Update on Biomarkers of Chronic Inflammatory Processes Underlying Diabetic Neuropathy.

There is an increasing prevalence of diabetes mellitus (DM), particularly type 2 DM (T2DM), and its associated complications. T2DM is linked to insulin resistance, chronic inflammation, and oxidative stress, which can lead to both macrovascular and microvascular complications, including peripheral diabetic neuropathy (PDN). Inflammatory processes play a key role in the development and progression of T2DM and its complications, with specific markers like C-reactive protein (CRP), interleukins (ILs), and tumor necrosis factor (TNF)-α being associated with increased risk. Other key inflammatory markers such as nuclear factor kappa B (NF-κB) are activated under hyperglycemic and oxidative stress conditions and contribute to the aggravation of PDN by regulating inflammatory gene expression and enhancing endothelial dysfunction. Other important roles in the inflammatory processes are played by Toll-like receptors (TLRs), caveolin 1 (CAV1), and monocyte chemoattractant protein 1 (MCP1). There is a relationship between vitamin D deficiency and PDN, highlighting the critical role of vitamin D in regulating inflammation and immune responses. The involvement of macrophages in PDN is also suspected, emphasizing their role in chronic inflammation and nerve damage in diabetic patients. Vitamin D supplementation has been found to reduce neuropathy severity, decrease inflammatory markers, and improve glycemic control. These findings suggest that addressing vitamin D deficiency could offer therapeutic benefits for PDN. These molecular pathways are critical in understanding the pathogenesis of DM complications and may offer potential biomarkers or therapeutic targets including anti-inflammatory treatments, vitamin D supplementation, macrophage phenotype modulation, and lifestyle modifications, aimed at reducing inflammation and preventing PDN. Ongoing and more extensive clinical trials with the aim of investigating anti-inflammatory agents, TNF-α inhibitors, and antioxidants are needed to advance deeper into the understanding and treatment of painful diabetic neuropathy.

Risk factors for cognitive dysfunction amongst patients with cardiovascular diseases.

Background: The impact of cardiovascular diseases on cognition raises important research questions. The study aimed to investigate the relationship between demographic data, cardiovascular diseases, kidney disease and depressive symptoms on cognition. Methods: A cross-sectional study of patients with cardiovascular diseases was performed. The Montreal Cognitive Assessment (MoCA) was applied for cognitive evaluation. Based on MoCA three groups were defined: preserved cognition, mild, and advanced cognitive dysfunction (CD). Data were analyzed using Cronbach alpha (Cα) and McDonald's ω (Mω) for internal consistency. The Chi-square test, Cramer's V test, and correlation analyses were also applied. Results: Of 628 patients, 55.2% had mild CD, and the mean age was 67.95 (SD 9.53) years. Cα and Mω were 0.7, indicating good internal consistency. We found a moderate positive correlation between depression and the severity of CD (r = 0.25, p = 0.0001). A weak association between CD and female gender (p = 0.016), atrial fibrillation (p = 0.03), stroke (p = 0.009), and a moderate association for age group (p < 0.0001), education level (p < 0.0001), smoking (p < 0.0001), and renal dysfunction (p < 0.0001) was found. Age ≥ 70 years, eGFR 30-59 mL/min/1.73m2 significantly increased the likelihood for mild and advanced CD, while smoking and > 9 classes decreased it. Female gender, history of atrial fibrillation, and stroke significantly increased the likelihood of advanced CD. Conclusion: Mild CD was the most common in patients with cardiovascular diseases. Older age, lower education, being a non-smoker, and renal dysfunction were risk factors for both mild and advanced CD. Female gender, previous diagnosis of atrial fibrillation, and stroke are risk factors for advanced CD.

Investigation of Neuromuscular Activation in Older Female Adults during a Dynamic and Challenging Virtual Reality Activity: A Cross-Sectional Study.

The use of virtual reality (VR) in older adults promotes improvements in mobility, strength, and balance. Changes in neuromuscular activation have been found to be associated with these improvements; however, during VR activities, this aspect has not been thoroughly investigated. The aim of this study was to investigate neuromuscular activation among older female adults during VR activities. Sixteen older female adults, with the use of VR, performed dynamic punching movements involving elbow flexion/extension for one minute, and the muscle activation of the bicep brachii was recorded with electromyography (EMG) and normalized to the maximal voluntary isometric contraction of elbow flexion. The one-minute activity was divided into three time phases: 0-10 s, 25-35 s, and 50-60 s. The five highest EMG amplitude values (%) in each phase were selected and averaged. Differences between phases were analyzed using repeated ANOVA (αadj = 0.017). The EMG amplitude for the first phase was 39.1 ± 2.6%, that for the second phase was 44.8 ± 3.0%, and that for the third phase was 49.6 ± 3.1%. Statistically significant differences were found in all phases, with the first phase demonstrating a lower EMG amplitude (%) compared to the second (p = 0.002) and third phases (p = 0.000). The third phase demonstrated a higher EMG amplitude (%) compared to the second phase (p = 0.025). Engagement in VR activities can have significant effects on neuromuscular activation in older female adults, with our findings revealing a significant increase in the EMG amplitude within one minute of commencing a dynamic and challenging activity such as virtual boxing.

The Risk of Atrial Fibrillation and Previous Ischemic Stroke in Cognitive Decline.

Objectives: Our study investigated the inverse relationship between cognitive decline (CD) and the presence of documented atrial fibrillation (AFib), ischemic stroke, heart failure, lower extremity peripheral artery disease, and diabetes mellitus. Methods: We conducted a retrospective cross-sectional study between December 2016 and November 2019. A total of 469 patients were enrolled who underwent cognitive evaluation with three cognitive tests (Montreal Cognitive Assessment-MOCA, Mini-Mental State Examination-MMSE, and General Practitioner Assessment of Cognition-GPCOG). We used the standard cut-off values, and the optimal thresholds were obtained from the receiver operating characteristic curves. Results: The standard cut-off level of the MOCA (<26 points) was associated with the presence of AFib (OR: 1.83, 95% CI: 1.11-3.01) and the optimal cut-off level with <23 points with ischemic stroke (OR: 2.64, 95% CI: 1.47-4.74; p = 0.0011). The optimal cut-off value of the MMSE (<28 points) was associated with the presence of ischemic stroke (OR: 3.07, 95% CI: 1.56-6.07; p = 0.0012), AFib (OR: 1.65, 95% CI: 1.05-2.60; p = 0.0287), and peripheral artery disease (OR: 2.72, 95% CI: 1.38-5.36; p = 0.0039). GPCOG < 8 points were associated with ischemic stroke (OR: 2.18, 95% CI: 1.14-4.14; p = 0.0176) and heart failure (OR: 1.49, 95% CI: 1.01-2.21; p = 0.0430). Conclusions: Our research highlighted the broader utility of cognitive assessment. The MOCA and MMSE scores proved to be associated with documented AFib. Higher cognitive test results than the standard threshold for CD of the MMSE, GPCOG, and lower MOCA scores represented risk factors for the presence of previous ischemic stroke.

Werner helicase interacting protein 1 contributes to G-quadruplex processing in human cells.

Genome replication is frequently impeded by highly stable DNA secondary structures, including G-quadruplex (G4) DNA, that can hinder the progression of the replication fork. Human WRNIP1 (Werner helicase Interacting Protein 1) associates with various components of the replication machinery and plays a crucial role in genome maintenance processes. However, its detailed function is still not fully understood. Here we show that human WRNIP1 interacts with G4 structures and provide evidence for its contribution to G4 processing. The absence of WRNIP1 results in elevated levels of G4 structures, DNA damage and chromosome aberrations following treatment with PhenDC3, a G4-stabilizing ligand. Additionally, we establish a functional and physical relationship between WRNIP1 and the PIF1 helicase in G4 processing. In summary, our results suggest that WRNIP1 aids genome replication and maintenance by regulating G4 processing and this activity relies on Pif1 DNA helicase.

Mental health competencies are stronger determinants of well-being than mental disorder symptoms in both psychiatric and non-clinical samples.

The present study aimed to investigate whether the strength of mental health competencies and the severity of mental disorder symptoms, and their interaction, differ in the strength of their associations with several dimensions of well-being in Hungarian adult psychiatric and non-clinical samples. All respondent in the psychiatric sample (129 patients (44 male, 85 female)) and in the non-clinical community sample (253 adults (43 male, 210 female)) completed the Mental Health Test, six measures of well-being and mental health, and the Symptom Checklist-90-Revised. Including both mental health competencies and mental disorder symptoms in a regression model in both samples can predict patients' well-being even more accurately. Mental health competencies were positively related; mental disorder symptoms were negatively related to subjective well-being. In all models and in both samples, mental health competencies were found to be stronger determinants of well-being than mental disorder symptoms. The interaction of mental health competencies and mental disorder symptoms is no more predictive of well-being in either psychiatric or non-clinical samples than when the effects of each are considered separately. The assessment of mental health competencies has an important predictive value for well-being in the presence of psychopathological symptoms and/or mental disorders.

Cardiovascular Effects of Herbal Products and Their Interaction with Antihypertensive Drugs-Comprehensive Review.

Hypertension is a highly prevalent population-level disease that represents an important risk factor for several cardiovascular complications and occupies a leading position in mortality statistics. Antihypertensive therapy includes a wide variety of drugs. Additionally, the potential antihypertensive and cardioprotective effects of several phytotherapy products have been evaluated, as these could also be a valuable therapeutic option for the prevention, improvement or treatment of hypertension and its complications. The present review includes an evaluation of the cardioprotective and antihypertensive effects of garlic, Aloe vera, green tea, Ginkgo biloba, berberine, ginseng, Nigella sativa, Apium graveolens, thyme, cinnamon and ginger, and their possible interactions with antihypertensive drugs. A literature search was undertaken via the PubMed, Google Scholar, Embase and Cochrane databases. Research articles, systematic reviews and meta-analyses published between 2010 and 2023, in the English, Hungarian, and Romanian languages were selected.

Assessment of vitamin B12 levels and cardiovascular risk factors in metformin- and non-metformin-treated type 2 diabetic patients.

Oxidative stress enhances cardiovascular risk. Metformin decreases intestinal absorption of vitamin B12. Our objective was the evaluation of type 2 diabetics focusing on differences due to their treatment. A prospective study on 224 type 2 diabetics was realized between 2015-2018 in Targu Mures, Romania, divided into 2 subgroups (metformin vs. other therapy - 2nd/3rd generation sulfonylureas, insulin, dietary regimen -, followed for at least one year) and non-diabetic controls (n=25) for oxidative stress level comparison. Serum homocysteine (HC), vitamin B12 were determined by chemiluminescence (Immulite One). Lipid peroxidation was assessed by serum malondialdehyde (MDA) measurement (HPLC). Biochemical tests, minerals, cystatin C, high-sensitivity C reactive protein (hs-CRP) were measured on Konelab20Xti, glycated hemoglobin on Nycocard Reader. GraphPad InStat-3 was used for statistics. Negative correlation occured between serum vitamin B12 and HC, this vitamin's level was significantly lower and serum zinc was significantly higher in patients on metformin. Hyperhomocysteinemia was present in 87% of the subjects, 46% had zinc deficiency and 41% elevated hs-CRP. Serum cystatin C showed positive correlation with creatinine. Serum MDA was significantly higher in diabetics compared to control patients. Elevated hs-CRP and homocysteine represent raised cardiovascular risk. Intense oxidative stress, vitamin, mineral deficiencies are frequent in diabetic subjects.

The Management of COVID-19-Related Coagulopathy: A Focus on the Challenges of Metabolic and Vascular Diseases.

The course of COVID-19 is highly dependent on the associated cardiometabolic comorbidities of the patient, which worsen the prognosis of coronavirus infection, mainly due to systemic inflammation, endothelium dysfunction, and thrombosis. A search on the recent medical literature was performed in five languages, using the PubMed, Embase, Cochrane, and Google Scholar databases, for the review of data regarding the management of patients with a high risk for severe COVID-19, focusing on the associated coagulopathy. Special features of COVID-19 management are presented, based on the underlying conditions (obesity, diabetes mellitus, and cardiovascular diseases), emphasizing the necessity of a modern, holistic approach to thromboembolic states. The latest findings regarding the most efficient therapeutic approaches are included in the article, offering guidance for medical professionals in severe, complicated cases of SARS-CoV-2 infection. We can conclude that severe COVID-19 is closely related to vascular inflammation and intense cytokine release leading to hemostasis disorders. Overweight, hyperglycemia, cardiovascular diseases, and old age are important risk factors for severe outcomes of coronavirus infection, involving a hypercoagulable state. Early diagnosis and proper therapy in complicated SARS-CoV-2-infected cases could reduce mortality and the need for intensive care during hospitalization in patients with cardiometabolic comorbidities.

Pathways of Coagulopathy and Inflammatory Response in SARS-CoV-2 Infection among Type 2 Diabetic Patients.

Chronic inflammation and endothelium dysfunction are present in diabetic patients. COVID-19 has a high mortality rate in association with diabetes, partially due to the development of thromboembolic events in the context of coronavirus infection. The purpose of this review is to present the most important underlying pathomechanisms in the development of COVID-19-related coagulopathy in diabetic patients. The methodology consisted of data collection and synthesis from the recent scientific literature by accessing different databases (Cochrane, PubMed, Embase). The main results are the comprehensive and detailed presentation of the very complex interrelations between different factors and pathways involved in the development of arteriopathy and thrombosis in COVID-19-infected diabetic patients. Several genetic and metabolic factors influence the course of COVID-19 within the background of diabetes mellitus. Extensive knowledge of the underlying pathomechanisms of SARS-CoV-2-related vasculopathy and coagulopathy in diabetic subjects contributes to a better understanding of the manifestations in this highly vulnerable group of patients; thus, they can benefit from a modern, more efficient approach regarding diagnostic and therapeutic management.

Clinical Presentation Is Dependent on Age and Calendar Year of Diagnosis in Celiac Disease: A Hungarian Cross-Sectional Study.

International trends indicate that celiac disease (CeD) is becoming more common, while the clinical presentation of CeD tends to change. We aimed to investigate factors associated with the clinical presentation of CeD. We reviewed all CeD cases diagnosed at our tertiary center, University of Pécs (Hungary), between 1992 and 2019. We collected data of verified CeD patients on clinical presentations (classified by the Oslo Classification), the age at and calendar year of diagnosis, and sex, serology and histology at diagnosis. To assess the associations of baseline variables with clinical presentations, we applied univariate and multivariate (binary logistic regression) statistics. A total of 738 CeD patients were eligible for inclusion. In the univariate analysis, patients with classical CeD were more common in the latest calendar period (p < 0.001) and tended to be older (p = 0.056), but we failed to observe a significant association between the clinical presentation and sex, serology or histology at diagnosis. In the multivariate analysis, only age at diagnosis and calendar year were independently associated with clinical presentations (OR = 1.02, CI: 1.01-1.04 and OR = 0.93, CI: 0.89-0.98, respectively). Our findings confirmed that classical CeD is independently associated with age at diagnosis and calendar year of diagnosis of CeD, whereas other parameters were not significantly associated with clinical presentations.

Relationship between Nutrition, Lifestyle Habits and Laboratory Parameters in Hypertensive Patients with/without Cognitive Dysfunction.

(1) Background: Cognitive dysfunction is a major concern in hypertensive patients. Lifestyle habits and nutrition influence laboratory parameters, with an impact on clinical course. The objective of the study was to evaluate nutrition and lifestyle habits in hypertensive patients with/without cognitive dysfunction and establish correlations to laboratory parameters. MATERIAL AND METHODS: 50 patients admitted to the Cardiovascular Rehabilitation Clinic in Târgu Mureș were enrolled in this study between March-June 2021. We evaluated their cognitive function, and they filled in a questionnaire about lifestyle and nutrition. Biochemical blood tests were performed using a Konelab Prime 60i analyzer. IBM-SPSS22 and GraphPad InStat3 were used for statistics. RESULTS: Mean age of hypertensive patients (n = 50) was 70.42 ± 4.82 (SD) years, half of them had cognitive dysfunction. Zinc deficiency was present in 74% of the subjects. The subgroup with cognitive dysfunction had significantly higher BMI (p = 0.009) and microalbuminuria (p = 0.0479), as well as significantly lower magnesium intake (p = 0.032) and cholesterol intake (p = 0.022), compared to those with normal cognitive status. CONCLUSIONS: Nutrition is in a close relationship with laboratory parameters; significant differences (microalbuminuria, cholesterol intake, BMI, etc.) are present between hypertensive patients with/without cognitive dysfunction. A healthy diet is important for the maintenance of metabolic balance, the achievement of optimal body weight, and the prevention of complications.

Digital Biomarkers for Supporting Transitional Care Decisions: Protocol for a Transnational Feasibility Study.

BACKGROUND: Virtual Health and Wellbeing Living Lab Infrastructure is a Horizon 2020 project that aims to harmonize Living Lab procedures and facilitate access to European health and well-being research infrastructures. In this context, this study presents a joint research activity that will be conducted within Virtual Health and Wellbeing Living Lab Infrastructure in the transitional care domain to test and validate the harmonized Living Lab procedures and infrastructures. The collection of data from various sources (information and communications technology and clinical and patient-reported outcome measures) demonstrated the capacity to assess risk and support decisions during care transitions, but there is no harmonized way of combining this information. OBJECTIVE: This study primarily aims to evaluate the feasibility and benefit of collecting multichannel data across Living Labs on the topic of transitional care and to harmonize data processes and collection. In addition, the authors aim to investigate the collection and use of digital biomarkers and explore initial patterns in the data that demonstrate the potential to predict transition outcomes, such as readmissions and adverse events. METHODS: The current research protocol presents a multicenter, prospective, observational cohort study that will consist of three phases, running consecutively in multiple sites: a cocreation phase, a testing and simulation phase, and a transnational pilot phase. The cocreation phase aims to build a common understanding among different sites, investigate the differences in hospitalization discharge management among countries, and the willingness of different stakeholders to use technological solutions in the transitional care process. The testing and simulation phase aims to explore ways of integrating observation of a patient's clinical condition, patient involvement, and discharge education in transitional care. The objective of the simulation phase is to evaluate the feasibility and the barriers faced by health care professionals in assessing transition readiness. RESULTS: The cocreation phase will be completed by April 2022. The testing and simulation phase will begin in September 2022 and will partially overlap with the deployment of the transnational pilot phase that will start in the same month. The data collection of the transnational pilots will be finalized by the end of June 2023. Data processing is expected to be completed by March 2024. The results will consist of guidelines and implementation pathways for large-scale studies and an analysis for identifying initial patterns in the acquired data. CONCLUSIONS: The knowledge acquired through this research will lead to harmonized procedures and data collection for Living Labs that support transitions in care. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/34573.

Cocreating a Harmonized Living Lab for Big Data-Driven Hybrid Persona Development: Protocol for Cocreating, Testing, and Seeking Consensus.

BACKGROUND: Living Labs are user-centered, open innovation ecosystems based on a systematic user cocreation approach, which integrates research and innovation processes in real-life communities and settings. The Horizon 2020 Project VITALISE (Virtual Health and Wellbeing Living Lab Infrastructure) unites 19 partners across 11 countries. The project aims to harmonize Living Lab procedures and enable effective and convenient transnational and virtual access to key European health and well-being research infrastructures, which are governed by Living Labs. The VITALISE consortium will conduct joint research activities in the fields included in the care pathway of patients: rehabilitation, transitional care, and everyday living environments for older adults. This protocol focuses on health and well-being research in everyday living environments. OBJECTIVE: The main aim of this study is to cocreate and test a harmonized research protocol for developing big data-driven hybrid persona, which are hypothetical user archetypes created to represent a user community. In addition, the use and applicability of innovative technologies will be investigated in the context of various everyday living and Living Lab environments. METHODS: In phase 1, surveys and structured interviews will be used to identify the most suitable Living Lab methods, tools, and instruments for health-related research among VITALISE project Living Labs (N=10). A series of web-based cocreation workshops and iterative cowriting processes will be applied to define the initial protocols. In phase 2, five small-scale case studies will be conducted to test the cocreated research protocols in various real-life everyday living settings and Living Lab infrastructures. In phase 3, a cross-case analysis grounded on semistructured interviews will be conducted to identify the challenges and benefits of using the proposed research protocols. Furthermore, a series of cocreation workshops and the consensus seeking Delphi study process will be conducted in parallel to cocreate and validate the acceptance of the defined harmonized research protocols among wider Living Lab communities. RESULTS: As of September 30, 2021, project deliverables Ethics and safety manual and Living lab standard version 1 have been submitted to the European Commission review process. The study will be finished by March 2024. CONCLUSIONS: The outcome of this research will lead to harmonized procedures and protocols in the context of big data-driven hybrid persona development among health and well-being Living Labs in Europe and beyond. Harmonized protocols enable Living Labs to exploit similar research protocols, devices, hardware, and software for interventions and complex data collection purposes. Economies of scale and improved use of resources will speed up and improve research quality and offer novel possibilities for open data sharing, multidisciplinary research, and comparative studies beyond current practices. Case studies will also provide novel insights for implementing innovative technologies in the context of everyday Living Lab research. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/34567.

To ventilate or not to ventilate during bystander CPR - A EuReCa TWO analysis.

BACKGROUND: Survival after out-of-hospital cardiac arrest (OHCA) is still low. For every minute without resuscitation the likelihood of survival decreases. One critical step is initiation of immediate, high quality cardiopulmonary resuscitation (CPR). The aim of this subgroup analysis of data collected for the European Registry of Cardiac Arrest Study number 2 (EuReCa TWO) was to investigate the association between OHCA survival and two types of bystander CPR namely: chest compression only CPR (CConly) and CPR with chest compressions and ventilations (FullCPR). METHOD: In this subgroup analysis of EuReCa TWO, all patients who received bystander CPR were included. Outcomes were return of spontaneous circulation and survival to 30-days or hospital discharge. A multilevel binary logistic regression analysis with survival as the dependent variable was performed. RESULTS: A total of 5884 patients were included in the analysis, varying between countries from 21 to 1444. Survival was 320 (8%) in the CConly group and 174 (13%) in the FullCPR group. After adjustment for age, sex, location, rhythm, cause, time to scene, witnessed collapse and country, patients who received FullCPR had a significantly higher survival rate when compared to those who received CConly (adjusted odds ration 1.46, 95% confidence interval 1.17-1.83). CONCLUSION: In this analysis, FullCPR was associated with higher survival compared to CConly. Guidelines should continue to emphasise the importance of compressions and ventilations during resuscitation for patients who suffer OHCA and CPR courses should continue to teach both.

Long-term safety and effectiveness of berotralstat for hereditary angioedema: The open-label APeX-S study.

BACKGROUND: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein recently approved for prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE). The objective of this report is to summarize results from an interim analysis of an ongoing long-term safety study of berotralstat in patients with HAE. METHODS: APeX-S is an ongoing, phase 2, open-label study conducted in 22 countries (ClinicalTrials.gov, NCT03472040). Eligible patients with a clinical diagnosis of HAE due to C1 inhibitor deficiency (HAE-C1-INH) were centrally allocated to receive berotralstat 150 or 110 mg once daily. The primary objective was to determine long-term safety and the secondary objective was to evaluate effectiveness. RESULTS: Enrolled patients (N = 227) received berotralstat 150 mg (n = 127) or 110 mg (n = 100) once daily. The median (range) duration of exposure was 342 (11-540) and 307 (14-429) days for the 150-mg and 110-mg groups, respectively. Treatment-emergent adverse events (TEAEs) occurred in 91% (n = 206) of patients. The most common TEAEs across treatment groups were upper respiratory tract infection (n = 91, 40%), abdominal pain (n = 57, 25%), headache (n = 40, 18%), and diarrhea (n = 31, 14%) and were mostly mild to moderate. Fifty percent (n = 113) of patients had at least one drug-related adverse event (AE; 150 mg, n = 57 [45%]; 110 mg, n = 56 [56%]), and discontinuations due to AEs occurred in 19 (8%) patients (150 mg, n = 13 [10%]; 110 mg, n = 6 [6%]). Three (1.3%) patients experienced a drug-related serious TEAE. Among patients who received berotralstat through 48 weeks (150 mg, n = 73; 110 mg, n = 30), median HAE attack rates were low in month 1 (150 mg, 1.0 attacks/month; 110 mg, 0.5 attacks/month) and remained low through 12 months (0 attacks/month in both dose groups). Mean HAE attack rates followed a similar trend, and no evidence for patient tolerance to berotralstat emerged. In both dose groups, angioedema quality of life scores showed clinically meaningful changes from baseline. CONCLUSIONS: In this analysis, both berotralstat doses, 150  and 110 mg once daily, were generally well tolerated. Effectiveness results support the durability and robustness of berotralstat as prophylactic therapy in patients with HAE. TRIAL REGISTRATION: The study is registered with ClinicalTrials.gov (NCT03472040).

Oxidative stress and peripartum outcomes (Review).

Pregnancy, labor and childbirth are accompanied by excessive oxidative aggression. The excessive formation of free radicals [reactive oxygen species (ROS), reactive nitrogen species (RNS), chlorine reactive species (CRS)] causes cellular oxidative damage, which can be scavenged by enzymatic or non-enzymatic antioxidants in normal healthy pregnancy, physiological labor and delivery without any complications. An imbalance between the pro-oxidant and antioxidant factors may lead to oxidative stress, which contributes to the development of many diseases. This oxidative aggression can be a precursor for pathologies in the pregnant woman including eclampsia, miscarriage, preterm labor, and intrauterine growth retardation; in the offspring it may lead to bronchopulmonary dysplasia/chronic lung disease, necrotizing enterocolitis, retinopathy of prematurity, and periventricular leukomalacia. This review summarizes the studies conducted to identify the mechanisms of oxidative stress and the effect of cell membrane oxidation, the mechanisms that are behind oxidative stress-related diseases, and also those studies which have demonstrated the effect of antioxidants in preventing diseases or diminishing the effects of oxidative stress in the body, in obstetrics and neonatology.

Randomized Trial of the Efficacy and Safety of Berotralstat (BCX7353) as an Oral Prophylactic Therapy for Hereditary Angioedema: Results of APeX-2 Through 48 Weeks (Part 2).

BACKGROUND: Berotralstat (BCX7353) is a recently approved, oral, once-daily kallikrein inhibitor for hereditary angioedema (HAE) prophylaxis. In the APeX-2 trial, berotralstat reduced HAE attack rates over 24 weeks, with a favorable safety and tolerability profile. OBJECTIVE: Evaluate berotralstat safety, tolerability, and effectiveness over 48 weeks. METHODS: APeX-2 is a phase 3, parallel-group, multicenter trial (NCT03485911) in patients with HAE due to C1 esterase inhibitor deficiency. Part 1 was double-blind and placebo-controlled, with patients randomized to 24 weeks of berotralstat 150 mg, 110 mg, or placebo. In part 2, patients continued berotralstat the same dose or, if initially randomized to placebo, were rerandomized to berotralstat 150 mg or 110 mg through weeks 24 to 48. The primary end point was safety and tolerability. RESULTS: One hundred eight patients received 1 or more doses of berotralstat in part 2. Treatment-emergent adverse events (TEAEs) occurred in 30 of 39 patients (77%) in the placebo group during part 1, and 25 of 34 patients (74%) re-randomized from placebo to berotralstat 110 mg or 150 mg in part 2, with drug-related TEAEs in 13 of 39 (33%), and 11 of 34 (32%) in the same groups. Most TEAEs were mild or moderate, with no serious drug-related TEAEs. The most common TEAEs were upper respiratory tract infections, abdominal pain, diarrhea, and vomiting. Mean (±standard error of the mean) monthly attack rates at baseline and week 48 were 3.06 (±0.25) and 1.06 (±0.25) in the berotralstat 150mg 48-week group and 2.97 (±0.21) and 1.35 (±0.33) in the berotralstat 110mg 48-week group. CONCLUSIONS: The safety, tolerability, and effectiveness of berotralstat were maintained over 48 weeks of treatment.

Oral berotralstat for the prophylaxis of hereditary angioedema attacks in patients in Japan: A phase 3 randomized trial.

BACKGROUND: With no approved treatments in Japan for the prevention of hereditary angioedema (HAE) attacks, there is a significant unmet need for long-term prophylactic therapies for Japanese patients with HAE. Berotralstat (BCX7353) is an oral, once-daily, highly selective inhibitor of plasma kallikrein in development for prophylaxis of angioedema attacks in HAE patients. METHODS: APeX-J is a phase 3, randomized, double-blind, placebo-controlled, parallel-group, 3-part trial conducted in Japan (University Hospital Medical Information Network identifier, UMIN000034869; ClinicalTrials.gov identifier, NCT03873116). Patients with a clinical diagnosis of type 1 or 2 HAE underwent a prospective run-in period of 56 days to determine eligibility, allowing enrollment of those with ≥2 expert-confirmed angioedema attacks. Patients were randomly assigned (1:1:1) and stratified by baseline attack rate (≥2 vs. <2 expert-confirmed attacks/month between screening and randomization) to receive once-daily berotralstat 110 mg, berotralstat 150 mg, or placebo. The primary endpoint was the rate of expert-confirmed angioedema attacks during dosing in the 24-week treatment period. RESULTS: Nineteen patients were randomized to receive once-daily berotralstat 110 mg (n = 6), berotralstat 150 mg (n = 7), or placebo (n = 6). Treatment with berotralstat 150 mg significantly reduced HAE attacks relative to placebo (1.11 vs. 2.18 attacks/month, p = .003). The most frequently reported treatment-emergent adverse events (TEAEs) in berotralstat-treated patients (n = 13) were nasopharyngitis (n = 4, 31%), abdominal pain, cough, diarrhea, and pyrexia (n = 2 each, 15%). CONCLUSIONS: Orally administered, once-daily berotralstat 150 mg significantly reduced the frequency of HAE attacks and was safe and well tolerated, supporting its use as a prophylactic therapy in patients with type 1 or 2 HAE in Japan.

Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks. OBJECTIVE: Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial). METHODS: APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period. RESULTS: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n = 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred. CONCLUSION: Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day.