Oral Treatment Research Articles

Preclinical evaluation of combined therapy with amiodarone and low-dose benznidazole in a mouse model of chronic Trypanosoma cruzi infection

Chagasic chronic cardiomyopathy (CCC) is the primary clinical manifestation of Chagas disease (CD), caused by Trypanosoma cruzi. Current therapeutic options for CD are limited to benznidazole (Bz) and nifurtimox. Amiodarone (AMD) has emerged as most effective drug for treating the arrhythmic form of CCC. To address the effects of Bz and AMD we used a preclinical model of CCC. Female C57BL/6 mice were infected with T. cruzi and subjected to oral treatment for 30 consecutive days, either as monotherapy or in combination. AMD in monotherapy decreased the prolonged QTc interval, the incidence of atrioventricular conduction disorders and cardiac hypertrophy. However, AMD monotherapy did not impact parasitemia, parasite load, TNF concentration and production of reactive oxygen species (ROS) in cardiac tissue. Alike Bz therapy, the combination of Bz and AMD (Bz/AMD), improved cardiac electric abnormalities detected T. cruzi-infected mice such as decrease in heart rates, enlargement of PR and QTc intervals and increased incidence of atrioventricular block and sinus arrhythmia. Further, Bz/AMD therapy ameliorated the ventricular function and reduced parasite burden in the cardiac tissue and parasitemia to a degree comparable to Bz monotherapy. Importantly, Bz/AMD treatment efficiently reduced TNF concentration in the cardiac tissue and plasma and had beneficial effects on immunological abnormalities. Moreover, in the cardiac tissue Bz/AMD therapy reduced fibronectin and collagen deposition, mitochondrial damage and production of ROS, and improved sarcomeric and gap junction integrity. Our study underlines the potential of the Bz/AMD therapy, as we have shown that combination increased efficacy in the treatment of CCC.

Estrogens prevent the hypothalamus-periphery crosstalk induced by olanzapine intraperitoneal treatment in female mice: Effects on brown/beige adipose tissues and liver

Olanzapine (OLA) is a highly obesogenic second-generation antipsychotic (SGA). Recently we demonstrated that, contrarily to OLA oral treatment, intraperitoneal (i.p.) administration resulted in weight loss and absence of hepatic steatosis in wild-type (WT) and protein tyrosine phosphatase 1B (PTP1B)-deficient (KO) male mice. This protection relied on two central-peripheral axes connecting hypothalamic AMPK with brown/inguinal white adipose tissue (BAT/iWAT) uncoupling protein-1 (UCP-1) and hypothalamic JNK with hepatic fatty acid synthase (FAS). Herein, we addressed OLA i.p. treatment effects in WT and PTP1B-KO female mice. Contrarily to our previous results in WT females receiving OLA orally, the i.p. treatment did not induce weight gain or hyperphagia. Molecularly, in females OLA failed to diminish hypothalamic phospho-AMPK or elevate BAT UCP-1 and energy expenditure (EE) despite the preservation of iWAT browning. Conversely, OLA i.p. treatment in ovariectomized mice reduced hypothalamic phospho-AMPK, increased BAT/iWAT UCP-1 and EE, and induced weight loss as occurred in males. Pretreatment of hypothalamic neurons with 17β-estradiol (E2) abolished OLA effects on AMPK. Moreover, neither hypothalamic JNK activation nor hepatic FAS upregulation were found in WT and PTP1B-KO females receiving OLA via i.p. Importantly, this axis was reestablished upon ovariectomy. In this line, E2 prevented OLA-induced phospho-JNK in hypothalamic neurons. These results support the role of estrogens in sex-related dimorphism in OLA treatment. This study evidenced the benefit of OLA i.p. administration in preventing its obesogenic effects in female mice that could offer clinical value.

A phase 1, randomized, double-blind, placebo-controlled trial investigating the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide in healthy Chinese subjects.

The trial (NCT04016974) investigated the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide, the first orally administered glucagon-like peptide-1 analogue for type 2 diabetes, in healthy Chinese subjects. This single-centre, multiple-dose, placebo-controlled trial randomized 32 healthy Chinese adults to once-daily oral semaglutide (3 mg escalating to 14 mg) or placebo for 12 weeks. Blood samples were collected regularly during treatment and follow-up. The primary endpoint was the area under the semaglutide concentration-time curve over a dosing interval (0-24 h) at steady state (AUC0-24h,sema,SS). Secondary pharmacokinetic endpoints included the maximum observed semaglutide plasma concentration at steady state (Cmax,sema,SS). Supportive secondary pharmacodynamics endpoints included changes in body weight and fasting plasma glucose. Treatment with all oral semaglutide doses showed dose-dependent increases in semaglutide exposure in healthy Chinese subjects at steady state, determined by AUC0-24h,sema,SS (233, 552 and 1288 h·nmol/L for 3, 7 and 14 mg of oral semaglutide, respectively) and Cmax,sema,SS. Oral semaglutide treatment was associated with significant reductions in body weight (p = .0001) and fasting plasma glucose (p = .0011) versus placebo at the end of treatment. The safety and tolerability of oral semaglutide were consistent with the known profile of glucagon-like peptide-1 receptor agonists, with no severe or blood-glucose-confirmed symptomatic hypoglycaemic events, serious adverse events or deaths. The most frequent adverse events were gastrointestinal disorders. At steady state, oral semaglutide exposure was dose dependent and close to dose proportionality in healthy Chinese subjects. This is consistent with previous clinical pharmacology results for oral semaglutide.

Chronic Pruritus: A Review.

Chronic pruritus, defined as itch experienced for 6 weeks or longer, affects approximately 22% of people in their lifetime. Approximately 1% of physician visits are for the chief concern of chronic pruritus. Chronic pruritus is associated with adverse outcomes, including impaired sleep and reduced quality of life. Chronic pruritus can be categorized by etiology into inflammatory, neuropathic, or a combination of inflammatory and neuropathic pruritus. Chronic pruritus is due to inflammation in approximately 60% of patients and may be caused by eczema, psoriasis, or seborrheic dermatitis. Chronic pruritus is due to a neuropathic or mixed etiology in approximately 25% of patients. Neuropathic causes of chronic pruritus include postherpetic neuralgia and notalgia paresthetica and are typically due to localized or generalized nerve dysregulation. Approximately 15% of people with chronic pruritus have other causes including systemic diseases with secondary itch, such as uremic pruritus and cholestatic pruritus, medication-induced pruritus such as pruritus due to immunotherapy, and infectious etiologies such as tinea corporis and scabies. When few primary changes are present, a thorough history, review of symptoms, and laboratory evaluation should be performed, particularly for people with chronic pruritus lasting less than 1 year. Clinicians should consider the following tests: complete blood cell count, complete metabolic panel, and thyroid function testing to evaluate for hematologic malignancy, liver disease, kidney disease, or thyroid disease. First-line treatment for inflammatory chronic pruritus includes topical anti-inflammatory therapies such as hydrocortisone (2.5%), triamcinolone (0.1%), or tacrolimus ointment. Approximately 10% of patients do not respond to topical therapies. In these patients, referral to dermatology and systemic oral or injectable treatments such as dupilumab or methotrexate may be considered. When no underlying systemic disease associated with pruritus is identified, patients are likely to have neuropathic chronic pruritus or mixed etiology such as chronic pruritus of unknown origin. In these patients, neuropathic topical treatments such as menthol, pramoxine, or lidocaine can be used either alone or in combination with immunomodulatory agents such as topical steroids. Other effective therapies for neuropathic pruritus include gabapentin, antidepressants such as sertraline or doxepin, or opioid receptor agonist/antagonists such as naltrexone or butorphanol. Chronic pruritus can adversely affect quality of life and can be categorized into inflammatory, neuropathic, or a combined etiology. First-line therapies are topical steroids for inflammatory causes, such as hydrocortisone (2.5%) or triamcinolone (0.1%); topical neuropathic agents for neuropathic causes, such as menthol or pramoxine; and combinations of these therapies for mixed etiologies of chronic pruritus.

Metformin treatment prevents experimental metabolic syndrome-induced femoral bone marrow adiposity in rats.

Motivation for the study. Most research supports a negative association between metabolic syndrome and bone health, although there is an overall lack of consensus. Therefore, there is a need for research in this area to develop a better understanding. Main findings. Metabolic syndrome induced by a fructose-rich diet increases the adipogenic predisposition of bone marrow progenitor cells and femoral medullary adiposity in rats. Furthermore, this can be partially prevented by co-treatment with metformin. Implications. Experimental metabolic syndrome has negative effects on bone tissue and can be prevented by oral treatment with metformin as a normoglycemic drug. To determine the effect of metformin (MET) treatment on adipogenic predisposition of bone marrow progenitor cells (BMPC), bone marrow adiposity and bone biomechanical properties. 20 young adult male Wistar rats were sorted into four groups. Each of the groups received the following in drinking water: 100% water (C); 20% fructose (F); metformin 100 mg/kg wt/day (M); or fructose plus metformin (FM). After five weeks the animals were sacrificed. Both humeri were dissected to obtain BMPC, and both femurs were dissected to evaluate medullary adiposity (histomorphometry) and biomechanical properties (3-point bending). BMPC were cultured in vitro in adipogenic medium to evaluate RUNX2, PPAR-γ and RAGE expression by RT-PCR, lipase activity and triglyceride accumulation. The fructose-rich diet (group F) caused an increase in both triglycerides in vitro, and medullary adiposity in vivo; being partially or totally prevented by co-treatment with metformin (group FM). No differences were found in femoral biomechanical tests in vivo, nor in lipase activity and RUNX2/PPAR-γ ratio in vitro. DRF increased RAGE expression in BMPC, being prevented by co-treatment with MET. Metabolic syndrome induced by a fructose-rich diet increases femoral medullary adiposity and, in part, the adipogenic predisposition of BMPC. In turn, this can be totally or partially prevented by oral co-treatment with MET.

Specification for the clinical application of non fiber-optic transmission technology Er:YAG laser in dentistry

Non fiber-optic transmission technology Er:YAG laser is becoming more widely used in clinical applications, whose therapeutic effects have been recognized by domestic and international researches. However, there is no standardized application for non fiber-optic transmission technology Er:YAG laser in oral medicine. Domestic multidisciplinary dental experts have been organized by The Oral Health Branch Association of China Association of Gerontology and Geriatrics to discuss and formulate this standard comprising its application requirements in specialties of dentistry, aiming to promote the standardization of non fiber-optic transmission technology Er:YAG laser clinical use, which could help to better utilize the advantages of laser in oral treatment and to improve the effectiveness of disease treatment.

Shaping and shifting schemas on supervised injectable opioid treatment: findings from a cross-sectional qualitative study in two German treatment facilities.

Supervised injectable opioid treatment (SIOT) is a promising alternative for people living with opioid use disorder (OUD) who have not sufficiently benefitted from oral opioid substitution treatment. Yet, SIOT utilization remains limited in Germany. We propose that this is due to beliefs, or schemas, on SIOT among people living with OUD. Drawing from medical sociology and social psychology, this study explores the emergence and evolution of such schemas on SIOT. We conducted semi-structured interviews with 34 individuals currently in or eligible for SIOT in two German outpatient treatment facilities and paralleled an inductive qualitative content analysis with the exploration of individual cases. The analysis revealed that peer-to-peer interaction and individuals' practical experiences in therapy are crucial in constructing and changing idiosyncratic and shared schemas of SIOT. When facing ambiguous information, cognitive strategies like subtyping served to mitigate uncertainty. This research has important practical implications for integrating experiential knowledge into clinical care and improve information sharing among people living with OUD. A nuanced understanding of the complex network of informal advice-seeking and -giving among people living with OUD is indispensable to adequately expand treatment modalities of proven effectiveness.

Impact of SMAASH-C, a novel nutritional supplement, on drug-seeking and toxicity in female and male rats.

Relapse to drug use after abstinence is a major challenge in treating substance use disorder. Exposure to drug-associated cues during abstinence can trigger intense craving and precipitate relapse. New and more effective anti-relapse interventions are critically needed, particularly for cocaine use disorder since no effective pharmacological intervention is available. We discovered that a nutritional supplement we developed as part of a nutritional approach for managing patients with substance use disorder reduced patient reports of drug craving and relapse. The goal of this study was to determine the efficacy of this supplement, SMAASH-C, at reducing drug-craving/relapse vulnerability in males and females in rat models with cocaine. Effects were determined following extended-access cocaine self-administration (24-hr/day for 10 days) and a two-week treatment regimen at a moderate and moderate-to-high dose (0.4 and 0.8 g/kg/day) as well as a 6-week regimen at a moderate dose (0.4 g/kg/day; Experiment 2). We also determined its efficacy to offset serum markers of organ toxicity in response to chronic cocaine self-administration and abstinence (aspartate transaminase, alanine transaminase, amylase; urea nitrogen). In females, both the 2- and 6-week SMAASH-C treatment regimens reduced cocaine-seeking (extinction or cue-induced reinstatement), particularly when drug-seeking was heightened (e.g., during estrus). Despite a lack of efficacy to reduce drug-seeking in males, SMAASH-C treatment normalized cocaine/abstinence-induced increases in serum levels of aspartate transaminase and amylase, which are markers of liver and pancreatic toxicity respectively. Thus, the beneficial effects of oral SMAASH-C treatment over abstinence following chronic cocaine self-administration appears to be sex-specific.

Screening for atrial fibrillation in patients with symptoms of cognitive impairment

Abstract Introduction A diagnosis of atrial fibrillation increases the risk for dementia (1). Large register studies including approximately 400,000 patients with atrial fibrillation, have suggested that oral anti-coagulation treatment is associated with a 30-50% reduction of dementia development (2). Still, there are no studies investigating the true prevalence of atrial fibrillation in patients with cognitive problems. Purpose We studied the incidence of silent atrial fibrillation in patients with symptoms of cognitive impairment, participation rate in atrial fibrillation screening and the tolerance of the screening method in this specific population. Method Patients ≥70 years of age, referred from primary care for cognitive investigation at a specialised memory clinic, were invited to undergo a long-term ECG recording using an ECG-patch for two weeks. Patients with a known diagnosis of atrial fibrillation or who already were prescribed oral anti-coagulation treatment were excluded. Participants with detected atrial fibrillation (>30 seconds) were referred to a cardiologist for follow-up and oral anti-coagulation treatment was initiated according to clinical guidelines. Results During the inclusion period n=734 patients were examined for symptoms of cognitive impairment at a memory clinic. Of those, n=191 (26%) had already known atrial fibrillation and n=2 (0.3%) had oral anti-coagulation treatment for other reasons. Of the patients eligible for inclusion n=255/541 (47%) agreed to participate in screening for atrial fibrillation. Participants had a median age of 77 (IQR 74-82) years and median CHA2DS2-VASc score 3 (IQR 3-5). Long-term ECG was recorded for a median of 13.7 (IQR 12.6-14.0) days. Among the 255 participants n=14 (6%) had new atrial fibrillation detected. Total prevalence of atrial fibrillation in the population undergoing cognitive investigation increased with two percent units after screening to 28%. Conclusion The incidence of atrial fibrillation is remarkably high in patients with symptoms of cognitive impairment. Participation rate in screening is high in the selected population and the screening method is well-tolerated.

Time-trends of sex differences in stroke risk in atrial fibrillation: Are female patients still at higher risk today? A nationwide cohort study

Abstract Background Female sex is associated with higher risk of stroke in patients with atrial fibrillation (AF), particularly in the presence of other stroke risk factors. This has implications for oral anticoagulant treatment (OAC) decision-making, based on points of the CHA2DS2-VASc score. However, stroke rates have declined over recent years, and management has evolved over time towards a holistic approach that may have diminished the sex differences in AF-related stroke. Purpose To examine the changes in stroke risk over time in relation to risk differences between males and females not treated with oral anticoagulants in a nationwide cohort study. Methods This was an observational cohort study including patients with a hospital diagnosis of AF between 2007 and 2021. Data were obtained from the Danish nationwide registries. We identified a cohort of adult patients who were not receiving OAC treatment for up to 30 days after their AF diagnosis. Patients were followed up for thromboembolic events within one year after the AF diagnosis. Survival analysis was applied to describe the yearly rate of events and to estimate the risk ratio for females vs males of thromboembolism according to baseline risk levels, i.e., the CHA2DS2-VA score level (leaving out the ‘Sc’ sex criterion). Results A total of 188,704 AF patients (median age 75 years (IQR: 64 to 84); 49.7% female) who did not receive OAC treatment were included. The risk of thromboembolism during the entire study period was overall higher in females (3.5% in males vs. 4.7% among females). The overall one-year thromboembolic risk declined over time from 4.9% between 1997-2000 to 3.3% between 2017-2020, with male-female risk differences less evident in recent years (Figure 1a). The relative risk of stroke diminished from 1.22 (95%CI 1.10-1.34) in years 1997-2000 to 1.02 (95%CI 0.85-1.19) in years 2017-2020 for patients with a CHA2DS2-VA score of ≥2 (Figure 1b). For patients with a score of <2, the relative risk was lowest between 2005-2008 (1.02 (95%CI 0.63-1.42)) and was 1.18 (95%CI 0.54-1.83) in the latest time period. Formal statistical test for time trends according to score level revealed non-significant results (p-value=0.10 for score 0-1; p-value=0.17 for score levels of ≥2). Conclusion The risk of stroke among patients with AF has been declining over the last two decades. The excess stroke risk observed among females relative to males has also diminished, most evident among AF patients with ≥2 prevalent stroke risk factors.

Aronia melanocarpa fruit juice prevents hepatic impairment in rats subjected to metabolic syndrome

AbstractThis study evaluated the effects of Aronia melanocarpa fruit juice (AMFJ) on the liver in a model of high-fat, high-fructose (HFHF) diet-induced metabolic syndrome (MS). Fifty rats were allocated to five groups – Control, MS, MS+AMFJ2.5, MS+AMFJ5, and MS+AMFJ10. The control group was fed a standard diet, while the other groups were provided a HFHF diet. During MS induction, daily oral treatment was performed. Control and MS groups received 10.0 mL kg−1 distilled water, while the other three groups received AMFJ at doses of 2.5, 5.0, and 10.0 mL kg−1, respectively. After 10 weeks, liver samples were collected and inspected histologically as well as immunohistochemically to determine the expression of Bax, Bcl-2, and MAC387. Bax/Bcl-2 ratio was calculated. In MS rats, steatotic, inflammatory and degenerative alterations of the liver were detected, Bax and MAC387 were markedly elevated, while Bcl-2 was non-significantly reduced. The Bax/Bcl-2 ratio significantly increased. The histopathological alterations were prevented by the AMFJ treatment. Compared to MS group, Bax and MAC387 values were significantly lower and Bcl-2 value was higher resulting in significantly lower (P < 0.001) Bax/Bcl-2 ratio in all AMFJ-treated groups. AMFJ, administered during MS induction in rats, prevented the occurrence of inflammatory, steatotic, degenerative, and pro-apoptotic changes in the liver.

#2061 Perirenal fat thickness as a potential marker for cardiovascular risk in chronic kidney disease: the influence of vitamin D analogs

Abstract Background and Aims Patients with CKD show high cardiovascular complication rates. There are classical cardiovascular risk factors, such as obesity, dyslipidemia, and diabetes; however, other cardiovascular disease risk factors are associated with mineral metabolism disorders (phosphorus, hyperparathyroidism, etc.) typically appear in CKD. Due to their pleiotropic effects, vitamin D analogs, such as cholecalciferol, calcitriol, or paricalcitol, have proven effective in controlling bone mineral disease secondary to CKD and cardiovascular pathologies. On the other hand, visceral adiposity has been shown as a risk factor in the general population and in patients with CKD. Specifically, the fat deposited in regions such as the epicardium generates a complex autocrine and paracrine hormonal mechanism that has been associated with cardiovascular complications. Although it has not been widely evaluated, the adipose tissue surrounding the kidneys (perirenal fat [PRF]) could provide additional information of interest in the CKD population. The aim of the study is to assess the relationship between cardiovascular disease, PRF, and the effect of therapeutic interventions for bone and mineral metabolism in patients with CKD. Method This prospective observational and cross-sectional study was designed to evaluate the usage of vitamin D analogs in patients with CKD, focusing on cardiovascular history and PRF accumulation. All the patients were evaluated at the outpatient clinic in Consuelo Hospital in Valencia Spain (January-November 2022). Eighty-three patients with different grades of CKD (G1A1 to G5A3 not on dialysis) were included and follow-up for 24 months. All the patient's data from electronic medical and analytical records were entered into a protocol sheet. The patients that meet the inclusion criteria (eGFR ≤90 or>15 ml/min/1.73 m2; age ≥18 years at the time of signing informed consent, and a life expectancy higher than 1 year) were eligible to participate in the study. As exclusion criteria, patients with an active inflammatory process such as infection, active cancer, or other inflammatory states were excluded beyond those mentioned in inclusion. Patients with an AKI, ADPKD, or CKD requiring RRT were also excluded. Patients were discriminated according to their history of cardiovascular disease (coronary artery disease, stroke, and peripheral vascular disease) and the use of Vitamin D analogs (Cholecalciferol, Calcitriol, and Paricalcitol). The thickness of the PRF was measured in centimeters (cm) through a B-mode ultrasound with a 3.5-MHz convex transductor (Alpinion®; Alpinion Medical Systems, Korea). Patients underwent a bilateral renal ultrasound, and the kidneys were measured anteroposteriorly, transversally, and longitudinally. PRF was measured in the distal third between the cortex and the hepatic border and/or spleen. Results The mean age of the patients was 58.3 ± 16 years. Patients with a cardiovascular disease history showed significantly higher levels of urea (62.0 vs 45.2 mg/dl, p < 0.05), uric acid (5.5 vs 4.3 mg/dl; p < 0.03), intact parathyroid hormone (iPTH) (186.2 vs 65.2 pcg/dl; p0.05) and decreased eGFR (53.55 vs 89.00 ml/min/1.73 mts2). The mean PRF thickness (0.99 vs 0.80 cm; SD ± 0.30; p0.05) was also observed to be elevated with respect to the group who had no previous cardiovascular events (Fig. 1). Moreover, this group showers higher levels (1.2 vs 7.1; p < 0.005) of CRP. Those patients on oral treatment with Paricalcitol (1 mcg/day) had lesser PRF accumulation than those treated with Cholecalciferol (1000 IU/day) or Calcitriol (0.5 mcg/day) (p < 0.05) (Fig. 2). It was not adjusted for confounding factors such as weight, height, or BMI. Conclusion These results show a close relationship between the presence of cardiovascular disease history and a higher accumulation of PRF. The mechanisms by which paricalcitol could influence the decrease in PRF are so far unknown, however, some studies have shown an association between PTH elevation and obesity. Finally, achieving a decrease in the latter could reduce visceral adipose tissue, thus reducing the cardiovascular risk in CKD-affected patients.

Enhancing oral squamous cell carcinoma detection: a novel approach using improved EfficientNet architecture

ProblemOral squamous cell carcinoma (OSCC) is the eighth most prevalent cancer globally, leading to the loss of structural integrity within the oral cavity layers and membranes. Despite its high prevalence, early diagnosis is crucial for effective treatment.AimThis study aimed to utilize recent advancements in deep learning for medical image classification to automate the early diagnosis of oral histopathology images, thereby facilitating prompt and accurate detection of oral cancer.MethodsA deep learning convolutional neural network (CNN) model categorizes benign and malignant oral biopsy histopathological images. By leveraging 17 pretrained DL-CNN models, a two-step statistical analysis identified the pretrained EfficientNetB0 model as the most superior. Further enhancement of EfficientNetB0 was achieved by incorporating a dual attention network (DAN) into the model architecture.ResultsThe improved EfficientNetB0 model demonstrated impressive performance metrics, including an accuracy of 91.1%, sensitivity of 92.2%, specificity of 91.0%, precision of 91.3%, false-positive rate (FPR) of 1.12%, F1 score of 92.3%, Matthews correlation coefficient (MCC) of 90.1%, kappa of 88.8%, and computational time of 66.41%. Notably, this model surpasses the performance of state-of-the-art approaches in the field.ConclusionIntegrating deep learning techniques, specifically the enhanced EfficientNetB0 model with DAN, shows promising results for the automated early diagnosis of oral cancer through oral histopathology image analysis. This advancement has significant potential for improving the efficacy of oral cancer treatment strategies.

#437 A multicenter, single-arm study of roxadustat in Chinese patients with chronic kidney disease-associated anemia receiving peritoneal dialysis

Abstract Background and Aims Anemia increases morbidity and mortality in patients with chronic kidney disease (CKD). Phase 3 studies have demonstrated the efficacy of roxadustat for anemia treatment in patients with CKD undergoing dialysis; however, data from Chinese patients undergoing peritoneal dialysis (PD) are limited. We evaluated the efficacy and safety of roxadustat in Chinese patients with CKD-anemia undergoing PD. Method In this phase 4, single-arm, multicenter study, we planned to enroll at least 150 Chinese patients with CKD-anemia undergoing PD (either erythropoiesis-stimulating agent [ESA]-treated or ESA-naïve at enrollment), including at least 50 patients with type 2 diabetes mellitus (T2DM) and 50 patients without diabetes mellitus (DM). Study visits occurred every 2 weeks until Week 8 and then every 4 weeks. All patients received oral roxadustat treatment three times per week for 24 weeks according to the approved product package insert. The primary efficacy endpoint was the proportion of patients with a mean hemoglobin (Hb) ≥100 g/L at Weeks 20–24. The secondary efficacy endpoints were subgroup analyses (T2DM vs. non-DM). The exploratory endpoints were the dose required to maintain Hb at ≥100 g/L over Weeks 20–24, the proportion of time when Hb was 100–130 g/L, changes in residual renal function (RRF), urea clearance index (Kt/V), and creatinine clearance (Ccr), amongst others. For the safety analyses, adverse events (AEs) were assessed during treatment and at 4 weeks after completion. Results Overall, 195 patients (116 male [59.5%]) with a mean (standard deviation [SD]) age of 46.3 (12.3) years were enrolled from 22 centers, and 172 (88.2%) completed the study (main reasons for discontinuation: withdrawal, 7 [3.6%]; AE, 5 [2.6%]; switched from PD to hemodialysis, 5 [2.6%]). Overall, 189 patients (96.9%) were ESA-treated and 43 (22.1%) had T2DM. The median (interquartile range) dialysis duration was 16.1 (5.2–43.2) months. The mean (SD) baseline Hb was 98.1 (10.7) g/L, and the ferritin level and transferrin saturation were 320.9 (287.5) μg/L and 35.5% (17.0%), respectively. The mean (SD) treatment duration was 154.3 (35.6) days, and the mean (SD) weekly dose was 244.9 (88.7) mg. The intention-to-treat (ITT) set and safety analysis set (SAF) included all 195 patients. In the ITT set, 85.1% (95% confidence interval [CI] 79.8%–90.5%) of patients had Hb ≥100 g/L over Weeks 20–24. According to the subgroup analysis, 89.2% (95% CI 78.5%–99.9%) of T2DM patients and 84.0% (95% CI 77.8%–90.1%) of non-DM patients had Hb ≥100 g/L over Weeks 20–24 (Fig. 1). The mean (SD) weekly dose required to maintain Hb at ≥100 g/L at Weeks 20–24 was 215.9 (100.0) mg, and the proportion of time that Hb was 100–130 g/L was 76.4% (23.2%). There was a slight decrease in RRF and Ccr. Table 1 shows the RRF, Kt/V, and Ccr results. Of the 195 SAF patients, 158 (81.0%) had ≥1 treatment-emergent AE (TEAE), 20 (10.3%) had drug-related TEAEs, 40 (20.5%) had treatment-emergent serious AEs, and 1 (0.5%) had a TEAE that led to death. The top three TEAEs were upper respiratory tract infection (25 [12.8%]), hypokalemia (17 [8.7%]), and hypoalbuminemia (15 [7.7%]). Conclusion Treatment with roxadustat for 24 weeks effectively corrected anemia in Chinese CKD patients undergoing PD and maintained Hb at ≥100 g/L in the majority of patients, irrespective of baseline T2DM. The AEs were consistent with the characteristics of patients with CKD undergoing PD and with the known safety profile of roxadustat.

Combination therapy of beta-blockers and digoxin is associated with increased risk of major adverse cardiovascular events and all-cause mortality in patients with atrial fibrillation: a report from the GLORIA-AF registry.

The effect of digoxin and beta-blockers on cardiovascular outcomes and mortality remains unclear. The study aimed to determine differences in cardiovascular (CV) outcomes and death rates among patients with atrial fibrillation (AF) who were prescribed with beta-blockers, digoxin or combination therapy. Data from phase II/III of the prospective Global Registry on Long-Term Oral Anti-thrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) were analysed. The risk of major cardiovascular events (MACE) and death among patients with different prescriptions using COX proportional hazard regression was considered. Propensity score (PS) matching and weighting were further used to adjust for potential confounders of prescription use. A total of 14,201 patients [median age: 71.0 (IQR 64.0-77.0) years; 46.2% female] were recruited. After a median follow-up of 3.0 (IQR 2.4-3.1) years, 864 MACE, and 988 all-cause deaths were recorded. The incidence rate (IR) of MACE was 22.4 (95%CI 21.0-24.0) per 1000 person-years, while the IR of all-cause death was 25.4 (95%CI 23.8-27.0) per 1000 person-years. After multivariate adjustment with Cox regression, the risk of MACE (HR 1.35, 95% CI 1.09-1.68) and the risk of all-cause death (HR 1.28, 95%CI 1.04-1.57) were significantly higher in the combination therapy group, compared to the beta-blockers alone group. The risks of MACE and all-cause death remained significant in both PS matched and PS weighted cohort Among AF patients, combination therapy of beta-blockers and digoxin was associated with higher risks of MACE and all-cause death compared to beta-blockers alone.

#2387 Case study of a patient with gouty nephropathy treated with immunosorbent therapy

Abstract Background and Aims Gouty nephropathy is a kidney disease caused by chronic hyperuricemia, in which uric acid crystals are deposited in the kidneys leading to tubular and glomerular damage, which in turn affects kidney function. Patient female, 68 years old, 7 years ago, no obvious cause of the first toe joint of the right foot, the right ankle joint redness, swelling and pain, the local skin temperature increases, serious limitation of activities, had checked the high uric acid (specific unknown), diagnosed as “gout”, simple treatment after the symptoms are relieved, but did not have systematic treatment, and gradually appeared in the left foot, the first toe joint, the left ankle joint, double knee joint redness, swelling and pain, oral pain medication treatment, pain disappears after still no systematic treatment. After that, redness, swelling and pain appeared gradually in the first toe joint of the left foot, left ankle joint and both knee joints, and the pain disappeared without systematic treatment after taking pain-relieving medicines. He was admitted to our hospital as an outpatient with the diagnosis of “gout”. Method Immunosorbent therapy was given once/day on days 1-3, along with Jinshuibao and urotoxin clearing granules. Immunosorbent therapy was given again three times on the 8th-10th day of admission. Results Before admission, uric acid: 899.3 µmol/L; creatinine: 586.1 µmol/L, both seriously out of the normal range. 3 days later, uric acid: 770.4 µmol/L, creatinine: 468.7 µmol/L. At the time of discharge, serum uric acid: 298.5 µmol/L and creatinine: 182.6 µmol/L were detected and restored to the normal range. Conclusion The case demonstrated the presence of gout with arthritic symptoms, vascular damage, anemia, and hepatic and renal impairment. The patient's gout progressively worsened due to prolonged absence of systemic treatment. After admission, the levels of uric acid and creatinine were effectively controlled and restored by immunosorbent therapy. This indicates that immunosorbent therapy plays a positive role in removing uric acid from the body and improving renal function. Meanwhile, the management and control of gout was further strengthened by combining the comprehensive treatment with Jinshuibao and uremic acid granules.

Nocturia and obstructive sleep apnoea.

Nocturia, the need to urinate at night, is a common symptom in patients with obstructive sleep apnoea (OSA). Continuous positive airway pressure treatment can reduce nocturia in some patients, but the underlying mechanisms are complex and not fully understood. OSA affects the autonomic nervous system, oxidative stress and endothelial damage. Furthermore, the commonly held theory attributing polyuria to a false signal of cardiac overload and response natriuresis has limitations. A comprehensive approach to the management of nocturia in OSA, considering factors such as comorbidities, medication use, alcohol consumption and lifestyle, is needed. Effective management of nocturia in OSA requires a multidisciplinary approach, and urologists should be aware of the potential effect of OSA on physiology and refer patients for further testing at a sleep centre. In addition to continuous positive airway pressure, other interventions such as oral appliances and surgical obstruction treatment could be beneficial for some patients. Overall, understanding the complex interplay between OSA and nocturia is crucial for optimizing patient outcomes.

#1622 Minimal changes disease and myasthenia gravis: a logical association

Abstract Background and Aims Minimal changes disease (MCD) is responsible for 10-25% of nephrotic syndrome cases in adults. It can have a primary or secondary aetiology, being associated with diseases like infections, atopy or even haematological malignancies. There is a described association between MCD and myasthenia gravis (MG) in the literature, which we will explore in this case report. Clinical Case An autonomous 67 years old female, healthy except for overweight develops diplopia and dysphagia, being diagnosed with anti-musk MG (antibodies titters 2,2002 nmol/L). Thymoma presence was excluded by CT scan. She starts oral treatment with pyridostigmine without response. Two months later she develops generalized oedema. Analytically she had normal kidney function (Cr 0.7 mg/dL; BUN 28.5 mg/dL), hypoalbuminemia (2.09 g/dL), dyslipidaemia and nephrotic proteinuria of PCR 8g/g creat, without leucoeritrocyturia. Reno-vesical echography was normal. No alterations in immunological study except for a low IgG 396 mg/dL. Anti-PLA2R was negative. Kidney biopsy was performed, having 4 glomerulus that looked normal in optical microscopy. In our centre we do not have electronic microscopy available, so the biopsy was interpreted as MCD. She started prednisolone (PDN) 1 mg/kg/day with clinical improvement and resolution of the symptoms and proteinuria (0.062 g/g creat). In November 2022, while she was tapering the PDN, she had a myasthenic crisis, with MCD recurrency. She did 5 plasmapheresis sessions, the PDN dose was increased to 1 mg/kg/day and two rituximab administrations (1000 mg each) were done. There was an improvement in MG symptoms during 3 weeks and then she aggravated again. The proteinuria slowly decreased during 6 weeks until RPC 1.3 g/g creat and then started to aggravate when the corticosteroids were tapered. It was decided to initiate mycophenolate mofetil (MMF), there was improvement and both diseases are controlled until today, the patient is asymptomatic under 7.5 mg/day of prednisolone, with a PCR 0.2 g/g creat. Discussion The production of a circulating permeability factor by abnormal T cells, that causes the podocytes damage, is one of the possible explanations for MCD. There are reports of improvements with plasmapheresis (PF) by permeability factor remotion from circulation. MG is also caused by T cells antibodies attack, but the attack occurs against channels essential for the neuromuscular membrane function. The similarities of the mechanisms make the existence of a common branch in the t cells dysregulation seem plausible. Anti musk MG is very responsive to PF but it has a limited effect in time. Rituximab depletes B cells responsible for promoting the impaired T cells responses. It has been associated with longer remissions in cortico-sensitive MCD with relapsing disease. The exact same mechanism occurs when rituximab is used in MG. In this case the patient did not have a satisfactory response to rituximab as the patient kept dependent of high PDN doses, so we decided to initiate MMF with a complete remission of both pathologies and allowing the use of lower PDN doses. Take Home Message The association between MCD and myasthenia gravis is rare, especially in patients without thymoma. When we analyse the diseases physiopathology, we find common mechanisms that can justify the association. The identification of this relation can be advantageous making possible early rituximab use, that has been showing good results in both pathologies. In this particular clinical case, there was a recurrence with rituximab when we tapered the PDN, so the patient started MMF with good response and allowing lower PDN doses.

#1988 VExUS score as a method to guide diuretic treatment in CKD patients with congestive nephropathy by right heart failure

Abstract Background and Aims Congestive nephropathy is a kidney dysfunction caused by the impact of elevated venous pressures on renal hemodynamics and most of all it is due to right heart failure. Venous congestion can lead to a circulation vicious hormonal activation, increased intra-abdominal pressure, excessive renal tubular reabsorption of sodium and volume overload. In CKD with right heart failure, management of the patient is difficult because may be hard to identify a condition of fluid overload and when to stop intravenous diuretic treatment. Inferior caval vein (ICV) diameter and ICV index (reduction of diameter with respiration) have been used to identify fluid overload and guide diuretic treatment. However, in CKD patients with heart failure the ICV may not change rapidly and could overestimate the need of intravenous diuretics. This is why VExUS has been useful in both diagnosis and monitoring therapeutic. The VExUS method is a new approach, documented in the literature for the first time once in 2020. In this study we report the usefulness of the VExUS (Venous Excess Ultrasound Score) method for the diagnosis of overload volume and venous congestion and in setting an adequate therapy. It consists of Doppler evaluation of the abdominal veins: hepatic, portal and intrarenal. In fact, the acute renal failure, in the patients studied, is to be attributed in the first instance to venous congestion rather than underfilling, resulting from decompensation and therefore requiring diuretic therapy. Method This retrospective study was conducted in CKD patients (stages 3-4) with acute kidney injury (creatinine level: 6.3-2.6 mg/dl) due to right heart failure admitted at the U.O.C. Nephrology at the S. Maria della Pietà Hospital in Nola and UOC Nephrology of Univ. of Campania. The VExUS method defines 3 degrees (score 0-3) of congestion based on the severity of the anomalies on hepatic, portal and intrarenal venous Doppler. All patients have been treated with diuretics i.v. based on a VEXUS score>1, and then returned to oral treatment when VEXUS score returned to 0. VExUS assessment was performed at admission, repeated every 48 hours and the last score has been considered here (on average 1 week). The relationship between change in VExUS score and ICV index vs creatinine levels was studied by correlation analysis. Lung POCUS (point of care pulmonary ultrasonography) has also been used for all patients to identify a possible contemporary overload caused by LV failure. Results Thirty patients have been included. The use of diuretics reduced the VExUS score and the ICV diameter. However, diuretic treatment changed the ICV diameter by a smaller extent (−30%) compared to the VExUS score (−80%), and one patient showed clear reduction of VExUS score, without any modification of the ICV diameter, suggesting that the latter is a slower indicator of recovery compared to VExUS. Indeed, the change of VExUS score was highly correlated to the improvement of creatinine levels (Pearson's correlation 0.837, p < 0.001). The change of IVC diameter explained in comparison a smaller amount of variability of the creatinine improvement (Pearson's correlation 0.65, p = 0.008). Conclusion VExUS is a promising and reliable tool in the management of congestive nephropathy in patients with CKD and right heart failure. VExUS is superior to VCI diameter and should be used routinely, along with clinical, laboratory, and other ultrasound parameters, because of its usefulness, repeatability, low cost and ease of execution.

Safety of Antiandrogens for the Treatment of Female Androgenetic Alopecia with Respect to Gynecologic Malignancies

The most common type of alopecia in women is female androgenetic alopecia (FAGA), characterized by progressive hair loss in a patterned distribution. Many oral therapies, including spironolactone (an aldosterone antagonist), androgen receptor blockers (e.g., flutamide/bicalutamide), 5-alpha-reductase inhibitors (e.g., finasteride/dutasteride), and oral contraceptives, target the mechanism of androgen conversion and binding to its respective receptor and therefore could be administered for the treatment of FAGA. Despite significant advances in the oral treatment of FAGA, its management in patients with a history of gynecological malignancies, the most common cancers in women worldwide, may still be a concern. In this review, we focus on the safety of antiandrogens for the treatment of FAGA patients. For this purpose, a targeted literature review was conducted on PubMed, utilizing the relevant search terms. To sum up, spironolactone seems to be safe for the systemic treatment of FAGA, even in high-risk populations. However, a general uncertainty remains regarding the safety of other medications in patients with a history of gynecologic malignancies, and further studies are needed to evaluate their long-term safety in patients with FAGA and risk factors to establish an optimal risk assessment and treatment selection protocol.