National Academy of Medicine

Indole-tetrahydroazepine derivatives of iboga alkaloids (ibogalogs) exhibit antidepressant, anxiolytic, promnesic, and antineuropathic effects, mainly via serotonergic targets. However, their physicochemical properties relevant to redox biology, including antioxidant activity and membrane stability, have remained poorly characterized. We investigated the antioxidant properties of three ibogalogs: ibogaminalog (DM506), ibogainalog (IBG), and tabernanthalog (TBG), using model lipid membranes (liposomes), human erythrocytes, and rat hippocampal and cortical synaptosomes exposed to AAPH-induced oxidative stress. Physicochemical descriptors, bond dissociation enthalpies, and ionization potentials were also calculated to assess membrane interactions and the antioxidant potential. All ibogalogs protected erythrocytes by reducing hemolysis, potassium efflux, and malondialdehyde levels, with the strongest effects observed for TBG; none induced hemolysis or K+ efflux at 0.01-10 μM. Ibogalogs also decreased lipid peroxidation in rat hippocampal and cortical synaptosomes. In liposomal systems, TBG showed the highest efficacy against lipid-peroxyl-radical-induced peroxidation, whereas DM506 and IBG mainly slowed autoxidation. Theoretical analysis indicated that the methoxy group substitution critically influences bond dissociation enthalpies, radical delocalization, and antioxidant potency. This first physicochemical characterization of antioxidant properties of ibogalogs enhances the understanding of their membrane-protective actions, complementing their neuromodulatory profiles.

Background. Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age, which collectively impair fertility. Insulin-sensitizing agents have emerged as a key therapeutic strategy to improve metabolic, hormonal, and reproductive outcomes in this population. Aim. This review critically evaluates current evidence on insulin-sensitizing agents in women with PCOS, addressing both their mechanisms of action at the metabolic and ovarian levels and their effects on reproductive outcomes. Material and Methods. A review of randomized controlled trials, meta-analyses, and high-quality observational studies published up to 2025 evaluated the effects of metformin, myo-inositol, and berberine on reproductive outcomes in women with PCOS. Results. Insulin-sensitizing agents improve metabolic dysfunction and ovulatory outcomes in PCOS. Metformin increases ovulation and clinical pregnancy rates, particularly in women with insulin resistance or higher BMI, though its effect on live birth is inconsistent. Myo-inositol and berberine show beneficial effects on metabolic parameters and ovulatory function, but evidence for live birth and miscarriage remains limited. Conclusions. Insulin-sensitizing therapies support reproductive function in women with PCOS, particularly in metabolically compromised phenotypes. Metformin has the strongest evidence base, whereas myo-inositol and berberine are promising adjunctive or alternative options. Future high-quality randomized trials focusing on live birth and miscarriage outcomes, standardized reporting, and precise patient stratification are needed to optimize the clinical use of these agents in PCOS-related infertility.

INTRODUCTION. Currently, preclinical development of analgetic drugs is facing a large number of obstacles, mostly due to the limited validity of models and methods for pain assessment. To overcome the translational barrier in the development of analgetics, it is necessary to revise the existing methods for assessing pain sensitivity and develop new approaches that include both the study of reflexive and affective pain component. AIM. This study aimed to systematize a contemporary view of pain assessment methods in laboratory animals and develop applicability criteria in preclinical trials of new analgesics. DISCUSSION. The literature review included 75 references, among them original research and systematic reviews over the past 35 years. Pain is a multidimensional phenomenon that includes sensory, discriminatory and affective-motivational components. Standard nociceptive tests effectively evaluate sensory hypersensitivity, however, they are not sensitive enough when studying chronic pain based on an affective component. Less widely used non-reflexive methods (grimace scale, ultrasound vocalization, burrowing test) allow assessing the affective component; still, they have low specificity and are insufficiently validated for various pain models. A combined, polymodal approach enhances the objectivity, reproducibility, and translational predictivity of preclinical research towards the development of new analgetics. CONCLUSIONS. Nociceptive tests are a tool for assessing efficacy of anesthetics both at a primary screening and in preclinical trials. Standard nociceptive tests do not allow assessing affective pain component, thus development of new anesthetics necessitates an introduction of non-reflexive pain assessment in the preclinical trials. A combination of reflexive and non-reflexive pain assessment methods is a base for new research strategies in preclinical trials.

Background: Post-COVID-19 cognitive impairment, commonly referred to as "brain fog," represents a significant clinical problem, yet its underlying mechanisms remain incompletely understood. New research indicates that long-term cognitive consequences of SARS-CoV-2 infection may result from chronic immunological dysregulation and neurometabolic changes. Objective: We aimed to assess the associations between cognitive performance, cerebral glucose metabolism, and inflammatory markers in patients with COVID-19 brain fog symptoms. Methods: This study included 47 patients with post-COVID-19 cognitive complaints enrolled in the COVMENT trial. Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA). Brain glucose metabolism was evaluated with FDG PET-CT, and inflammatory markers, including C-reactive protein (CRP), monocyte-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio, eosinophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio (PLR), were measured. Correlation analyses, logistic regression, and ROC analysis were performed to explore relationships between these factors. Results: A lower score of the MoCA abstraction domain correlated significantly with lower FDG uptake in multiple brain regions, including inferior parietal lobules and precuneus. Among inflammatory markers, only PLR demonstrated significant associations with both brain metabolism and abstraction performance. Lower PLR values were associated with greater neurometabolic impairment, and PLR < 130.1 was associated with abnormal abstraction performance. Conclusions: Post-COVID-19 cognitive dysfunction can be associated with selective neurometabolic alterations in brain regions supporting abstract reasoning. PLR seems to be associated with both cognitive performance and regional brain metabolism, suggesting a potential link between chronic immune dysregulation and neurocognitive impairment in post-COVID-19.

(1) Background: Insulin resistance (IR) is increasingly recognized not only as a key factor in metabolic and cardiovascular disorders but also as an important contributor to cognitive decline. The growing prevalence of obesity, type 2 diabetes mellitus, and cardiovascular disease (CVD), paralleled by rising rates of dementia, highlights the need for an integrative model linking these conditions. The emerging cardio-metabolic-brain axis proposes a unified model explaining how biomarkers of metabolic stress, adipose-tissue-derived mediators, and abnormalities in laboratory parameters interact with vascular injury and neurodegeneration. (2) Methods: A comprehensive literature review was conducted using MEDLINE, SCOPUS, and Web of Science databases, complemented by additional searches in Embase and Cochrane Library. Studies from the past decade were screened using keywords such as "insulin resistance", "cardio-metabolic-brain axis", "cognitive decline", and "cardiovascular disease". Both epidemiological and mechanistic studies were analyzed to summarize current evidence and identify research gaps. (3) Results and Conclusions: Evidence indicates that insulin resistance contributes to endothelial dysfunction, chronic inflammation, and oxidative stress, driving the metabolic abnormalities characteristic of obesity and type 2 diabetes and promoting both atherosclerosis and neurodegeneration. Individuals with elevated IR-regardless of diabetes status-display higher risks of cardiovascular events and measurable cognitive decline. Brain insulin resistance further impairs glucose utilization, disrupts synaptic function, and facilitates amyloid accumulation, reflecting mechanisms observed in Alzheimer's disease. These findings support IR as a key biomarker linking metabolic stress, vascular injury, and neural vulnerability within the cardio-metabolic-brain axis. Early identification of IR, together with targeted lifestyle and pharmacological interventions, may therefore offer dual benefits for cardiovascular and brain health. Continued longitudinal research is needed to validate this integrative model and refine therapeutic strategies aimed at improving insulin sensitivity.

Alcohol consumption remains a major public health problem in Poland, with high per capita intake. While youth drinking is decreasing, the industry is exploring marketing tactics targeted at young people. In 2024, the launch of fruit-flavored alcohol pouches in Poland raised concerns due to packaging that could appeal to minors. This study aimed to assess the regulatory gaps that allowed the launch of this product and to examine responses from governmental bodies, public institutions and the general public. An exploratory, web-based review of publicly available Polish-language sources from June 2024 to January 2025 was conducted. To accomplish this, targeted keyword searches were carried out across online news portals, government websites, and social media platforms. Sources were selected based on their credibility and relevance, and then cross-verified to ensure accuracy. A descriptive analysis was performed to identify product and manufacturer descriptions, create a timeline of events, and examine institutional and public reactions. The study provides a timeline of key events, from the launch of alcohol pouches to their eventual withdrawal following media scrutiny and government intervention. Observers, including politicians, and public commentators, emphasized the strong visual resemblance between the alcohol pouches and non-alcoholic fruit pouches intended for children. Existing Polish regulations proved insufficient to prevent the introduction of such products, highlighting the need for urgent policy updates. Public reaction and strong media criticism played a key role in prompting the regulatory changes. This case highlights the risks posed by alcohol products resembling non-alcoholic fruit pouches and underscores gaps in Polish alcohol regulations. Stricter packaging rules, clearer labelling requirements, and improved enforcement mechanisms are essential to protect vulnerable groups, especially minors. The findings highlight the need for better industry monitoring and adoption of a more proactive regulatory approach in order to close legal gaps and protect public health.

Abstract Background Electrical cardioversion (ECV) for atrial fibrillation (AF) restores sinus rhythm (SR), however, the extent and durability of changes in the left atrium (LA) and ventricle (LV) following cardioversion remain unclear. The aim of this study was to assess echocardiographic changes following successful ECV and to identify parameters that may predict the maintenance of SR. Methods Patients undergoing ECV were prospectively enrolled, with detailed echocardiographic data collected at three time points: before ECV, 24 hours and 30 days post-ECV. Statistical analyses included the Friedman test, Wilcoxon signed-rank test, and Mann–Whitney U test with Bonferroni correction. Effect sizes were assessed using Kendall’s W coefficient (W), effect size r, and eta-squared (η²). Results Out of the initial 94 patients (mean age 65.9 ±9.3 years; 69% male; 42.6% obese), SR was maintained in 76 patients at 24 hours and in 49 patients (52%) at 30 days post-ECV. Two patients were lost to 30-day follow-up. The most common comorbidities in the study group were hypertension (79.8%), heart failure (28.7%), and diabetes mellitus (28.7%). In patients with sustained SR, significant and lasting improvements were observed in both the LA and LV. These improvements were reflected in several parameters, including global atrioventricular strain (GAVS), LA reservoir strain (LASr), E/LASr ratio, LA emptying fraction (LAEF), LA stiffness index (LASI), LV ejection fraction (LVEF), LV global longitudinal strain (GLS LV), and LV global work index (GWI) (Table 1). Changes were evident at 24 hours and became more pronounced by day 30. Additionally, parameters assessable only during SR showed significant improvements between the 24-hour and 30-day post-ECV assessments. These included LA contraction strain (LASct), LA contraction strain index (CSI = LASct/LASr), A wave, E/A ratio, and lateral A’ wave (Table 2). In between-group analyses (patients with vs. without maintained SR), only LV parameters, including global wasted work (GWW), global work efficiency (GWE), LV systolic volume (LVESV), LV systolic diameter (LVSd), and GWI, demonstrated moderate effect sizes (η² = 0.05–0.08), indicating limited but potential predictive value for ECV success. Moreover, several of the parameters (such as LASr, E/LASr, GAVS, LASct, CSI, A wave, lateral A’ wave and E/A ratio) that exhibited the most pronounced changes following ECV (W or r ≥ 0.7) may reflect reverse atrioventricular remodeling. Conclusions Successful cardioversion results in significant and sustained improvements in both LA and LV structure and function. Interestingly, only parameters reflecting LV mechanics, but not LA function, were predictive of successful electrical cardioversion. Echocardiographic indices such as GWW, GWE, GWI, LVESV, and LVSd demonstrated notable improvements, and further studies are needed to verify their clinical value as potential predictors of cardioversion success and long-term SR stability.

Prior research regarding multiple sclerosis (MS) has extensively examined the inflammatory processes, while the mechanisms of neurodegeneration, particularly cerebral atrophy, remain less understood. The purpose of this systematic review was to summarize the current knowledge about the degree and pattern of atrophy in various types of MS, and its relationship with the clinical progression of the disease and the impact of treatment on brain volume loss. A systematic review was performed in accordance with the PRISMA guidelines. Relevant articles published between 1 January 2018 and 1 July 2024 available in the PubMed and Cochrane Library databases were obtained using a systematic search strategy. The following keywords were used to screen the publications: 'multiple sclerosis' and/or 'MS' and 'atrophy'. The eligibility criteria that identified and described outcomes were pre-established by the authors. Studies constituting clinical research protocols, theoretical inspections, articles describing other measurement methods or comparing measuring methods, conference abstracts and articles in a language other than English were excluded. Of the 1,911 records obtained from the systematic search based on keywords, 26 were included in the final review. Publications enabled the analysis of atrophy in patients compared to the healthy population, the evaluation of atrophy concerning different MS subtypes, its correlation with disability progression, the patterns of atrophy and the impact of disease-modifying therapies. Moreover, clinical trials involving atrophy measurements in MS patients were also collected. This systematic review confirmed the role of assessing volumetric changes in brain regions as a useful tool in the diagnosis of MS, assessment of its progression, and response to treatment. Given the relatively small number of new reports in the last six years, it also indicated the need for further research, especially using atrophy to assess the efficacy of therapy.

Abstract Background The association between inflammatory bowel disease (IBD) and venous thromboembolism (VTE) is well-studied in the adult population. However, in paediatric-onset IBD (PIBD; &amp;lt; 18 years) data are scarce. Most studies are limited in size, as pointed out by the recently published ESPGHAN-ECCO guidelines for the treatment of paediatric acute severe ulcerative colitis. Several studies have indicated an increased risk of cerebral venous sinus thrombosis (CSVT). Assessing the risk among children and adolescents across clinical characteristics is crucial to guide clinical decisions about prophylactic treatment. Methods We used data from nationwide population-based registers to identify patients diagnosed with PIBD in Denmark (1996-2022) and Sweden (2006-2023). Patients with PIBD were matched on the date of first IBD diagnostic listing with up to 10 reference individuals from the general population by age, sex, and place of residence. Occurrence of VTE was compared in absolute (incidence rate difference, IRD) and relative terms (hazard ratios, HR) with 95% confidence intervals (95%CI). Data from Denmark and Sweden were combined using random effects meta-analyses. Comparisons included VTE overall, by VTE subtypes, sex, age, IBD subtypes, and time since diagnosis; and in the data from Sweden only, by disease activity (steroid prescriptions or addition/change of immunomodulators or advanced therapies, hospitalisation or surgery for IBD) and hospitalisation. Results We included 4,009 (Denmark) + 6,781 (Sweden) patients with PIBD and 39,096 + 64,497 reference individuals. Median follow-up time was 9.6 and 8.9 years, respectively. The incidence rate of VTE among patients with IBD was 1.3 per 1,000 person-years (95%CI: 1.1-1.5), and 0.4 (95%CI: 0.2-0.7) among reference individuals, with an IRD of 0.9 (95%CI: 0.7-1.2) per 1,000 person-years and an HR of 3.3 (95%CI: 1.8-6.3) (Table 1). The HR within the first 2 years of IBD was 18.8 (95%CI: 10.3-34.1). While CSVT and other thrombotic events had the highest HRs among VTE subtypes, the absolute risk of CSVT was low, at 1 per 10,000 person-years. In Sweden, disease activity, and hospitalisation, particularly hospitalisation for IBD, were strongly associated with VTE. Conclusion PIBD was associated with a substantially increased relative risk of VTE compared to the general population, although the absolute risk, including that for CSVT, was very low. Clinicians should carefully consider the risk of VTE in this population, in particular early on in the disease course, and during disease activity and hospitalisation. Conflict of interest: Dr. Bröms, Gabriella: Dr Bröms has served as a speaker for Takeda and Janssen and worked on projects at Karolinska Institute, partly financed by Janssen, Pfizer and UCB, unrelated to this study. Trudu, Beatrice: None. Modin, Frederikke Agerbo: None. Moshtaghi-Svensson, John: None. Burisch, Johan: Dr. Burisch reports grants from AbbVie, Janssen-Cilag, MSD, Takeda, Tillots Pharma, Bristol Myers Squibb, and Novo Nordisk Foundation personal fees from AbbVie, Janssen-Cilag, Celgene, MSD, Pfizer, Takeda, Tillots Pharma, Bristol Myers Squibb, Samsung Bioepis, Pharmacosmos, Ferring, Galapagos, Eli Lilly, Dr Falk Pharma, Celltrion, Zealand Pharma and Orion Pharma. Forss, Anders: Served as speaker/advisory board member for Janssen Cilag AB, Pfizer and Tillotts Pharma. Jansson, Sabine: Dr Jansson has received travel support from Ferring Pharmaceuticals and research grants from Takeda Pharma A/S, and Ferring Pharmaceuticals. Unrelated to the work submitted. Ludvigsson, Jonas: Dr Ludvigsson has received financial support from Merck/MSD for a study on inflammatory bowel disease and fibrosis and for developing a paper reviewing national healthcare registers in China. Dr Ludvigsson also has an ongoing research collaboration on celiac disease with Takeda. Earlier support includes a grant from Janssen for an unrelated study on behalf of the Swedish IBD quality register (SWIBREG). Mårild, Karl: Dr Mårild has received payment for two lectures for Pfizer Osooli, Mehdi: Dr Osooli participated in projects at Karolinska institute partly financed by pharmaceutical companies. All unrelated to this study. de Ridder, Lissy: Non-financial Support: Pfizer Other: Abbvie, Pfizer, Janssen, Eli Lilly, Takeda, Medtronic, Alvotech Wewer, Vibeke: None. SWIBREG Study Group, Swibreg: None Malham, Mikkel: None. Olen, Ola: Dr Olén has led projects at Karolinska Institutet financed by grants from Pfizer, Janssen, Alfasigma, AbbVie, Takeda, Bristol Myers Squibb, and Ferring. OO has served as speaker for lectures organized by Janssen, Pfizer, Takeda, and Bristol Myers Squibb.

This article provides perspectives on the use of Cerebrolysin as an adjunct treatment to reperfusion therapy in acute ischemic stroke (AIS). In the evolving landscape of AIS reperfusion therapy, we hypothesize that adjunctive cerebroprotective therapy, such as Cerebrolysin, is likely to further improve patient outcomes. Beyond its established neurorecovery benefits, recent data indicate that Cerebrolysin also offers protection to the neurovascular unit and the blood-brain barrier. This paper introduces the CErebrolysin in RECanalization And Perfusion (CERECAP) program, a collaborative initiative of independent academic investigations exploring the favorable trends of Cerebrolysin in reperfusion. The CERECAP program has generated compelling data demonstrating Cerebrolysin's alignment with current AIS reperfusion therapy concepts, particularly its role in early intervention targeting multiple pathways. We review these studies and discuss the critical need to clearly define the patient population that benefit most from adjunctive Cerebrolysin therapy in AIS.