • The NIH Science of Behavior Change (SOBC) program offers an approach for this science. • Articles highlight research reflecting the recommended SOBC developmental progression. This article introduces the special section, "An Experimental Therapeutics Focus on Novel Mechanistic Targets in Cognitive Behavioral Treatments." The purpose of this special section is to highlight research that follows the recommended Science of Behavior Change (SOBC) developmental progression for an experimental medicine approach to identifying and testing mechanisms of behavior change. Emphasis was placed on the earlier stage "pipeline" of investigations of novel mechanisms for behavior change: mechanisms that are undergoing the initial stages of validation. In this series, seven empirical articles are presented and are followed by an article detailing a checklist for reporting mechanistic research studies in order to improve communication of findings in the field. The final article in this series discusses the history, current status, and future directions for the SOBC approach to mechanistic science as viewed by National Institute of Health program officials. [ABSTRACT FROM AUTHOR]

• Mechanistic target of error sensitivity (error-related negativity [ERN]) is identified. • Impact of a computerized intervention on error sensitivity is examined. • Convergent validity between parent and child reports and error-related brain activity. • Error sensitivity relates to child anxiety. • The intervention decreases error sensitivity. • The intervention may decrease the ERN among children with a large ERN. In the current study, we utilize an experimental medicine approach to examine the extent to which a single-session, computerized intervention impacts a transdiagnostic neural marker of risk (i.e., the error-related negativity [ERN]) in 70 children between the ages of 6 and 9 years. The ERN is a deflection in the event-related potential occurring after an individual makes a mistake on a lab-based task and has been shown to be transdiagnostically associated with a variety of anxiety disorders (e.g., social anxiety, generalized anxiety), obsessive-compulsive disorder, and depressive disorders in over 60 studies to date. Building on these findings, work has been done to link an increased ERN to negative reactions to, and avoidance of, making mistakes (i.e., error sensitivity). In the current study, we capitalize on this previous work by examining the extent to which a single-session, computerized intervention may engage the target of "error sensitivity" (measured by the ERN, as well as self-report of error sensitivity). We examine the convergence of multiple measures of the construct of "error sensitivity" (i.e., child self-report, parent report on child, and child electroencephalogram [EEG]). We also examine relationships between these three measures of "error sensitivity" and child anxiety symptoms. Overall, results suggested that treatment condition predicted changes in self-reported error sensitivity but not changes in ERN. Based on the lack of previous work in this area, we view this study as a novel, preliminary, first step toward using an experimental medicine approach to examine our ability to engage the target of the ERN (i.e., error sensitivity) early in development. [ABSTRACT FROM AUTHOR]

Objective To observe the effects of Shuangxin Formula on hypersensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6), 5-hydroxytryptamine (5-HT), adrenocorticotrophic hormone (ACTH) and cortisol (COR) in patients with depression after percutaneous coronary intervention (PCI) with syndrome of heart blood stasis. Methods Patients admitted to wards and outpatients of Dongfang Hospital, Beijing University of Chinese Medicine between April 2021 and December 2021 were selected. According to a random number table, 72 patients who met the inclusion criteria were divided into the experimental group and the control group, with 36 cases per group. The control group was treated with conventional western medicine after PCI, and placebo. The experimental group was treated with conventional western medicine after PCI and Shuangxin Formula. The treatment period for both groups was 4 weeks. The serum levels of hs-CRP, IL-6, 5-HT, ACTH, and COR in the experimental group and the control group before and after treatment were determined by enzyme-linked immunosorbent assay, and the correlation was analyzed. The total quantitative score of traditional Chinese medicine syndrome and the single score of traditional Chinese medicine symptoms were compared before and after treatment. Results After 4 weeks' treatment, the serum levels of hs-CRP, IL-6, ACTH, and COR in the two groups decreased(P <0. 01), and the levels of hs-CRP, IL-6, ACTH, and COR in the experimental group were lower than in the control group (P <0. 01). After 4 weeks' treatment, the serum level of 5-HT was higher than before treatment in both group (P<0. 01), and the serum level of 5-HT in the experimental group was higher than in the control group (P<0. 01). Before and after treatment, the level of 5-HT was negatively correlated with the serum levels of hs-CRP and IL-6 in the two groups (P<0. 05, P<0. 01); the levels of hs-CRP and IL-6 were positively correlated with the levels of ACTH and COR (P<0. 05, P<0. 01); and the level of 5-HT was negatively correlated with the levels of ACTH and COR (P<0. 01). After treatment, the total quantitative score of traditional Chinese medicine syndrome and the single score of traditional Chinese medicine symptoms in both groups were lower than those before treatment (P <0. 05, P <0. 01). The total quantitative score of traditional Chinese medicine syndrome and the single score of traditional Chinese medicine symptoms in the experimental group were lower than in the control group (P<0. 01). Conclusion Shuangxin Formula may reduce the inflammatory response by reducing the levels of the inflammatory factors hs-CRP and IL-6, and then upregulating the excitability of 5-HT, and inhibiting the levels of the HPA axis-related factors ACTH and COR, thus playing the role of spirit-heart treatment. [ABSTRACT FROM AUTHOR]

BACKGROUND. The stomach-derived hormone ghrelin stimulates appetite, but the ghrelin receptor is also expressed in brain circuits involved in motivation and reward. We examined ghrelin effects on decision making beyond food or drug reward using monetary rewards. METHODS. Thirty participants (50% women and 50% men) underwent 2 fMRI scans while receiving i.v. ghrelin or saline in a randomized counterbalanced order. RESULTS. Striatal representations of reward anticipation were unaffected by ghrelin, while activity during anticipation of losses was attenuated. Temporal discounting rates of monetary reward were lower overall in the ghrelin condition, an effect driven by women. Discounting rates were inversely correlated with neural activity in a large cluster within the left parietal lobule that included the angular gyrus. Activity in an overlapping cluster was related to behavioral choices and was suppressed by ghrelin. CONCLUSION. This is, to our knowledge, the first human study to extend the understanding of ghrelin's significance beyond the canonical feeding domain or in relation to addictive substances. Contrary to our hypothesis, we found that ghrelin did not affect sensitivity to monetary reward anticipation, but rather resulted in attenuated loss aversion and lower discounting rates for these rewards. Ghrelin may cause a motivational shift toward caloric reward rather than globally promoting the value of reward. TRIAL REGISTRATION. EudraCT 2018-004829-82. FUNDING. Swedish Research Council (2013-07434), Marcus and Marianne Wallenberg foundation (2014.0187) and National Institute on Drug Abuse/National Institute on Alcohol Abuse and Alcoholism Intramural Research Program. [ABSTRACT FROM AUTHOR]

Much has been written on Claude Bernard as a relentless promoter of the experimental method in physiology. Although the paper will touch Bernard's experimental intuitions and his experimental practice as well, its focus is slightly different. It will address the laboratory, that is, the space in which experimentation in the life sciences takes place, and it will analyze the scattered remarks that Bernard made on the topic both in his books and in his posthumously published writings. The paper is divided into four parts. The introduction briefly sketches the coming into being of the physiological laboratory in the first half of the nineteenth century. The second section will give an overview of Claude Bernard's own itinerary in physiology and his personal laboratory experience. The third part of the paper will have a look at the image of the laboratory that Claude depicted in his Introduction to Experimental Medicine. In the subsequent section and by contrast, the image of the laboratory will come into focus as it can be reconstructed from Bernard's notebook that he kept between 1850 and 1860, the Cahier rouge. Finally, the fifth part of the paper will spotlight Claude Bernard's comparison of the sciences and the arts and their respective practices. A brief concluding statement tries to summarize Bernard's epistemological position toward experimentally practiced science. [ABSTRACT FROM AUTHOR]

Synaptic loss occurs early in many neurodegenerative diseases and contributes to cognitive impairment even in the absence of gross atrophy. Currently, for human disease there are few formal models to explain how cortical networks underlying cognition are affected by synaptic loss. We advocate that biophysical models of neurophysiology offer both a bridge from preclinical to clinical models of pathology and quantitative assays for experimental medicine. Such biophysical models can also disclose hidden neuronal dynamics generating neurophysiological observations such as EEG and magnetoencephalography. Here, we augment a biophysically informed mesoscale model of human cortical function by inclusion of synaptic density estimates as captured by 11C-UCB-J PET, and provide insights into how regional synapse loss affects neurophysiology. We use the primary tauopathy of progressive supranuclear palsy (Richardson's syndrome) as an exemplar condition, with high clinicopathological correlations. Progressive supranuclear palsy causes a marked change in cortical neurophysiology in the presence of mild cortical atrophy and is associated with a decline in cognitive functions associated with the frontal lobe. Using parametric empirical Bayesian inversion of a conductance-based canonical microcircuit model of magnetoencephalography data, we show that the inclusion of regional synaptic density—as a subject-specific prior on laminar-specific neuronal populations—markedly increases model evidence. Specifically, model comparison suggests that a reduction in synaptic density in inferior frontal cortex affects superficial and granular layer glutamatergic excitation. This predicted individual differences in behaviour, demonstrating the link between synaptic loss, neurophysiology and cognitive deficits. The method we demonstrate is not restricted to progressive supranuclear palsy or the effects of synaptic loss: such pathology-enriched dynamic causal models can be used to assess the mechanisms of other neurological disorders, with diverse non-invasive measures of pathology, and is suitable to test the effects of experimental pharmacology. [ABSTRACT FROM AUTHOR]

Background: Biomedicine, i.e. the application of basic sciences to medicine, has become the cornerstone for the study of etiopathogenesis and treatment of diseases. Biomedicine has enormously contributed to the progress of medicine and healthcare and has become the preferred approach to medical problems in the West. The developments in statistical inference and machine learning techniques have provided the foundation for personalised medicine where clinical management can be fully informed by biomedicine. The deployment of precision medicine may impact the autonomy and self-normativity of the patients. Understanding the relationship between biomedicine and medical practice can help navigate the benefits and challenges offered by precision medicine. Methods: Conventional content analysis was applied to "Le Normal and le Pathologique" (Canguilhem G. The Normal and the Pathological. Princeton: Princeton University Press; 1991) and further investigated with respect to its relationship with techne and precision medicine using PubMed and Google Scholar and the Standford Encyclopedia of Philosophy to search for the following keywords singularly or in combination: "Canguilhem", "techne", "episteme", "precision medicine", "machine learning AND medicine". Results: The Hippocratic concept of techne accounts for many characteristics of medical knowledge and practice. The advances of biomedicine, experimental medicine and, more recently, machine learning offer, in contrast, the model of a medicine based purely on episteme. I argue that Canguilhem medical epistemology establishes a framework where episteme and data-driven medicine is compatible with the promotion of patient's autonomy and self-normativity. Conclusions: Canguilhem's medical epistemology orders the relationship of applied medicine with experimental sciences, ethics and social sciences. It provides guidance to define the scope of medicine and the boundaries of medicalization of healthy life. Finally, it sets an agenda for a safe implementation of machine learning in medicine. [ABSTRACT FROM AUTHOR]

The mental health of young people (YP) is a major public health concern that has worsened during the COVID-19 pandemic. Whilst engaging with culture and the arts may have mental health benefits there is a dearth of experimental research regarding the impact of online arts and culture on depression and anxiety in YP. In particular online interventions, which may improve accessibility. Objective: We aimed to compare a co-produced online intervention encompassing the diverse human stories behind art and artefacts, named Ways of Being (WoB), with a typical museum website, the Ashmolean (Ash) on negative affect (NA), positive affect (PA) and psychological distress (K10). Methods: In this parallel group RCT, 463 YP aged 16-24 were randomly assigned, 231 to WoB and 232 to Ash. Results: Over the intervention phase (an aggregate score including all post-allocation timepoints to day-five) a group difference was apparent in favour of WoB for NA (WoB-Ash n=448, NA -0.158, p=0.010) but no differences were detected for PA or K10 and differences were not detected at week six. Group differences in NA in favour of WoB were detected in specific subgroups, e.g. ethnic minorities and males. Across participants (from both groups) mean K10 and NA improved between baseline and six weeks despite increased COVID-19 restrictions. Trial recruitment was rapid, retention high and feedback positive with broad geographical, occupational and ethnic diversity. Conclusions: Online engagement with arts and culture has the potential to impact on mental health in a measurable way in YP with high unmet mental health needs. [ABSTRACT FROM AUTHOR]

According to Claude Bernard, each of the sciences investigates different natural phenomenausing experimental methods unique to that science, especially experimental medicine. However, Bernard also argued that these sciences share a “common” experimental methodthat depends on both the “head” and the “hand”. What he accomplished with his commonmethod is to combine both rationalism and empiricism—head and hand, respectively—toundergird the unity of the experimental sciences while maintaining their plurality. Bernard’sexperimental method as articulated in terms of the rational head and the empirical handmetaphor is relevant today to the unity of science vs. pluralism debate, as well as totherationalism vs. empiricism debate and to the hypothesis-driven vs. data-driven sciencedebate—each of which is explored in turn after briefly reconstructing Bernard’s philosophyof experimental medicine. And his metaphor of head and hand provides a means forexamining the natural and biomedical sciences as they evolve with regard to specialization. [ABSTRACT FROM AUTHOR]

COVID-19 causes significant thrombosis and coagulopathy, with elevated D-dimer a predictor of adverse outcome. The precise mechanism of this coagulopathy remains unclear; one hypothesis is that loss of angiotensin-converting enzyme 2 activity during viral endocytosis leads to pro-inflammatory angiotensin-II accumulation, loss of angiotensin-1-7 and subsequent vascular endothelial activation. We undertook a double-blind randomized, placebo-controlled experimental medicine study to assess the effect of TRV027, a synthetic angiotensin-1-7 analogue on D-dimer in 30 patients admitted to hospital with COVID-19. The study showed a similar rate of adverse events in TRV027 and control groups. There was a numerical decrease in D-dimer in the TRV027 group and increase in D-dimer in the placebo group; however, this did not reach statistical significance (P = .15). A Bayesian analysis demonstrated that there was a 92% probability that this change represented a true drug effect. [ABSTRACT FROM AUTHOR]

Background: Dysfunction of dopaminergic pathways has been considered to play a pivotal role in Parkinson's disease (PD), affecting the processing of emotional and rewarding information, and potentially leading to symptoms of depression or apathy. However, some aspects of motivation in PD might be affected by non-dopaminergic mechanisms. Aim and method: The objective of this experimental medicine study was to investigate the contribution of serotonergic modulation via administration of citalopram (20 mg) for 7 days on motivated decision-making in twenty PD patients, measured using several different computerised tasks and clinical questionnaires that probe different aspects of decision-making. Twenty healthy controls were additionally tested without medication to assess any baseline differences between the two groups. Results: Results indicated that PD patients were overall less motivated than controls on an effort- and reward-based decision-making task. Citalopram increased or decreased willingness to exert effort for reward, depending on whether baseline motivation was high or low, respectively. A task assessing decision-making under risk revealed higher levels of risk aversion for potential losses in PD patients, which neither serotonin nor the patient's regular dopaminergic medication seemed to restore. However, citalopram in PD was associated with more risk-seeking choices for gains, although patients and controls did not differ on this at baseline. Conclusion: The results provide evidence for a role of the serotonergic system in influencing some aspects of motivated decision-making in PD processes. [ABSTRACT FROM AUTHOR]

Background: Sequential B cell-targeted immunotherapy with BAFF antagonism (belimumab) and B cell depletion (rituximab) may enhance B cell targeting in ANCA-associated vasculitis (AAV) through several mechanisms. Methods: Study design: COMBIVAS is a randomised, double-blind, placebo-controlled trial designed to assess the mechanistic effects of sequential therapy of belimumab and rituximab in patients with active PR3 AAV. The recruitment target is 30 patients who meet the criteria for inclusion in the per-protocol analysis. Thirty-six participants have been randomised to one of the two treatment groups in a 1:1 ratio: either rituximab plus belimumab or rituximab plus placebo (both groups with the same tapering corticosteroid regimen), and recruitment is now closed (final patient enrolled April 2021). For each patient, the trial will last for 2 years comprising a 12-month treatment period followed by a 12-month follow-up period. Participants: Participants have been recruited from five of seven UK trial sites. Eligibility criteria were age ≥ 18 years and a diagnosis of AAV with active disease (newly diagnosed or relapsing disease), along with a concurrent positive test for PR3 ANCA by ELISA. Interventions: Rituximab 1000 mg was administered by intravenous infusions on day 8 and day 22. Weekly subcutaneous injections of 200 mg belimumab or placebo were initiated a week before rituximab on day 1 and then weekly through to week 51. All participants received a relatively low prednisolone (20 mg/day) starting dose from day 1 followed by a protocol-specified corticosteroid taper aiming for complete cessation by 3 months. Outcomes: The primary endpoint of this study is time to PR3 ANCA negativity. Key secondary outcomes include change from baseline in naïve, transitional, memory, plasmablast B cell subsets (by flow cytometry) in the blood at months 3, 12, 18 and 24; time to clinical remission; time to relapse; and incidence of serious adverse events. Exploratory biomarker assessments include assessment of B cell receptor clonality, B cell and T cell functional assays, whole blood transcriptomic analysis and urinary lymphocyte and proteomic analysis. Inguinal lymph node and nasal mucosal biopsies have been performed on a subgroup of patients at baseline and month 3. Discussion: This experimental medicine study provides a unique opportunity to gain detailed insights into the immunological mechanisms of belimumab-rituximab sequential therapy across multiple body compartments in the setting of AAV. Trial registration: ClinicalTrials.gov NCT03967925. Registered on May 30, 2019. [ABSTRACT FROM AUTHOR]

Objectives: While the assessment of actual food intake is essential in the evaluation of behaviour change interventions for weight‐loss, it may not always be feasible to collect this information within traditional experimental paradigms. For this reason, measures of food preference (such as measures of food value and choice) are often used as more accessible alternatives. However, the predictive validity of these measures (in relation to subsequent food consumption) has not yet been studied. Our aim was to investigate the extent to which three commonly used measures of preference for snack foods (explicit food value, unhealthy food choice and implicit preference) predicted self‐reported real‐world snacking occasions. Design: Ecological Momentary Assessment (EMA) design. Method: Over a seven‐day study period, participants (N = 49) completed three daily assessments where they reported their healthy and unhealthy snack food consumption and completed the three measures of preference (explicit food value, unhealthy food choice and implicit preference). Results: Our findings demonstrated some weak evidence that unhealthy Visual Analogue Scale scores predicted between‐subject increases in unhealthy snacking frequency (OR = 1.018 [1.006, 1.030], p =.002). No other preference measures significantly predicted self‐reported healthy or unhealthy snacking occasions (ps >.05). Conclusions: These findings raise questions in relation to the association between measures of preference and self‐reported real‐world snack food consumption. Future research should further evaluate the predictive and construct validity of these measures in relation to food behaviours and explore the development of alternative assessment methods within eating behaviour research. [ABSTRACT FROM AUTHOR]

Citizen science approaches are widely and successfully used in biological, environmental, and ecological sciences; however, they are rarely applied in other domains, such as translational health research, notably in the field of liver disease and metabolism. We have designed a study that aims to explore the application of the citizen science approach in a translational experimental medicine study on non-alcoholic fatty liver disease (NAFLD) and a 12-week lifestyle and weight loss program. In this methodological paper, we describe the process of involving citizen scientists in the study. We will recruit a convenience sample of 31 participants (with and without NAFLD) and a half-dozen citizen scientists (members of the public). Citizen scientists will work alongside clinical and non-clinical researchers in a translational experimental medicine study on NAFLD. Citizen scientists will be involved in the co-design and/or review of data collection tools (e.g., semi-structured open-ended questionnaire surveys and semi-structured wellbeing diaries completed by the participants), co-analysis of data on participants' experiences and motivations, co-drafts of research findings and papers, and suggestions for policy recommendations. Citizen scientists will be trained in the research tasks they will undertake, and will be either co-authors or their names will be mentioned in the acknowledgements in research paper(s) based on the level of research contributions. Lessons learned from implementing citizen science in this study will help to reveal the advantages, limitations, and implications of involving citizen scientists in the translational medicine research. Knowing citizen scientists' motivations, expectations, training needs, and overall experience of involvement in this study could provide insights, which could inform the planning and conduct of future translational research studies. Involving citizen scientists in translational medicine research is an important step in extending research opportunities for members of the public; however, there may be methodological challenges, which may be identified and resolved by more research studies. [ABSTRACT FROM AUTHOR]

The main potential of the EVs is linked to their ability to transfer signaling stimuli and deliver therapeutic cargo to optimize the functional status of the cells or modify cell-cell and cell-ECM communications. The overall goal of regenerative medicine is to restore the functional performance of the tissues and organs that have been severely damaged or lost due to traumas and diseases. Another crucial aspect of reconstruction of cellular microenvironments for regenerative medicine such as efficient and reliable production of large amounts of cells for transplantation and tissue engineered tissues growth is addressed in a review by Nogueira et al. [[3]] that discusses the transition of the bioreactor cell culture technologies to the application of disposable processing tanks. [Extracted from the article]

Advancing mechanism-focused research in implementation science is a priority given its potential to improve tailoring and efficiency of implementation strategies. Experimental therapeutics, or experimental medicine, offers an approach for mechanism testing that has been promoted by the NIH Science of Behavior Change and endorsed by the National Institute for Mental Health. This approach has been applied across the translational spectrum – with initial applications to biological research and more recent applications to psychosocial treatment development research. We describe further advancement of experimental therapeutics along the translational spectrum and describe how it is ideally suited to inform precision experimental tests of implementation strategy mechanisms, which we term precision implementation. Such an approach to mechanism testing will allow for identification of causal dose-response relationships between implementation strategies, presumed mechanisms, and implementation outcomes. We discuss the tension between the scientific rigor required to conduct mechanism-focused research using experimental therapeutics and the "real world" conditions in which implementation research takes place. We provide a series of example studies that show "beginning to end" application of this framework in research focused on provider implementation of an evidence-based intervention in routine clinical care settings. [ABSTRACT FROM AUTHOR]

Background and Objectives Although poor diet is a major driver of morbidity and mortality in people aged 60 and older, few dietary interventions are widely implemented for this population. We mapped behavior change theories, agents, and techniques in dietary interventions for adults aged 60 and older and explored relationships between these factors and ability to retain at least 80% of the study participants. Research Design and Methods We conducted a scoping review using MEDLINE, CINAHL, and Web of Science through April 2021 for dietary interventions in adults aged 60 and older. We collated, summarized, and calculated frequency distributions of behavior change theories, behavior change agents, and behavior change techniques (BCTs) using BCTv1 taxonomy with regard to participant retention across 43 studies. Results Only 49% and 30% of the studies reported behavior theory and change agents, respectively. Of the studies reporting on theory and agents, the most common were social cognitive theory and the related mechanism of self-efficacy. The most common BCTv1 clusters were "shaping knowledge" and "goals and planning." Several BCTv1 clusters such as "antecedents" and "reward and threat" and evidence for concordance between BCTs and change agents were more common in interventions with higher retention rates. Discussion and Implications Mechanistically concordant studies with BCTs that involve resource allocation and positive reinforcement through rewards may be advantageous for retention in dietary intervention for older adults. Future studies should continue developing theory and mechanism-oriented research. Furthermore, future studies should consider diversifying the portfolio of currently deployed BCTs and strengthening a concordance between BCTs and mechanisms of change. [ABSTRACT FROM AUTHOR]

Background: Whilst timely clinical characterisation of infections caused by novel SARS-CoV-2 variants is necessary for evidence-based policy response, individual-level data on infecting variants are typically only available for a minority of patients and settings. Methods: Here, we propose an innovative approach to study changes in COVID-19 hospital presentation and outcomes after the Omicron variant emergence using publicly available population-level data on variant relative frequency to infer SARS-CoV-2 variants likely responsible for clinical cases. We apply this method to data collected by a large international clinical consortium before and after the emergence of the Omicron variant in different countries. Results: Our analysis, that includes more than 100,000 patients from 28 countries, suggests that in many settings patients hospitalised with Omicron variant infection less often presented with commonly reported symptoms compared to patients infected with pre-Omicron variants. Patients with COVID-19 admitted to hospital after Omicron variant emergence had lower mortality compared to patients admitted during the period when Omicron variant was responsible for only a minority of infections (odds ratio in a mixed-effects logistic regression adjusted for likely confounders, 0.67 [95% confidence interval 0.61–0.75]). Qualitatively similar findings were observed in sensitivity analyses with different assumptions on population-level Omicron variant relative frequencies, and in analyses using available individual-level data on infecting variant for a subset of the study population. Conclusions: Although clinical studies with matching viral genomic information should remain a priority, our approach combining publicly available data on variant frequency and a multi-countryclinical characterisation dataset with more than 100,000 records allowed analysis of data from a wide range of settings and novel insights on real-world heterogeneity of COVID-19 presentation and clinical outcome. Funding: Bronner P. Gonçalves, Peter Horby, Gail Carson, Piero L. Olliaro, Valeria Balan, Barbara Wanjiru Citarella, and research costs were supported by the UK Foreign, Commonwealth and Development Office (FCDO) and Wellcome [215091/Z/18/Z, 222410/Z/21/Z, 225288/Z/22/Z]; and Janice Caoili and Madiha Hashmi were supported by the UK FCDO and Wellcome [222048/Z/20/Z]. Peter Horby, Gail Carson, Piero L. Olliaro, Kalynn Kennon and Joaquin Baruch were supported by the Bill & Melinda Gates Foundation [OPP1209135]; Laura Merson was supported by University of Oxford’s COVID-19 Research Response Fund - with thanks to its donors for their philanthropic support. Matthew Hall was supported by a Li Ka Shing Foundation award to Christophe Fraser. Moritz U.G. Kraemer was supported by the Branco Weiss Fellowship, Google.org, the Oxford Martin School, the Rockefeller Foundation, and the European Union Horizon 2020 project MOOD (#874850). The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views of the European Commission. Contributions from Srinivas Murthy, Asgar Rishu, Rob Fowler, James Joshua Douglas, François Martin Carrier were supported by CIHR Coronavirus Rapid Research Funding Opportunity OV2170359 and coordinated out of Sunnybrook Research Institute. Contributions from Evert-Jan Wils and David S.Y. Ong were supported by a grant from foundation Bevordering Onderzoek Franciscus; and Andrea Angheben by the Italian Ministry of Health “Fondi Ricerca corrente–L1P6” to IRCCS Ospedale Sacro Cuore–Don Calabria. The data contributions of J.Kenneth Baillie, Malcolm G. Semple, and Ewen M. Harrison were supported by grants from the National Institute for Health Research (NIHR; award CO-CIN-01), the Medical Research Council (MRC; grant MC_PC_19059), and by the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE) (award 200907), NIHR HPRU in Respiratory Infections at Imperial College London with PHE (award 200927), Liverpool Experimental Cancer Medicine Centre (grant C18616/A25153), NIHR Biomedical Research Centre at Imperial College London (award IS-BRC-1215-20013), and NIHR Clinical Research Network providing infrastructure support. All funders of the ISARIC Clinical Characterisation Group are listed in the appendix. [ABSTRACT FROM AUTHOR]

There is growing interest in the antidepressant potential of statins. We tested whether statin use is associated with cognitive markers previously found to indicate psychological vulnerability to depression within the context of the COVID-19 pandemic. Between April 2020 and February 2021, we conducted an observational online study of 2043 adults in the United Kingdom. Participants completed cognitive tasks assessing processes related to depression vulnerability, including affective bias and reward processing. We also measured working memory, medication use, and current psychiatric symptoms. Using mixed analysis of covariance and regression models, we compared participants on statins alone (n = 81), antihypertensive medication alone (n = 126), both medications (n = 111), and on neither medication (n = 1725). Statin use was associated with reduced recognition of angry and fearful faces (F 1 = 9.19, p =.002; F 1 = 6.9, p =.009) and with increased misclassification of these expressions as positive. Increased recognition of angry faces at baseline predicted increased levels of depression and anxiety 10 months later (β = 3.61, p =.027; β = 2.37, p =.002). Statin use was also associated with reduced learning about stimuli associated with loss (F 1,1418 = 9.90, p =.002). These indicators of reduced negative bias were not seen in participants taking antihypertensive medication alone, suggesting that they were related to statin use in particular rather than nonspecific demographic factors. In addition, we found no evidence of an association between statin use and impairment in working memory. Statin use was associated with cognitive markers indicative of reduced psychological vulnerability to depression, supporting their potential use as a prophylactic treatment for depression. [ABSTRACT FROM AUTHOR]

Objective: To assess the limitations of intended change from one type of high sensitivity (hs) cardiac troponin (cTn) to another (hs-cTnT and hs-cTnI) in a real clinical setting. Design: An observation study. Settings: Acute emergency unit, Cardiology department, Institute for clinical and experimental medicine (IKEM), Praha. Material and Methods: Parallel testing of hs-cTnT (Cobas, Roche) and hs-cTnI (Architect, Abbott) in 567 consecutive patients of cardiology emergency. Method comparison (Passing-Bablok), calculation of time interval between sampling, assessment of delta concentration between two consecutive concentrations of hs-cTn, and comparison of classification. The time intervals between two consecutive samples were sorted into tertiles, and delta concentration was evaluated for the time interval up to 6 hours. A classification of the agreement for rule-in and rule-out diagnostics was evaluated according to the ESC Guidelines 2020 (kappa statistics). Results: There were 821 pairs of hs-cTnT and hs-cTnI results. Passing-Bablok test revealed a slope of 3.07 (95% CI 2.77-3.40), an intercept of -30.1 (95% CI -3.9 to -25.0), the equation was hs-cTnI = -30.4 + 3.07 * hs-cTnT, r= 0.934, p<0.001. The delta concentrations in the 1st tertile (42-65 min), 2nd tertile (66-112 min), and 3rd tertile (115-359 min) were (median and IQR) 3.3 (1.5-5.7); 2.6 (1.3-4.5); 48.5 (3.7-172.7) ng/L for hs-cTnT and 1.4 (0.4-2.9); 1.6 (0.6-9.5); 57.8 (5.5-755.9) ng/L for hs-cTnI. The classification agreement between hs-cTnT and hs-cTnI (ESC 1hour algorithm) was 63 % (kappa 0.425) and 77 % (kappa 0.716) for ESC 2-hour algorithm). The comparison of rule-in and rule-out classification revealed up- and down classification both for hs-cTnT and hs-cTnI. Conclusion: A relationship between hs-cTnT and hs-cTnI exists, however, recalculation is impossible. A study revealed a low adherence to the recommended diagnostic algorithms with very high variability in the time intervals between sampling. The delta concentration of hs-cTnT is lower than the delta concentration of hs-cTnI for a shorter interval between samples, and vice versa, the delta concentration of hs-cTnI is higher with the longer time interval between samples. The classification agreement between hs-cTnT and hs-cTnI was moderate for the ESC 1-hour algorithm and suitable for the ESC 2hour algorithm. Switching from one type of high-sensitivity cardiac troponin to another is not trivial, and real data analysis, clinical assessment, and communication with clinicians is required. [ABSTRACT FROM AUTHOR]

The article discusses the results of a study which examined how the transcription and splicing regulation by NLRC5 shapes the interferon (IFN) response in human pancreatic β cells in early type 1 diabetes (T1D). Topics covered include how exposure of human induced pluripotent-derived islet-like cells to IFNα induces expression of HLA class I and other genes involved in antigen presentation, the global impact of NLRC5 on IFNα-modulated genes and the role of IFNα in T1D.

LAG-3 (Lymphocyte activation gene 3) protein is a checkpoint receptor that interacts with LSEC-tin, Galectin-3 and FGL1. This interaction leads to reduced production of IL-2 and IFN-γ. LAG-3 is widely expressed in different tumor types and modulates the tumor microenvironment through immunosuppressive effects. Differential expression in various tumor types influences patient prognosis, which is often associated with coexpression with immune checkpoint inhibitors, such as TIM-3, PD-1 and CTLA-4. Here, we discuss expression profiles in different tumor types. To date, many clinical trials have been conducted using LAG-3 inhibitors, which can be divided into anti-LAG-3 monoclonal antibodies, anti-LAG-3 bispecifics and soluble LAG-3-Ig fusion proteins. LAG-3 inhibitors supress T-cell proliferation and activation by disallowing for the interaction between LAG-3 to MHC-II. The process enhances anti-tumor immune response. In this paper, we will review the current state of knowledge on the structure, function and expression of LAG-3 in various types of cancer, as well as its correlation with overall prognosis, involvement in cell-based therapies and experimental medicine. We will consider the role of compounds targeting LAG-3 in clinical trials both as monotherapy and in combination, which will provide data relating to the efficacy and safety of proposed drug candidates. [ABSTRACT FROM AUTHOR]

Ischemic injury is one of the most adverse pathogenic factors that evoke irreversible changes in organs and tissues. Cardioprotection from ischemia-reperfusion injury is an important challenge for modern experimental and clinical medicine. This type of injury is a key link in the pathogenesis of coronary heart disease and, above all, acute myocardial infarction, a socioeconomically significant disease that is one of the main causes of disability and mortality among the adult population. The aim of the study was to elucidate the infarct-size limiting effect of postconditioning (Post) with L-lactate during myocardial ischemia-reperfusion in young and old rats under atropine-induced blockade of M-cholinergic receptors. In experiments on rats, it was found that Post with L-lactate has an infarct-size limiting effect during myocardial ischemia-reperfusion in both young and old animals, however, under conditions of systemic atropine administration (2 mg/kg), this effect was persistent in old rats only. Apparently, the activity of the peripheral M-cholinergic systems is of importance for the implementation mechanisms of the cardioprotective effects of Post with L-lactate in young, but not old rats. [ABSTRACT FROM AUTHOR]

Background: Streptococcus pyogenes is an important global human pathogen that causes pharyngitis, and antibacterial therapy has become an important part of the overall therapy for pharyngitis. As natural derivatives, honey and green tea are often recommended for patients with pharyngitis in traditional Chinese medicine without experimental theoretical basis on wether the combined effect of honey and green tea on pharyngitis is better than they alone. The aims of this study were to explore the effects of artificial honey (AH) and epigallocatechin-3-gallate (EGCG) on S. pyogenes and elucidate the possible mechanisms, which were investigated using MIC (the minimum inhibitory concentration), FIC (fractional inhibitory concentration) index, growth pattern, biofilm formation and RT-qPCR. Results: The MIC of AH on S. pyogenes was 12.5% (v/v) and the MIC of EGCG was 1250 μg/ml. The FIC index of AH and EGCG was 0.5. The planktonic cell growth, growth pattern and biofilm formation assays showed that AH and EGCG mixture had stronger inhibitory effect on S. pyogenes than they alone. RT-qPCR confirmed that the expression of hasA and luxS gene were inhibited by AH and EGCG mixture. Conclusions: AH and EGCG mixture can inhibit the planktonic cell growth, biofilm formation and some virulence genes expression of S. pyogenes, better than they alone. The combination of honey and green tea have the potential to treat pharyngitis as natural derivatives, avoiding drug resistance and double infection. [ABSTRACT FROM AUTHOR]

The article highlights that Genome-wide association studies are approaches used in genetic research to link single-nucleotide polymorphisms with susceptibility to diseases or quantitative trait. It also discusses that Genome-wide association of autoimmune and inflammatory diseases have identified various candidates, but the roles of these candidates in the onset and progression of immune-mediated diseases are largely unknown.

Rationale: Clinical studies suggest that the highly lipophilic, anti-inflammatory molecule, simvastatin, might be an ideal candidate for drug repurposing in the treatment of depression. The neuropsychological effects of simvastatin are not known, but their ascertainment would have significant translational value about simvastatin's influence on mood and cognition. Objectives: We aimed to investigate the effects of simvastatin on a battery of psychological tests and inflammatory markers in healthy volunteers. Methods: Fifty-three healthy subjects were randomly assigned to 7 days of either simvastatin (N = 27) or sucrose-based placebo (N = 26) given in a double-blind fashion. Then, participants were administered questionnaires measuring subjective rates of mood and anxiety, and a battery of tasks assessing emotional processing, reward learning, and verbal memory. Blood samples for C-reactive protein were also collected. Results: Compared to placebo, participants on simvastatin showed a higher number of positively valenced intrusions in the emotional recall task (F1,51 = 4.99, p = 0.03), but also an increase in anxiety scores (F1,51 = 5.37, p = 0.02). An exploratory analysis of the females' subgroup (N = 27) showed lower number of misclassifications as sad facial expression in the simvastatin arm (F1,25 = 6.60, p = 0.02). No further statistically significant changes could be observed on any of the other outcomes measured. Conclusions: We found limited evidence that 7-day simvastatin use in healthy volunteer induces a positive emotional bias while also being associated with an increase in anxiety, potentially reflecting the early effects of antidepressants in clinical practice. Such effect might be more evident in female subjects. Different drug dosages, treatment lengths, and sample selection need consideration in further experimental medicine and clinical studies. Trial registration: Clinicaltrials.gov: NCT04652089. [ABSTRACT FROM AUTHOR]

Ervin Bauer was Hungarian and Soviet scientist, who had a short, but bright and talented life. In 1935, working at the Institute of Experimental Medicine in the USSR, he published the book «Theoretical Biology», in which he proposed an idea of a special "non-equilibrium" state of living systems and the existence of internal machineries in the organism that work against thermodynamic equilibrium and increase the organism's capacity for work. Currently, this idea is called "the principle of sustainable non-equilibrium" or "Bauer's principle". During the repressions of the 1930s in the USSR, Bauer was executed, the book « Theoretical Biology» was banned. Currently, his works are poorly known, especially outside the post-socialist region. We believe that his ideas could help in rethinking not only the biochemistry and bioenergetics of cells and tissues of living organisms, but also biogeochemical and civilizational processes on a planetary scale. [ABSTRACT FROM AUTHOR]

The article discusses the collaboration between the World Health Organization (WHO) and the European Society of Intensive Care Medicine (ESICM) in launching the COVID-19 skills preparation course called C19_SPACE. The course aimed to strengthen the clinical knowledge of healthcare providers in critical care principles, such as hemodynamic support, respiratory support, sedation in the ICU, and managing sepsis. A total of 2863 trainees from 61 countries were enrolled in the program, achieving a median knowledge score of 92 out of 100. The program has successfully increased critical care workforce capacity and is being further developed to address wider needs in future health emergencies. [Extracted from the article]

This document is a correction notice for an article titled "Sepsis and obesity: a scoping review of diet-induced obesity murine models" published in the journal Intensive Care Medicine Experimental. The correction states that Table 5 was initially omitted from the article but has since been added. The publisher apologizes for any inconvenience caused. Springer Nature, the publisher, remains neutral regarding jurisdictional claims and institutional affiliations. The authors of the article are Mikaela Eng, Keshikaa Suthaaharan, Logan Newton, Fatima Sheikh, and Alison Fox-Robichaud. [Extracted from the article]