Chitosan-Peptide Composites for Tissue Engineering Applications: Advances in Treatment Strategies.

One of the most well-known instances of an interdisciplinary subject is tissue engineering, where experts from many backgrounds collaborate to address important health issues and improve people's quality of life. Many researchers are interested in using chitosan and its derivatives as an alternative to fabricating scaffold engineering and skin grafts in tissue because of its natural abundance, affordability, biodegradability, biocompatibility, and wound healing properties. Nanomaterials based on peptides can provide cells with the essential biological cues required to promote cellular adhesion and are easily fabricated. Due to such worthy properties of chitosan and peptide, they find their application in tissue engineering and regeneration processes. The implementation of hybrids of chitosan and peptide is increasing in the field of tissue engineering and scaffolding for improved cellular adherence and bioactivity. This review covers the individual applications of peptide and chitosan in tissue engineering and further discusses the role of their conjugates in the same. Here, the recent findings are also discussed, along with studies involving the use of these hybrids in tissue engineering applications.

Introgression and Mapping of Cotton Leaf Curl Disease (CLCuD) Resistance from Wild Gossypium armourianum Kearney into Upland Cotton (G. hirsutum L.).

Cotton leaf curl disease (CLCuD), caused by the whitefly transmitted geminivirus complex (Cotton leaf curl virus - CLCuV and their satellite molecules), is a serious threat to successful upland cotton production in northwest India, Pakistan, and China. The disease causes significant losses in fibre yield and the quality of cotton. Owing to the regular emergence of resistance breaking strains of CLCuV, all the previously available CLCuD resistant germplasms of upland cotton have become compromised and none of the extant upland cotton cultivars is resistant to this disease. Therefore, alternate sources of CLCuD resistance need to be explored, as genetic resistance is the only pragmatic and tenable management strategy to combat this malady. Here, we report for the first time the introgression and mapping of CLCuD resistance from a related non-progenitor wild diploid D-genome cotton species, G. armourianum into upland cotton. A backcross population (G. hirsutum/G. armourianum/G. hirsutum) was developed for this purpose. A single major QTL was found to be associated with resistance to CLCuD and was located on chromosome D01 through the genotyping-by-sequencing technique.

Proactive approaches in congestive heart failure: the significance of early goals of care discussion and palliative care.

Congestive Heart Failure (CHF) poses significant challenges to the healthcare system due to its high rates of morbidity and mortality as well as frequent readmissions. All of these factors contribute to increased healthcare delivery costs. Besides the burden on the healthcare system, CHF has far deeper effects on the patient in terms of psychological burden along with debilitating symptoms of dyspnea, all of which reduce quality of life. Prognostic awareness among patients about their disease along with initiating early goals of care discussion by those involved in the care (physicians, nurses, social worker and patient themselves) can help mitigate these challenges. Adopting a proactive approach to address patient preferences, values and end-of-life goals improves patient-centred care, enhances quality of life and reduces the strain on healthcare resources. In this narrative review, studies have been identified using PubMed search to shed knowledge on what is preventing the initiation of goals of care discussions. Some barriers include lack of knowledge about prognosis in both patients and caregivers, inexperience or discomfort in having those conversations and delaying it until CHF becomes too advanced.

Heart disease is the leading cause of death in the United States and by 2030, around 8.5 million people are expected to suffer from heart failure due to increasing rates of obesity, diabetes, smoking, high blood pressure and coronary heart disease. People with heart failure often have severe physical symptoms and emotional distress, which affects their quality of life. Palliative care, which aims to relieve symptoms and provide support, is essential for these patients and their families. It helps improve communication about the disease, reduces hospital readmissions and increases the chances of patients enrolling in hospice care. However, discussions about end-of-life care often do not happen in time or at all for heart failure patients. There are many barriers, including physician's inability to explain the downsides of life-sustaining treatments and patients and families struggling to accept the poor prognosis of the disease. It's important to develop scoring systems, like the Gagne Combined Comorbidity score, to help physicians identify patients at risk of poor outcomes and start end-of-life care discussions early. Signs that a patient might need palliative care include frequent hospital visits, severe ongoing symptoms and advanced treatments. Despite its importance, many heart failure patients do not receive timely palliative care. Early discussions about care preferences, integrating palliative care into regular treatment, and timely hospice referrals can greatly improve the quality of life for these patients and their families.

Linking hearts and minds: understanding the cardiovascular impact of bipolar disorder.

Bipolar disorder is a severe and recurring condition that has become a significant public health issue globally. Studies indicate a heightened risk and earlier onset of cardiovascular diseases among individuals with bipolar disorder, potentially increasing mortality rates. The chronic nature of bipolar disorder leads to disturbances across multiple systems, including autonomic dysfunction, over-activation of the hypothalamic-pituitary-adrenal axis and increased levels of peripheral inflammatory markers. These disruptions cause endothelial damage, the formation of plaques and blood clots, in addition to the medications used to treat bipolar disorder and genetic associations contributing to cardiovascular disease development. Understanding the complex interplay between bipolar disorder and cardiovascular events is essential for the prevention and effective management of cardiovascular conditions in individuals with bipolar disorder.

Bipolar disorder is a mental health condition that affects mood and behavior, significantly impacting the lives of many people around the world. People with this disorder are also at a higher risk for heart diseases, including heart attacks and strokes. Certain lifestyle factors, common among people with bipolar disorder, such as smoking, poor diet and lack of exercise, can cause inflammation and stress, which damage blood vessels and increase the likelihood of heart conditions. The relationship between bipolar disorder and heart disease is complex. The condition affects how the body handles stress and can disrupt normal heart functions. For instance, stress from bipolar disorder can lead to high blood pressure and irregular heartbeats and certain medications taken by those with bipolar disorder can further damage the heart. To better manage these risks, it's important to understand the connection between bipolar disorder and heart disease. Future research should focus on creating guidelines for regular heart health check-ups for people with bipolar disorder and improving overall care to help prevent unfavorable outcomes.

Tools for Screening, Predicting, and Evaluating Sepsis and Septic Shock: A Comprehensive Review.

Sepsis is characterized by life-threatening organ dysfunction due to dysregulated host response to infection. It can progress to cause circulatory and cellular/metabolic abnormalities, resulting in septic shock that may significantly increase mortality. The pathophysiology of sepsis involves a complex interplay of invading pathogens and the body's immune defense, causing alteration in normal homeostasis, eventually leading to derangements in the cellular, humoral, circulatory, and metabolic functions. Several scoring systems have been developed to rapidly predict or suspect sepsis, such as Sequential Organ Failure Assessment (SOFA), modified SOFA (mSOFA), quick SOFA (qSOFA), shock index (SI), and modified SI (mSI). Each of these scores has been utilized for triaging patients with sepsis, and as per medical advancements these scoring systems have been modified to include or exclude certain criteria to improve their clinical utility. This review aims to compare the individual scores and their usage for sepsis that may be used for laying the foundation for early recognition and prediction of sepsis and for formulating more precise definitions in the future.

Critical illness-related corticosteroid insufficiency: latest pathophysiology and management guidelines.

Intensive care unit (ICU) admissions in the United States exceed 5.7 million annually, often leading to complications such as post-intensive care syndrome and high mortality rates. Among these challenges, critical illness-related corticosteroid insufficiency (CIRCI) requires emphasis due to its complex, multiple-cause pathophysiology and varied presentations. CIRCI, characterized by adrenal insufficiency during critical illness, presents in up to 30% of ICU patients and may manifest as an exaggerated inflammatory response. Factors such as dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, altered cortisol metabolism, tissue corticosteroid resistance, and drug-induced suppression contribute to CIRCI. Diagnosis is a complex process, relying on a comprehensive assessment including clinical presentation, laboratory findings, and dynamic stimulatory testing. Treatment involves intensive medical care and exacting glucocorticoid therapy. Recent guidelines advocate for individualized approaches tailored to patient presentation and etiology. Understanding the pathophysiology and treatment of CIRCI is vital for clinicians managing critically ill patients and striving to improve outcomes. This research paper aims to explore the latest developments in the pathophysiology and management of CIRCI.

Beyond the Gut: Exploring Cardiovascular Implications of Celiac Disease.

Celiac disease (CD) is an autoimmune disorder that presents with gastrointestinal symptoms including diarrhea, weight loss, and abdominal bloating due to the inflammation in the small intestine. It has been associated with various extraintestinal manifestations, including mucocutaneous findings such as dermatitis herpetiformis, anemia, dental enamel defects, osteoporosis, and arthritis. Studies have revealed an increasing association between CD and cardiovascular diseases (CVDs), including atherosclerosis, cardiomyopathy, and arrhythmia. Chronic inflammation, nutritional deficiencies from malabsorption, endothelial dysfunction, thrombophilic autoantibodies, thrombocytosis, and protein C and S deficiency have been proposed as the probable mechanisms for the association between the 2 conditions. This article aims to provide a review of the pathophysiological mechanism of celiac disease causing various CVDs and to compare and contrast the existing studies suggesting both favorable and unfavorable CVD outcomes in patients with CD.

D-galactonate metabolism in enteric bacteria: a molecular and physiological perspective.

D-galactonate, a widely prevalent sugar acid, was first reported as a nutrient source for enteric bacteria in the 1970s. Since then, decades of research enabled a description of the modified Entner-Doudoroff pathway involved in its degradation and reported the structural and biochemical features of its metabolic enzymes, primarily in Escherichia coli K-12. However, only in the last few years, the D-galactonate transporter has been characterized, and the regulation of the dgo operon, encoding the structural genes for the transporter and enzymes of D-galactonate metabolism, has been detailed. Notably, in recent years, multiple evolutionary studies have identified the dgo operon as a dominant target for adaptation of E. coli in the mammalian gut. Despite considerable research on dgo operon, numerous fundamental questions remain to be addressed. The emerging relevance of the dgo operon in host-bacterial interactions further necessitates the study of D-galactonate metabolism in other enterobacterial strains.

In vitro mutagenesis using habituation and PBR autotrophy based indirect somatic embryogenesis (ISE) system in Kinnow mandarin.

Solid mutant induction using specialized habituation and PBR (Plant bio-regulator) autotrophy-mediated suspension-based ISE system was the prime aim of present investigation. Based on survival of cell clumps after mutagen treatment, the probit analysis was calculated. The result revealed LD50 at 54.31 Gy in gamma, while for EMS (ethyl methanesulfonate), it was 0.1% for 3 h and 0.5% for 1 h. Based on embryogenesis efficiency, a dose rate of 100 Gy and 0.1% EMS for a 3-h exposure were selected for regeneration. As compared to control, significant decrease in the embryogenesis efficiency was recorded at 100 Gy (85.92%) with similar reduction trends in embryo production (79.49%), germination (13.43%), conversion (2.48%), establishment (15.78%) and acclimatization (60.92%). The growth-related parameters such as root and shoot length and number of leaves/regenerant were also significantly reduced to 67.29%, 30.19% and 5.03%, respectively, in the regenerated plants after gamma irradiation as compared to control. In the EMS treatment, at the dose rate of 0.1% for 3-h, the embryogenesis efficiency was reduced to 43.67% with similar diminution trends in embryo production (59.49%), germination (8.95%), conversion (1.94%), establishment (4.37%) and acclimatization (29.9%). The growth-related parameters in the EMS treatment, decreased to 91.00% (root length), 71.34% (shoot length) and 35.03% (no. of leaves). The molecular marker based varied amplifications confirmed the occurrence of mutations in both gamma and EMS induced M1 regenerants. The study highlights the alternative high frequency in vitro mutagenesis protocol for induction of solid mutants in Kinnow mandarin and related citrus species.

Plant Fiber Composites for Biomedical Applications: Advances and Prospective.

Plant fibers are strong, robust, flexible, versatile, renewable, and sustainable, making them valuable for many applications. Fibers from plants are now utilized in biomedical applications as reinforcements for biological composites to enhance the mechanical characteristics of composite biological materials including rigidity, tensile strength, and endurance. Reinforcement composites with hybrid components were explored in biodevices for prospective utilization in orthopedics, prosthetics, tissue fabrication, and surgical dressings. This review presents an overview of plant fibers, including their characteristics, influencing variables, and numerous applications. The text explores several methods for creating synthetic composites using common, sustainable fibers and the distinct characteristics of the resulting biological materials. The text also analyses many instances of composite hybrids and their application in the biological field. The results are summarised and suggestions for potential improvements are presented. The current research primarily examines the concept, specifications, efficiency, and potential advancements of composites with hybrid characteristics made from plant fibers.

Breaking the association between gametocidal gene(s) and leaf rust resistance gene (LrS2427) in Triticum aestivum-Aegilops speltoides derivative by gamma irradiation.

Utilization of crop wild relatives of wheat can be very effective in building the genetic diversity to cater to the evolving strains of disease pathogens. Aegilops speltoides is a rich source of rust resistance genes however transferring those to wheat genome can be tedious due to co-transfer and preferential transmission of undesirable genes causing gametocidal activity. Such an unholy association was observed in Triticum aestivum-Ae. speltoides derivative line Sel. 2427 which possess the broad-spectrum leaf rust seedling resistance gene (LrS2427). Molecular analysis based on 35 K wheat breeder's array revealed the maximum percentage of Ae. speltoides genome introgression on homoeologous group 2. In situ hybridization studies revealed the presence of S genome in Sel. 2427, showing six translocations on four chromosomes. Karyotyping using repetitive probe (AAG)6 revealed that the two chromosomes involved are 2D and 2B. Genic regions causing gametocidal activity were identified by dissecting it into component traits and QTLs on 2D and 2B chromosomes were revealed in case of the trait seed shrivelling index. To break the inadvertent association of LrS2427 with gametocidal genes, F1(Agra Local X Sel. 2427) seeds were irradiated with gamma rays and stable leaf rust resistant mutants lacking gametocidal activity were developed. These mutants showed resistance to different races of leaf rust pathogen and showed superior agronomic performance as well. These mutants could be a great resource in wheat improvement for utilization of the leaf rust resistance gene LrS2427 without any yield penalty. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01491-8.

Shape Dependent Therapeutic Potential of Nanoparticulate System: Advance Approach for Drug Delivery.

Drug delivery systems rely heavily on nanoparticles because they provide a targeted and monitored release of pharmaceuticals that maximize therapeutic efficacy and minimize side effects. To maximize drug internalization, this review focuses on comprehending the interactions between biological systems and nanoparticles. The way that nanoparticles behave during cellular uptake, distribution, and retention in the body is determined by their shape. Different forms, such as mesoporous silica nanoparticles, micelles, and nanorods, each have special properties that influence how well drugs are delivered to cells and internalized. To achieve the desired particle morphology, shape-controlled nanoparticle synthesis strategies take into account variables like pH, temperatures, and reaction time. Top-down techniques entail dissolving bulk materials to produce nanoparticles, whereas bottom-up techniques enable nanostructures to self-assemble. Comprehending the interactions at the bio-nano interface is essential to surmounting biological barriers and enhancing the therapeutic efficacy of nanotechnology in drug delivery systems. In general, drug internalization and distribution are greatly influenced by the shape of nanoparticles, which presents an opportunity for tailored and efficient treatment plans in a range of medical applications.

Beyond survival: understanding post-intensive care syndrome.

Post-intensive care syndrome (PICS) refers to persistent or new onset physical, mental, and neurocognitive complications that can occur following a stay in the intensive care unit. PICS encompasses muscle weakness; neuropathy; cognitive deficits including memory, executive, and attention impairments; post-traumatic stress disorder; and other mood disorders. PICS can last long after hospital admission and can cause significant physical, emotional, and financial stress for patients and their families. Several modifiable risk factors, such as duration of sepsis, delirium, and mechanical ventilation, are associated with PICS. However, due to limited awareness about PICS, these factors are often overlooked. The objective of this paper is to highlight the pathophysiology, clinical features, diagnostic methods, and available preventive and treatment options for PICS.

Complex dichotomous links of nonalcoholic fatty liver disease and inflammatory bowel disease: exploring risks, mechanisms, and management modalities.

Nonalcoholic fatty liver disease (NAFLD) has been shown to be linked to inflammatory bowel disease (IBD) due to established risk factors such as obesity, age, and type 2 diabetes in numerous studies. However, alternative research suggests that factors related to IBD, such as disease activity, duration, and drug-induced toxicity, can contribute to NAFLD. Recent research findings suggest IBD relapses are correlated with dysbiosis, mucosal damage, and an increase in cytokines. In contrast, remission periods are characterized by reduced metabolic risk factors. There is a dichotomy evident in the associations between NAFLD and IBD during relapses and remissions. This warrants a nuanced understanding of the diverse influences on disease manifestation and progression. It is possible to provide a holistic approach to care for patients with IBD by emphasizing the interdependence between metabolic and inflammatory disorders.

Exploring the Ramifications of Delayed Hospital Discharges: Impacts on Patients, Physicians, and Healthcare Systems.

Prolonged hospital stays can significantly impede patients' recovery, negatively affecting anything from physical health via issues like hospital-acquired infections and increased complications due to immobility to psychological health. Several studies investigated the psychosocial impact of prolonged hospital stays, revealing a variety of patient perspectives, such as feeling uncertain and frustrated about their conditions, which can erode their trust in healthcare providers. Delayed discharges not only affect patients but also have multifaceted effects on healthcare providers, potentially reducing physician efficiency and contributing to higher rates of burnout among healthcare professionals. This article investigates the consequences of delayed versus early discharge on physicians, patients, and the overall hospital system. We conducted an extensive search through PubMed and Google Scholar using the keywords "delayed discharge," "hospital discharge," and "bed blocking" to identify all the recent studies highlighting the dynamics of patient discharge. Our results support the hypothesis that reducing delayed discharge rates will not only improve patient outcomes but also have widespread fiscal impacts. This review also outlines measures to reduce delayed discharges, ultimately leading to a significant enhancement in the healthcare system.

Efficacy and Safety of Vildagliptin and Remogliflozin as Add-on Therapy to Metformin in Patients of Type 2 Diabetes Mellitus: An open-label comparative study.

Objectives: This study aimed to evaluate the safety and efficacy of remogliflozin compared to vildagliptin as an add-on drug to metformin in type 2 diabetes mellitus (T2DM) treatment. Metformin is considered a first-line drug in T2DM. However, as the disease progresses with heightened insulin resistance and declining ß-cell function, the use of metformin alone is often inadequate to achieve optimum glucose levels. Methods: This prospective, randomised study was conducted at Maulana Azad Medical College and Associated Hospital in New Delhi, India, between February 2020 to January 2021. This study recruited 60 T2DM patients aged 35-70 years with glycated haemoglobin (HbA1c) >6.5% taking metformin at a daily dosage of 1,500-3,000 mg for ≥3 months. Patients were randomly assigned in a 1:1 ratio to receive either vildagliptin (50 mg) or remogliflozin (100 mg) twice daily for 90 days. The primary endpoint was a change in HbA1c levels from baseline to the end of 90 days whereas secondary endpoints were changes in lipid profile and weight. Results: The decrement in mean HbA1c levels was significantly higher in the remogliflozin group than in the vildagliptin group (-8.1% versus -2.4%; P <0.001). In addition, more significant weight loss was found in remogliflozin-treated patients (-5.2% versus -0.6%; P <0.01). Both treatments were well tolerated throughout the study. Conclusion: Compared to vildagliptin, remoglilflozin was significantly more effective in glycaemic control and weight loss in patients with T2DM and can therefore be considered as an add-on drug in T2DM not adequately controlled by metformin monotherapy.

Distinct biophysical and chemical mechanisms governing sucrose mineralization and soil organic carbon priming in biochar amended soils: evidence from 10 years of field studies.

While many studies have examined the role of biochar in carbon (C) accrual in short-term scale, few have explored the decadal scale influences of biochar on non-biochar C, e.g., native soil organic C (SOC) and added substrate. To address this knowledge gap, soils were collected from decade-old biochar field trials located in the United Kingdom (Cambisol) and China (Fluvisol), with each site having had three application rates (25-30, 50-60 and 75-100 Mg ha-1) of biochar plus an unamended Control, applied once in 2009. We assessed physicochemical and microbial properties associated with sucrose (representing the rhizodeposits) mineralization and the priming effect (PE) on native SOC. Here, we showed both soils amended with biochar at the middle application rate (50 Mg ha-1 biochar in Cambisol and 60 Mg ha-1 biochar in Fluvisol) resulted in greater substrate mineralization. The enhanced accessibility and availability of sucrose to microorganisms, particularly fast-growing bacterial genera like Arenimonas, Spingomonas, and Paenibacillus (r-strategists belonging to the Proteobacteria and Firmicutes phyla, respectively), can be attributed to the improved physicochemical properties of the soil, including pH, porosity, and pore connectivity, as revealed by synchrotron-based micro-CT. Random forest analysis also confirmed the contribution of the microbial diversity and physical properties such as porosity on sucrose mineralization. Biochar at the middle application rate, however, resulted in the lowest PE (0.3 and 0.4 mg of CO2-C g soil-1 in Cambisol and Fluvisol, respectively) after 53 days of incubation. This result might be associated with the fact that the biochar promoted large aggregates formation, which enclosed native SOC in soil macro-aggregates (2-0.25 mm). Our study revealed a diverging pattern between substrate mineralization and SOC priming linked to the biochar application rate. This suggests distinct mechanisms, biophysical and physicochemical, driving the mineralization of non-biochar carbon in a field where biochar was applied a decade before. Supplementary Information: The online version contains supplementary material available at 10.1007/s42773-024-00327-0.

Characterization of oxytocin and vasopressin receptors in the Southern giant pouched rat and comparison to other rodents.

Vasopressin and oxytocin are well known and evolutionarily ancient modulators of social behavior. The distribution and relative densities of vasopressin and oxytocin receptors are known to modulate the sensitivity to these signaling molecules. Comparative work is needed to determine which neural networks have been conserved and modified over evolutionary time, and which social behaviors are commonly modulated by nonapeptide signaling. To this end, we used receptor autoradiography to determine the distribution of vasopressin 1a and oxytocin receptors in the Southern giant pouched rat (Cricetomys ansorgei) brain, and to assess the relative densities of these receptors in specific brain regions. We then compared the relative receptor pattern to 23 other species of rodents using a multivariate ANOVA. Pouched rat receptor patterns were strikingly similar to hamsters and voles overall, despite the variation in social organization among species. Uniquely, the pouched rat had dense vasopressin 1a receptor binding in the caudate-putamen (i.e., striatum), an area that might impact affiliative behavior in this species. In contrast, the pouched rat had relatively little oxytocin receptor binding in much of the anterior forebrain. Notably, however, oxytocin receptor binding demonstrated extremely dense binding in the bed nucleus of the stria terminalis, which is associated with the modulation of several social behaviors and a central hub of the social decision-making network. Examination of the nonapeptide system has the potential to reveal insights into species-specific behaviors and general themes in the modulation of social behavior.

Effects of RBT-1 on preconditioning response biomarkers in patients undergoing coronary artery bypass graft or heart valve surgery: a multicentre, double-blind, randomised, placebo-controlled phase 2 trial.

Background: RBT-1 is a combination drug of stannic protoporfin (SnPP) and iron sucrose (FeS) that elicits a preconditioning response through activation of antioxidant, anti-inflammatory, and iron-scavenging pathways, as measured by heme oxygenase-1 (HO-1), interleukin-10 (IL-10), and ferritin, respectively. Our primary aim was to determine whether RBT-1 administered before surgery would safely and effectively elicit a preconditioning response in patients undergoing cardiac surgery. Methods: This phase 2, double-blind, randomised, placebo-controlled, parallel-group, adaptive trial, conducted in 19 centres across the USA, Canada, and Australia, enrolled patients scheduled to undergo non-emergent coronary artery bypass graft (CABG) and/or heart valve surgery with cardiopulmonary bypass. Patients were randomised (1:1:1) to receive either a single intravenous infusion of high-dose RBT-1 (90 mg SnPP/240 mg FeS), low-dose RBT-1 (45 mg SnPP/240 mg FeS), or placebo within 24-48 h before surgery. The primary outcome was a preoperative preconditioning response, measured by a composite of plasma HO-1, IL-10, and ferritin. Safety was assessed by adverse events and laboratory parameters. Prespecified adaptive criteria permitted early stopping and enrichment. This trial is registered with ClinicalTrials.gov, NCT04564833. Findings: Between Aug 4, 2021, and Nov 9, 2022, of 135 patients who were enrolled and randomly allocated to a study group (46 high-dose, 45 low-dose, 44 placebo), 132 (98%) were included in the primary analysis (46 high-dose, 42 low-dose, 44 placebo). At interim, the trial proceeded to full enrollment without enrichment. RBT-1 led to a greater preconditioning response than did placebo at high-dose (geometric least squares mean [GLSM] ratio, 3.58; 95% CI, 2.91-4.41; p < 0.0001) and low-dose (GLSM ratio, 2.62; 95% CI, 2.11-3.24; p < 0.0001). RBT-1 was generally well tolerated by patients. The primary drug-related adverse event was dose-dependent photosensitivity, observed in 12 (26%) of 46 patients treated with high-dose RBT-1 and in six (13%) of 45 patients treated with low-dose RBT-1 (safety population). Interpretation: RBT-1 demonstrated a statistically significant cytoprotective preconditioning response and a manageable safety profile. Further research is needed. A phase 3 trial is planned. Funding: Renibus Therapeutics, Inc.