The Effects of Dual GLP-1/Glucagon Receptor Agonists with Different Receptor Selectivity in Mouse Models of Obesity and Nonalcoholic Steatohepatitis.

There is an unmet need for nonalcoholic steatohepatitis (NASH) therapeutics, considering the increase in global obesity. Dual GLP-1/glucagon (GCG) receptor agonists have shown beneficial effects in circumventing the pathophysiology linked to NASH. However, dual GLP-1/GCG receptor agonists as a treatment of metabolic diseases need delicate optimization to maximize metabolism effects. The impacts of increased relative GLP-1/GCG receptor activity in NASH settings must be addressed to unleash the full potential. In this study, we investigated the potential of OXM-104 and OXM-101, two dual GLP-1/GCG receptor agonists with different receptor selectivity in the setting of NASH, to establish the relative receptor activities leading to the best metabolic outcome efficacies to reduce the gap between surgery and pharmacological interventions. We developed dual GLP-1/GCG receptor agonists with selective agonism. Despite the improved metabolic effects of OXM-101, we explored a hyperglycemic risk attached to increased relative GCG receptor agonism. Thirty-eight days of treatment with a dual GLP-1/GCG receptor agonist, OXM-104, with increased GLP-1 receptor agonism in obese NASH mice was found to ameliorate the development of NASH by lowering body weight, improving liver and lipid profiles, reducing the levels of the fibrosis marker PRO-C4, and improving glucose control. Similarly, dual GLP-1/GCG receptor agonist OXM-101 with increased relative GCG receptor agonism ameliorated NASH by eliciting dramatic body weight reductions to OXM-104, reflected in the improvement of liver and lipid enzymes and reduced PRO-C4 levels. Optimizing dual GLP-1/GCG agonists with increased relative GCG receptor agonism can provide the setting for future agonists to treat obesity, type 2 diabetes, and NASH without having a hyperglycemic risk. SIGNIFICANT STATEMENT: There is an unmet need for nonalcoholic steatohepatitis (NASH) therapeutics, considering the increase in global obesity. Dual GLP-1/glucagon (GCG) receptor agonists have shown beneficial effects in circumventing the pathophysiology linked to NASH. Therefore, this study has examined OXM-104 and OXM-101, two dual GLP-1/GCG receptor agonists in the setting of NASH, to establish the relative receptor activities leading to the best metabolic outcome efficacies to reduce the gap between surgery and pharmacological interventions.

Unraveling the leptospirosis epidemic: tales from the Philippine outbreak - a short communication.

Leptospirosis, also known as Weil's disease, is an emerging zoonotic infection that occurs worldwide but is particularly common in the tropics. There has been an increasing trend of leptospirosis in the Philippines since the outbreak occurred in 2020. The number of reported cases was 182 in 2020, 1661 in 2021, and 2794 in 2022. This present article aimed to access previously published studies on the prevalence, implications, and efforts to combat leptospirosis worldwide, with a particular focus on the Philippines from 2001 to 2023. In writing this article, we conducted a thorough search of databases such as PubMed, Researchgate, Web of Science, Scopus, and Google Scholar within 20 years. This present article found that more than 810 cases were reported from 1 January to 4 March 2023. The Cagayan Valley Region has 103 cases, the Zamboanga Peninsula has 77 cases, and the Western Visayas Region has 176 cases, making them the worst-hit areas. The increase in leptospirosis cases in the Philippines is primarily attributed to several factors. Firstly, the country is prone to natural disasters such as typhoons, floods, and landslides, which increase the risk of water sources and the environment being contaminated with Leptospira bacteria. To address the menace of leptospirosis in the Philippines, we urge the Philippine government to focus on improving healthcare infrastructure, providing swift, reliable, and effective treatments, implementing safety regulations, supplying personal protective equipment to medical authorities, and taking strict actions to improve water sanitation.

Liquid biopsies and minimal residual disease in myeloid malignancies.

Minimal residual disease (MRD) assessment through blood component sampling by liquid biopsies (LBs) is increasingly being investigated in myeloid malignancies. Blood components then undergo molecular analysis by flow cytometry or sequencing techniques and can be used as a powerful tool for prognostic and predictive purposes in myeloid malignancies. There is evidence and more is evolving about the quantification and identification of cell-based and gene-based biomarkers in myeloid malignancies to monitor treatment response. MRD based acute myeloid leukemia protocol and clinical trials are currently incorporating LB testing and preliminary results are encouraging for potential widespread use in clinic in the near future. MRD monitoring using LBs are not standard in myelodysplastic syndrome (MDS) but this is an area of active investigation. In the future, LBs can replace more invasive techniques such as bone marrow biopsies. However, the routine clinical application of these markers continues to be an issue due to lack of standardization and limited number of studies investigating their specificities. Integrating artificial intelligence (AI) could help simplify the complex interpretation of molecular testing and reduce errors related to operator dependency. Though the field is rapidly evolving, the applicability of MRD testing using LB is mostly limited to research setting at this time due to the need for validation, regulatory approval, payer coverage, and cost issues. This review focuses on the types of biomarkers, most recent research exploring MRD and LB in myeloid malignancies, ongoing clinical trials, and the future of LB in the setting of AI.

A Case of Cyanosis With Saturation Gap: Dapsone-Induced Methemoglobinemia.

Dapsone is an antibiotic used in the management of dermatologic infections and opportunistic infection prophylaxis in developed countries. Methemoglobinemia (MetHb) is a known complication of dapsone use that can result in cyanosis. MetHb is an aberrant form of hemoglobin produced physiologically by auto-oxidation. An impairment in the process of auto-oxidation due to genetic defects or the use of drugs/toxins causes its levels to rise. Management involves timely recognition and the use of methylene blue (MB) or ascorbic acid. We describe the diagnosis and management of a patient with acquired MetHb as a result of dapsone use.

Scedosporium apiospermum Pneumonia in an Immunocompetent Host.

Invasive fungal infections are being increasingly identified recently. Scedosporium is a significant cause of non-Aspergillus mold infection. It can cause disseminated disease in an immunocompromised host and localized pulmonary infection in immunocompetent ones, especially in those with preformed lung cavities. We present a case of scedosporiosis in an elderly female with bronchiectasis who presented with refractory pulmonary symptoms and infiltrates. The case emphasizes the need to keep the fungal infection in the differential diagnosis of refractory infiltrates in immunocompetent individuals without preformed cavities if they have bronchiectasis. Voriconazole monotherapy can be used as the first-line in proven cases of scedosporiosis.

Concealed Malignancy as a Rare Cause of Refractory Lactic Acidosis: A Fatal Case.

Lactic acidosis is a state in which there is a buildup of lactate in the body to form an excessively low pH in the blood. Elevated lactate levels are often thought to be indicative of relative tissue hypoxia or type A lactic acidosis. Shock, severe anemia, and thromboembolic events can all cause elevated lactate due to tissue hypoperfusion. Malignancy can also lead to an elevation in lactate, a phenomenon described as type B lactic acidosis. Here, we report a case of a 66-year-old male with elevated lactate level, which was refractory to medical treatment. Despite adequate management, including continuous renal replacement therapy, the lactate continued to rise, and consequently, the patient died due to cardiac arrest. Type B lactic acidosis must be considered in patients with elevated lactate levels without hypotension as it has a high mortality rate.

Using Polarized Spectroscopy to Investigate Order in Thin-Films of Ionic Self-Assembled Materials Based on Azo-Dyes.

Three series of ionic self-assembled materials based on anionic azo-dyes and cationic benzalkonium surfactants were synthesized and thin films were prepared by spin-casting. These thin films appear isotropic when investigated with polarized optical microscopy, although they are highly anisotropic. Here, three series of homologous materials were studied to rationalize this observation. Investigating thin films of ordered molecular materials relies to a large extent on advanced experimental methods and large research infrastructure. A statement that in particular is true for thin films with nanoscopic order, where X-ray reflectometry, X-ray and neutron scattering, electron microscopy and atom force microscopy (AFM) has to be used to elucidate film morphology and the underlying molecular structure. Here, the thin films were investigated using AFM, optical microscopy and polarized absorption spectroscopy. It was shown that by using numerical method for treating the polarized absorption spectroscopy data, the molecular structure can be elucidated. Further, it was shown that polarized optical spectroscopy is a general tool that allows determination of the molecular order in thin films. Finally, it was found that full control of thermal history and rigorous control of the ionic self-assembly conditions are required to reproducibly make these materials of high nanoscopic order. Similarly, the conditions for spin-casting are shown to be determining for the overall thin film morphology, while molecular order is maintained.