Comparison of different promoters to improve AAV vector-mediated gene therapy for neuronopathic Gaucher disease.

Gaucher Disease (GD) is an inherited metabolic disorder caused by mutations in the GBA1 gene. It can manifest with severe neurodegeneration and visceral pathology. The most acute neuronopathic form (nGD), for which there are no curative therapeutic options, is characterised by devastating neuropathology and death during infancy. In this study, we investigated the therapeutic benefit of systemically delivered AAV9 vectors expressing the human GBA1 gene at two different doses comparing a neuronal-selective promoter with ubiquitous promoters. Our results highlight the importance of a careful evaluation of the promoter sequence used in gene delivery vectors, suggesting a neuron-targeted therapy leading to high levels of enzymatic activity in the brain but lower GCase expression in the viscera, might be the optimal therapeutic strategy for nGD.

The treatment of advanced melanoma: Current approaches and new challenges.

In recent years, advances in melanoma treatment have renewed patient hope. This comprehensive review emphasizes the evolving treatment landscape, particularly highlighting first-line strategies and the interplay between immune-checkpoint inhibitors (ICIs) and targeted therapies. Ipilimumab plus nivolumab has achieved the best median overall survival, exceeding 70 months. However, the introduction of new ICIs, like relatlimab, has added complexity to first-line therapy decisions. Our aim is to guide clinicians in making personalized treatment decisions. Various features, including brain metastases, PD-L1 expression, BRAF mutation, performance status, and prior adjuvant therapy, significantly impact the direction of advanced melanoma treatment. We also provide the latest insights into the treatment of rare melanoma subtypes, such as uveal melanoma, where tebentafusp has shown promising improvements in overall survival for metastatic uveal melanoma patients. This review provides invaluable insights for clinicians, enabling informed treatment choices and deepening our understanding of the multifaceted challenges associated with advanced melanoma management.

Engineering an Autonucleolytic Mammalian Suspension Host Cell Line to Reduce DNA Impurity Levels in Serum-Free Lentiviral Process Streams.

We engineered HEK293T cells with a transgene encoding tetracycline-inducible expression of a Staphylococcus aureus nuclease incorporating a translocation signal. We adapted the unmodified and nuclease-engineered cell lines to grow in suspension in serum-free media, generating the HEK293TS and NuPro-2S cell lines, respectively. Transient transfection yielded 1.19 × 106 lentiviral transducing units per milliliter (TU/mL) from NuPro-2S cells and 1.45 × 106 TU/mL from HEK293TS cells. DNA ladder disappearance revealed medium-resident nuclease activity arising from NuPro-2S cells in a tetracycline-inducible manner. DNA impurity levels in lentiviral material arising from NuPro-2S and HEK293TS cells were undetectable by SYBR Safe agarose gel staining. Direct measurement by PicoGreen reagent revealed DNA to be present at 636 ng/mL in lentiviral material from HEK293TS cells, an impurity level reduced by 89% to 70 ng/mL in lentiviral material from NuPro-2S cells. This reduction was comparable to the 23 ng/mL achieved by treating HEK293TS-derived lentiviral material with 50 units/mL Benzonase.

PPAR-gamma agonist pioglitazone recovers mitochondrial quality control in fibroblasts from PITRM1-deficient patients.

Introduction: Biallelic variants in PITRM1 are associated with a slowly progressive syndrome characterized by intellectual disability, spinocerebellar ataxia, cognitive decline and psychosis. The pitrilysin metallopeptidase 1 (PITRM1) is a mitochondrial matrix enzyme, which digests diverse oligopeptides, including the mitochondrial targeting sequences (MTS) that are cleaved from proteins imported across the inner mitochondrial membrane by the mitochondrial processing peptidase (MPP). Mitochondrial peptidases also play a role in the maturation of Frataxin, the protein affected in Friedreich's ataxia. Recent studies in yeast indicated that the mitochondrial matrix protease Ste23, which is a homologue of the human insulin-degrading enzyme (IDE), cooperates with Cym1 (homologue of PITRM1) to ensure the proper functioning of the preprotein processing machinery. In humans, IDE could be upregulated by Peroxisome Proliferator-Activated Receptor Gamma (PPARG) agonists. Methods: We investigated preprotein processing, mitochondrial membrane potential and MTS degradation in control and patients' fibroblasts, and we evaluated the pharmacological effect of the PPARG agonist Pioglitazone on mitochondrial proteostasis. Results: We discovered that PITRM1 dysfunction results in the accumulation of MTS, leading to the disruption and dissipation of the mitochondrial membrane potential. This triggers a feedback inhibition of MPP activity, consequently impairing the processing and maturation of Frataxin. Furthermore, we found that the pharmacological stimulation of PPARG by Pioglitazone upregulates IDE and also PITRM1 protein levels restoring the presequence processing machinery and improving Frataxin maturation and mitochondrial function. Discussion: Our findings provide mechanistic insights and suggest a potential pharmacological strategy for this rare neurodegenerative mitochondrial disease.

A Novel Small NPC1 Promoter Enhances AAV-Mediated Gene Therapy in Mouse Models of Niemann-Pick Type C1 Disease.

Niemann-Pick disease type C1 (NP-C) is a prematurely lethal genetic lysosomal storage disorder with neurological and visceral pathology resulting from mutations in the NPC1 gene encoding the lysosomal transmembrane protein NPC1. There is currently no cure for NP-C, and the only disease modifying treatment, miglustat, slows disease progression but does not significantly attenuate neurological symptoms. AAV-mediated gene therapy is an attractive option for NP-C, but due to the large size of the human NPC1 gene, there may be packaging and truncation issues during vector manufacturing. One option is to reduce the size of DNA regulatory elements that are essential for gene expression, such as the promoter sequence. Here, we describe a novel small truncated endogenous NPC1 promoter that leads to high gene expression both in vitro and in vivo and compare its efficacy to other commonly used promoters. Following neonatal intracerebroventricular (ICV) injection into the CNS, this novel promoter provided optimal therapeutic efficacy compared to all other promoters including increased survival, improved behavioural phenotypes, and attenuated neuropathology in mouse models of NP-C. Taken together, we propose that this novel promoter can be extremely efficient in designing an optimised AAV9 vector for gene therapy for NP-C.

Microfluidic production of nanogels as alternative triple transfection reagents for the manufacture of adeno-associated virus vectors.

Adeno-associated viral vectors (AAVs) have proved a mainstay in gene therapy, owing to their remarkable transduction efficiency and safety profile. Their production, however, remains challenging in terms of yield, the cost-effectiveness of manufacturing procedures and large-scale production. In this work, we present nanogels produced by microfluidics as a novel alternative to standard transfection reagents such as polyethylenimine-MAX (PEI-MAX) for the production of AAV vectors with comparable yields. Nanogels were formed at pDNA weight ratios of 1 : 1 : 2 and 1 : 1 : 3, of pAAV cis-plasmid, pDG9 capsid trans-plasmid and pHGTI helper plasmid respectively, where vector yields at a small scale showed no significant difference to those of PEI-MAX. Weight ratios of 1 : 1 : 2 showed overall higher titers than 1 : 1 : 3, where nanogels with nitrogen/phosphate ratios of 5 and 10 produced yields of ≈8.8 × 108 vg mL-1 and ≈8.1 × 108 vg mL-1 respectively compared to ≈1.1 × 109 vg mL-1 for PEI-MAX. In larger scale production, optimised nanogels produced AAV at a titer of ≈7.4 × 1011 vg mL-1, showing no statistical difference from that of PEI-MAX at ≈1.2 × 1012 vg mL-1, indicating that equivalent titers can be achieved with easy-to-implement microfluidic technology at comparably lower costs than traditional reagents.

Risk factors for Gram-negative bacterial infection of cardiovascular implantable electronic devices: multicentre observational study (CarDINe Study).

BACKGROUND: Infections of cardiovascular implantable electronic devices (CIED) are mainly due to Gram-positive bacteria (GPB). Data about Gram-negative bacteria CIED (GNB-CIED) infections are limited. This study aimed to investigate risk factors, clinical and diagnostic characteristics, and outcome of patients with GNB-CIED. METHODS: A multicentre, international, retrospective, case-control-control study was performed on patients undergoing CIED implantation from 2015 to 2019 in 17 centres across Europe. For each patient diagnosed with GNB-CIED, one matching control with GPB-CIED infection and two matching controls without infection were selected. RESULTS: A total of 236 patients were enrolled: 59 with GNB-CIED infection, 59 with GPB-CIED infection and 118 without infection. No between-group differences were found regarding clinical presentation, diagnostic and therapeutic management. A trend toward a higher rate of fluorodeoxyglucose positron emission computed tomography (FDG PET/CT) positivity was observed among patients with GNB than in those with GPB-CIED infection (85.7% vs. 66.7%; P = 0.208). Risk factors for GNB-CIED infection were Charlson Comorbidity Index Score (relative risk reduction, RRR = 1.211; P = 0.011), obesity (RRR = 5.122; P = 0.008), ventricular-pacing ventricular-sensing inhibited-response pacemaker implantation (RRR = 3.027; P = 0.006) and right subclavian vein site of implantation (RRR = 5.014; P = 0.004). At 180-day survival analysis, GNB-CIED infection was associated with increased mortality risk (HR = 1.842; P = 0.067). CONCLUSIONS: Obesity, high number of comorbidities and right subclavian vein implantation site were associated with increased risk of GNB-CIED infection. A prompt therapeutic intervention that may be guided using FDG PET/CT is suggested in patients with GNB-CIED infection, considering the poorer outcome observed in this group.

Pocket histology at cardiac implantable electronic device replacement: What's new?

BACKGROUND: Repeated procedures involving the cardiac implantable electronic device (CIED) pocket increase the infection risk, and the extent of pocket adhesions may prolong the procedure time. Few data on pocket histology at the time of CIED replacement are available. OBJECTIVE: The purpose of this study was to describe CIED pocket histology in a cohort of patients undergoing CIED replacement or upgrade. METHODS: All consecutive patients undergoing CIED replacement or upgrade at our center between November 2019 and May 2020 were enrolled. Subclinical pocket infection was ruled out by physical inspection and laboratory parameters before the procedure. Pocket tissue specimens from the anterior and posterior pockets were obtained intraoperatively. A systematic histological analysis of capsular thickness, fibrous connective tissue, neovascularization, inflammation, and calcifications was performed. RESULTS: Thirty patients (6 women, 20%) were enrolled. The mean capsular thickness was 0.8 ± 0.3 mm in the anterior wall and 1.1 ± 0.4 mm in the posterior wall. Subcapsular fibrosis was mild and multifocal in the anterior wall and moderate and focal in the posterior wall. Neovascularization was focal in most cases, and vessel remodeling mainly involved the tunica media. Chronic inflammation was usually mild and nongranulomatous, and in a quarter of cases, subacute exudative fibrous inflammation was detected in the posterior pocket wall. CONCLUSION: The CIED pocket is a histopathologically dynamic environment, given the coexistence of both a subacute foreign body response and fibrous tissue growth, implying continuous remodeling due to an injury-repair mechanism. Strategies to interact with foreign body response might minimize inflammatory pocket activity, especially device encapsulation by tight fibrous tissue, and possibly complications related to repeated CIED procedures.

Prognostic value of renal failure in patients undergoing transvenous lead extraction: single centre experience and systematic review of the literature.

INTRODUCTION: Cardiac implantable electronic device infections (CIEDI) are challenging complications, associated with high mortality rate. Transvenous lead extraction (TLE) is the only curative treatment for CIEDI. Albeit continuous improvement in tools and techniques dramatically decreased TLE associated complications, survival after TLE for CIEDI is still poor. Renal failure (RF) is frequently reported in candidates to TLE, but due to variability in its definition, the real prevalence is not well defined. OBJECTIVE: Considering the impact of RF on mortality among patients affected by cardiovascular diseases, we aimed our research at defining the role of RF as a predictor of post-TLE mortality. METHOD AND RESULTS: We will provide the results of a systematic revision of literature on the impact of RF on mortality at different time points after TLE, according to the various definitions adopted for RF. Considering the high variability of literature in this field, we will provide the results of an explorative analysis comparing the different definitions of RF on clinical outcomes in a cohort of candidates to TLE for CIEDI in a high-volume referral center. CONCLUSION: We discuss the possible reasons of the negative impact of RF after TLE, providing new perspectives for future research.

Personalizing configuration for atrial fibrillation external electrical cardioversion to improve first shock efficacy.

BACKGROUND: Despite the common use of biphasic electrical cardioversion (ECV) to convert atrial fibrillation (AF), we lack definite recommendations on electrode configuration. METHODS: We adopted a quasi-experimental design enrolling all candidates to ECV for AF. In the first stage, two units were involved, one using antero-apical pads (AAP) and the second antero-posterior adhesive patches (APP). These data enabled the creation of a decision algorithm to personalize the ECV approach, which was subsequently validated during the second stage. RESULTS: A total of 492 patients were enrolled overall. In the first stage, APP and AAP presented similar conversion rates (87.4 vs. 86.9% at first attempt of a step-up protocol, P = 0.661). While body surface area (BSA) ≤2.12 m2 was an independent predictor in the overall population, the two components (height and weight) acted differently in the two configurations: being height ≤1.73 m2 a significant cut-off value in the AAP subgroup, and weight <83 kg in the APP subgroup. Considering these cut-offs, we developed a decision algorithm for electrode configuration. In the second stage, algorithm validation confirmed an improvement in the first shock efficacy with respect to the results of the first stage (93.2 vs. 87.2%, P = 0.025), with a significant reduction in shock impedance (70.8 ±â€Š15.3 vs. 81.8 ±â€Š15.6, P < 0.001). CONCLUSION: Patients with high BSA require high energy shocks for sinus rhythm restoration with ECV. Weight seems to affect more APP configuration, while height seems to impact more for the AAP. These findings have the potential to optimize ECV in clinical practice.

Comparison Between First Line Target Therapy and Immunotherapy in Different Prognostic Categories of BRAF Mutant Metastatic Melanoma Patients: An Italian Melanoma Intergroup Study.

Background: BRAF and MEK inhibitors target therapies (TT) and AntiPD1 immunotherapies (IT) are available first-line treatments for BRAF v600 mutant metastatic melanoma patients. ECOG PS (E), baseline LDH (L), and baseline number of metastatic sites (N) are well-known clinical prognostic markers that identify different prognostic categories of patients. Direct comparison between first-line TT and IT in different prognostic categories could help in first line treatment decision. Methods: This is a retrospective analysis conducted in 14 Italian centers on about 454 metastatic melanoma patients, divided in 3 groups: group A-patients with E = 0, L within normal range, and N less than 3; group B-patients not included in group A or C; group C-patients with E > 0, L over the normal range, and N more than 3. For each prognostic group, we compared TT and IT in terms of progression free survival (PFS), overall survival (OS), and disease control rate (DCR). Results: In group A, results in 140 TT and 36 IT-treated patients were, respectively, median PFS 35.5 vs 11.6 months (HR (95% CI) 1.949 (1.180-3.217) p value 0.009); median OS not reached vs 55 months (HR (95% CI) 1.195 (0.602-2.373) p value 0.610); DCR 99% vs 75% p value <0.001). In group B, results in 196 TT and 38 IT-treated patients were, respectively, median PFS 11.5 vs 5 months (HR 1.535 (1.036-2.275) p value 0.033); median OS 19 vs 20 months (HR 0.886 (0.546-1.437) p value 0.623); DCR 85% vs 47% p value <0.001). In group C, results in 41 TT and 3 IT-treated patients were, respectively, median PFS 6.4 vs 1.8 months (HR 4.860 (1.399-16) p value 0.013); median OS 9 vs 5 months (HR 3.443 (0.991-11.9) p value 0.052); DCR 66% vs 33% p value 0.612). Conclusions: In good prognosis, group A-TT showed statistically significant better PFS than IT, also in a long-term period, suggesting that TT can be a good first line option for this patient category. It is only in group B that we observed a crossing of the survival curves after the 3rd year of observation in favor of IT. Few patients were enrolled in group C, so few conclusions can be made on it.

Wrist Photoplethysmography Signal Quality Assessment for Reliable Heart Rate Estimate and Morphological Analysis.

Photoplethysmographic (PPG) signals are mainly employed for heart rate estimation but are also fascinating candidates in the search for cardiovascular biomarkers. However, their high susceptibility to motion artifacts can lower their morphological quality and, hence, affect the reliability of the extracted information. Low reliability is particularly relevant when signals are recorded in a real-world context, during daily life activities. We aim to develop two classifiers to identify PPG pulses suitable for heart rate estimation (Basic-quality classifier) and morphological analysis (High-quality classifier). We collected wrist PPG data from 31 participants over a 24 h period. We defined four activity ranges based on accelerometer data and randomly selected an equal number of PPG pulses from each range to train and test the classifiers. Independent raters labeled the pulses into three quality levels. Nineteen features, including nine novel features, were extracted from PPG pulses and accelerometer signals. We conducted ten-fold cross-validation on the training set (70%) to optimize hyperparameters of five machine learning algorithms and a neural network, and the remaining 30% was used to test the algorithms. Performances were evaluated using the full features and a reduced set, obtained downstream of feature selection methods. Best performances for both Basic- and High-quality classifiers were achieved using a Support Vector Machine (Acc: 0.96 and 0.97, respectively). Both classifiers outperformed comparable state-of-the-art classifiers. Implementing automatic signal quality assessment methods is essential to improve the reliability of PPG parameters and broaden their applicability in a real-world context.

Gene Therapy for Mitochondrial Diseases: Current Status and Future Perspective.

Mitochondrial diseases (MDs) are a group of severe genetic disorders caused by mutations in the nuclear or mitochondrial genome encoding proteins involved in the oxidative phosphorylation (OXPHOS) system. MDs have a wide range of symptoms, ranging from organ-specific to multisystemic dysfunctions, with different clinical outcomes. The lack of natural history information, the limits of currently available preclinical models, and the wide range of phenotypic presentations seen in MD patients have all hampered the development of effective therapies. The growing number of pre-clinical and clinical trials over the last decade has shown that gene therapy is a viable precision medicine option for treating MD. However, several obstacles must be overcome, including vector design, targeted tissue tropism and efficient delivery, transgene expression, and immunotoxicity. This manuscript offers a comprehensive overview of the state of the art of gene therapy in MD, addressing the main challenges, the most feasible solutions, and the future perspectives of the field.

Safety and Tolerability of COVID-19 Vaccines in Patients with Cancer: A Single Center Retrospective Analysis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 disease (COVID-19) has caused a worldwide challenging and threatening pandemic. Multinational, placebo-controlled, observer-blinded trials were conducted since the beginning of pandemic because safe and effective vaccines were needed urgently. In most trials of COVID-19 vaccines patients affected by malignancies or on treatment with immunosuppressive drugs were excluded. PATIENTS AND METHODS: A retrospective monocentric study was conducted at Medical Oncological Unit of Santa Chiara Hospital (Pisa, Italy) in this subset of population to investigate safety and tolerability of COVID-19 vaccines; 377 patients with solid tumor on treatment were enrolled. Vaccine-related adverse events were recorded using a face-to-face questionnaire including a toxicity grading scale. Most of the patients (94%) received mRNA vaccine as indicated by Italian health ministry guidelines. Mean age was 66 years (range 27-87), 62% of the patients were older than 65 years and 68% had at least one additional comorbidity. The majority (86%) of patients were in a metastatic setting and 29% received immunotherapy-based treatment. For statistical analysis, multivariate binary logistic regression models were performed and linear regression models were applied. RESULTS: Adverse events were mild and transient and ended in a few days without any sequelae. No severe or uncommon adverse events were recorded. In multivariate analysis, we found that the female sex was associated with a greater risk of more severe and longer lasting adverse events, and a higher risk of adverse events was found for patients treated with immunotherapy. CONCLUSIONS: Our results demonstrate that COVID-19 vaccines were safe and well-tolerated in this population of patients being treated for solid tumors.

His Bundle pacing for congenital complete AV block: An attempt to fix a broken heart?

Congenital complete atrioventricular block (CCAVB) is usually due to failure of atrioventricular nodal conduction with preservation of the His-Purkinje system. Most patients with CCAVB ultimately require pacemaker therapy to restore physiologic heart rates, dealing with the detrimental effects of chronic right ventricular (RV) pacing on cardiac structure and function. The ideal stimulation pattern aims to mimic the normal conduction to restore electromechanical coupling, preventing the harmful effects of lack of atrioventricular and inter-intraventricular synchrony. This can be done through conduction system pacing. Using His bundle pacing (HBP) for cardiac resynchronization therapy in two complete congenital atrioventricular block patients, we have reported better exercise tolerance and echocardiographic improvements related to reversible left ventricular dysfunction that can be corrected by restoration of the normal activation pathway via the His-Purkinje network.

Bridging the future of cardiac stimulation: physiologic or leadless pacing?

Cardiac simulation has moved from early life-saving pacemakers meant only to prevent asystole to current devices capable of physiologic stimulation for the treatment of heart rhythm and heart failure, that are also intended for remote patient and disease-progression monitoring. The actual vision of contemporary pacing aims to correct the electrophysiologic roots of mechanical inefficiency regardless of underlying structural heart diseases. The awareness of the residual cardiac dyssynchrony related to customary cardiac pacing has changed the concept of what truly represents "physiologic pacing". On a different perspective, leadless stimulation to abolish CIED surgery and prevent lead-related complications is becoming a priority both for young device recipients and for frail, elderly patients. Careful clinical evaluation attempts to bridge decision-making to patient-tailored therapy.

Ten-year follow-up of cardiac resynchronization therapy patients with non-ischemic dilated cardiomyopathy assessed by radionuclide angiography: a single-center cohort study.

PURPOSE: Relatively few data are available on long-term survival and incidence of ventricular arrhythmias in cardiac resynchronization therapy (CRT) patients. We investigated long-term outcomes of CRT patients with non-ischemic dilated cardiomyopathy stratified as responders or non-responders according to radionuclide angiography. METHODS: Fifty patients with non-ischemic dilated cardiomyopathy undergoing CRT were assessed by equilibrium Tc99 radionuclide angiography with bicycle exercise at baseline and after 3 months. Intra- and interventricular dyssynchrony were derived by Fourier phase analysis. Patient clinical outcome was assessed after 10 years. RESULTS: At 3 months, 50% of patients were identified as CRT responders according to an increase in LV ejection fraction ≥ 5%. During a follow-up of 109 ± 48 months, 30% of patients died and 6% underwent heart transplantation. Age and history of paroxysmal atrial fibrillation were found to be predictors of all-cause mortality. CRT responders showed lower risk of death from cardiac causes than non-responders. At follow-up, 38% of patients presented at least one episode of sustained ventricular tachycardia, with a similar percentage between responders and non-responders. CONCLUSION: At long-term follow-up, non-ischemic CRT recipients identified as responders by radionuclide angiography were found to be at lower risk of worsening heart failure death than non-responders. Long-term risk for sustained ventricular arrhythmia was similar between CRT responders and non-responders.

Preoperative checklist to reduce the risk of cardiac implantable electronic device infections.

Cardiac implantable electronic device (CIED) infection represents a dramatic event with a high mortality rate (>3x) despite antibiotic therapy and device extraction; therefore, the real winning strategy in this situation could be represented by prevention. Antibiotic prophylaxis and antibiotic-releasing envelope are effective in improving patient outcome; however, healthcare costs related to CIED infections remain high over the years. In this review we would keep the attention on a pre-surgical checklist to reduce the risk of CIED infections. In fact, checklist is an effective instrument for medical care quality improvement mainly used in surgery, but not very commonly in cath-lab and electrophysiology procedures. All steps of this checklist are of proven effectiveness in reducing the risk of CIED infections but, up till now, they are not considered together in a pre-surgical approach.

Use of Diltiazem in Chronic Rate Control for Atrial Fibrillation: A Prospective Case-Control Study.

Atrial fibrillation (AF) is a multifaceted disease requiring personalised treatment. The aim of our study was to explore the prognostic impact of a patient-specific therapy (PT) for rate control, including the use of non-dihydropyridine calcium channel blockers (NDDC) in patients with heart failure (HF) or in combination with beta-blockers (BB), compared to standard rate control therapy (ST), as defined by previous ESC guidelines. This is a single-centre prospective observational registry on AF patients who were followed by our University Hospital. We included 1112 patients on an exclusive rate control treatment. The PT group consisted of 125 (11.2%) patients, 93/125 (74.4%) of whom were prescribed BB + NDCC (±digoxin), while 85/125 (68.0%) were HF patients who were prescribed NDCC, which was diltiazem in all cases. The patients treated with a PT showed no difference in one-year overall survival compared to those with an ST. Notably, the patients with HF in ST had a worse prognosis (p < 0.001). To better define this finding, we performed three sensitivity analyses by matching each patient in the PT subgroups with three subjects from the ST cohort, showing an improved one-year survival of the HF patients treated with PT (p = 0.039). Our results suggest a potential outcome benefit of NDCC for rate control in AF patients, either alone or in combination with BB and in selected patients with HF.

Cimicifuga racemosa isopropanolic extract for menopausal symptoms: an observational prospective case-control study.

OBJECTIVE: We aimed to investigate the effectiveness of isopropanolic extract of Cimicifuga Racemosa (iCR) on reducing menopausal symptoms. MATERIALS AND METHODS: A single-center observational prospective case-control study was performed to assess the improvement of menopausal symptoms in menopausal women undergone iCR administration (cases) or no treatment (controls). Menopausal symptoms were assessed through a modified version of the Menopause Rating Scale questionnaire (mMRS) at T0 (baseline), T1 (1-month follow-up), and T2 (3 months follow-up). Univariate comparisons between cases and controls were performed by using the unpaired T test for two-tailed P value with α = 0.05 significance level. RESULTS: A total of 163 women (83 cases and 80 controls) were enrolled in the study. The difference in menopausal symptoms between cases and controls from T0 to T2, and from T0 to T1, was found significant for all analyses. In particular, the difference in all menopausal symptoms was 20.56 ± 0.90 points (95%CI: 18.77-22.33, p < .001) from T0 to T2, and 10.69 ± 0.6 (95%CI: 9.49-11.88, p < .001) from T0 to T1. CONCLUSION: iCR may be effective in reducing menopausal symptoms, both after 1 month and after 3 months of treatment. The improvement was higher in vasomotor symptoms, sleep problems, and irritability.