The effect of black cohosh extract and risedronate coadministration on bone health in an ovariectomized rat model.

Preparations of black cohosh extract are sold as dietary supplements marketed to relieve the vasomotor symptoms of menopause, and some studies suggest it may protect against postmenopausal bone loss. Postmenopausal women are also frequently prescribed bisphosphonates, such as risedronate, to prevent osteoporotic bone loss. However, the pharmacodynamic interactions between these compounds when taken together is not known. To investigate possible interactions, 6-month-old, female Sprague-Dawley rats underwent bilateral ovariectomy or sham surgery and were treated for 24 weeks with either vehicle, ethinyl estradiol, risedronate, black cohosh extract or coadministration of risedronate and black cohosh extract, at low or high doses. Bone mineral density (BMD) of the femur, tibia, and lumbar vertebrae was then measured by dual-energy X-ray absorptiometry (DEXA) at weeks 0, 8, 16, and 24. A high dose of risedronate significantly increased BMD of the femur and vertebrae, while black cohosh extract had no significant effect on BMD individually and minimal effects upon coadministration with risedronate. Under these experimental conditions, black cohosh extract alone had no effect on BMD, nor did it negatively impact the BMD-enhancing properties of risedronate.

Left atrial appendage occlusion for recurrent stroke while on oral anticoagulation: a case series.

Background: Clinical practice guidelines recommend oral anticoagulation (OAC) for stroke prevention in selected patients with atrial fibrillation (AF). However, some patients still experience thrombo-embolic events despite adequate anticoagulation. The optimal management of these cases remains uncertain, leading to practice pattern variability. We present a series of three cases illustrating the use of left atrial appendage occlusion (LAAO) as an adjunctive stroke prevention strategy in AF patients with recurrent thrombo-embolic events despite adequate anticoagulation. Case summary: Case one describes an 89-year-old female on apixaban who presented with a thrombus and underwent successful mechanical thrombectomy. Left atrial appendage occlusion was performed, and no subsequent thrombo-embolic events were reported. Case 2 involves a 72-year-old female on full-dose apixaban who experienced recurrent strokes despite adequate anticoagulation. Thrombectomy was performed twice, and complications arose during LAAO. The patient was discharged on warfarin + clopidogrel and remained event-free at the six-month follow-up. Case 3 features an 88-year-old female on rivaroxaban who experienced recurrent cerebral ischaemic events and gastrointestinal bleeding. Left atrial appendage occlusion using an Amplatzer Amulet™ device was successful, and the patient remained event-free at the one-year follow-up. Discussion: This case series emphasizes the complexity of stroke prevention in AF patients and underscores the need for an individualized approach. Incorporating LAAO alongside OAC can provide additional stroke protection for patients with inadequate response to anticoagulation. Further randomized controlled trials are needed to evaluate the efficacy and safety of this approach. In light of the limited evidence available, these cases contribute to the growing body of knowledge on the potential role of LAAO in secondary stroke prevention in AF patients with recurrent thrombo-embolic events despite appropriate anticoagulation.

Simultaneous measurement of orthogonal terahertz fields via an emission multiplexing scheme.

We propose a polarization sensitive terahertz time-domain spectrometer that can record orthogonally polarized terahertz fields simultaneously, using fibre-coupled photoconductive antennas and a scheme that modulated the emitter's polarization. The s and p channels of the multi-pixel terahertz emitter were modulated at different frequencies, thereby allowing orthogonal waveforms to be demultiplexed from the recorded signal in post-processing. The performance of the multi-pixel emitter used in this multiplexing scheme was comparable to that of a commercial single-polarization H-dipole antenna. The approach allowed two orthogonally polarized terahertz pulses to be recorded with good signal to noise (>1000:1) within half a second. We verified the capability of the spectrometer by characterizing a birefringent crystal and by imaging a polarization-sensitive metamaterial. This work has significant potential to improve the speed of terahertz polarization sensitive applications, such as ellipsometry and imaging.

Comparison between epileptic seizure prediction and forecasting based on machine learning.

Epilepsy affects around 1% of the population worldwide. Anti-epileptic drugs are an excellent option for controlling seizure occurrence but do not work for around one-third of patients. Warning devices employing seizure prediction or forecasting algorithms could bring patients new-found comfort and quality of life. These algorithms would attempt to detect a seizure's preictal period, a transitional moment between regular brain activity and the seizure, and relay this information to the user. Over the years, many seizure prediction studies using Electroencephalogram-based methodologies have been developed, triggering an alarm when detecting the preictal period. Recent studies have suggested a shift in view from prediction to forecasting. Seizure forecasting takes a probabilistic approach to the problem in question instead of the crisp approach of seizure prediction. In this field of study, the triggered alarm to symbolize the detection of a preictal period is substituted by a constant risk assessment analysis. The present work aims to explore methodologies capable of seizure forecasting and establish a comparison with seizure prediction results. Using 40 patients from the EPILEPSIAE database, we developed several patient-specific prediction and forecasting algorithms with different classifiers (a Logistic Regression, a 15 Support Vector Machines ensemble, and a 15 Shallow Neural Networks ensemble). Results show an increase of the seizure sensitivity in forecasting relative to prediction of up to 146% and in the number of patients that displayed an improvement over chance of up to 300%. These results suggest that a seizure forecasting methodology may be more suitable for seizure warning devices than a seizure prediction one.

Coronary angiography after out-of-hospital cardiac arrest without ST-segment elevation: a systematic review and meta-analysis of randomised trials.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) has a poor prognosis. The optimal timing and role of early coronary angiography (CAG) in OHCA patients without ST-segment elevation remains unclear. The goal of this study is to compare an early CAG versus delayed CAG strategy in OHCA patients without ST elevation. METHODS: We systematically searched PubMed, Embase and Cochrane databases, in June 2022, for randomised controlled trials (RCTs) comparing early versus delayed early CAG. A random effects meta-analysis was performed. RESULTS: A total of seven RCTs were included, providing a total of 1625 patients: 816 in an early strategy and 807 in a delayed strategy. In terms of outcomes assessed, our meta-analysis revealed a similar rate of all-cause mortality (pooled odds ratio [OR] 1.22 [0.99-1.50], P  = 0.06, I 2  = 0%), neurological status (pooled OR 0.94 [0.74-1.21], = 0.65, I 2  = 0%), need of renal replacement therapy (pooled OR 1.11 [0.78-1.74], P  = 0.47, I 2  = 0%) and major bleeding events (pooled OR 1.51 [0.95-2.40], P  = 0.08, I 2  = 69%). CONCLUSION: According to our meta-analysis, in patients who experienced OHCA without ST elevation, early CAG is not associated with reduced mortality or an improved neurological status.

Therapeutic avenues for γδ T cells in cancer.

γδ T cells are regarded as promising effector lymphocytes for next-generation cancer immunotherapies. In spite of being relatively rare in human peripheral blood, γδ T cells are more abundant in epithelial tissues where many tumors develop, and have been shown to actively participate in anticancer immunity as cytotoxic cells or as "type 1" immune orchestrators. A major asset of γδ T cells for tackling advanced cancers is their independence from antigen presentation via the major histocompatibility complex, which clearly sets them apart from conventional αß T cells. Here we discuss the main therapeutic strategies based on human γδ T cells. These include antibody-based bispecific engagers and adoptive cell therapies, either focused on the Vδ1+ or Vδ2+ γδ T-cell subsets, which can be expanded selectively and differentiated or engineered to maximize their antitumor functions. We review the preclinical data that supports each of the therapeutic strategies under development; and summarize the clinical trials being pursued towards establishing γδ T cell-based treatments for solid and hematological malignancies.

Breast Sarcomas, Phyllodes Tumors, and Desmoid Tumors: Turning the Magnifying Glass on Rare and Aggressive Entities.

Breast sarcomas (BSs), phyllodes tumors (PTs), and desmoid tumors (DTs) are rare entities that arise from connective tissue. BSs can be classified as either primary or secondary, whether they develop de novo or after radiation exposure or lymphedema. PIK3CA seems to play an important common role in different BS. Malignant PTs show similar behavior to BSs, while DTs are locally aggressive but rarely metastasize. BSs usually present as unilateral, painless, rapidly growing masses with rare nodal involvement. The diagnosis should be based on magnetic resonance imaging and a core needle biopsy. Staging should comprise a chest computed tomography (CT) scan (except for benign PT and DT), while abdominal and pelvic CT scans and bone scans should be added in certain subtypes. The mainstay of treatment for localized BS is surgery, with margin goals that vary according to subtype. Radiotherapy and chemotherapy can be used as neoadjuvant or adjuvant approaches, but their use in these settings is not standard. Advanced BS should be treated with systemic therapy, consistent with recommendations for advanced soft tissue sarcomas of other topographies. Given the rarity and heterogeneity of these entities, multidisciplinary and multi-institutional collaboration and treatment at reference centers are critical.

Quantitative evaluation of transdermal drug delivery patches on human skin with in vivo THz-TDS.

Transdermal drug delivery (TDD) has been widely used in medical treatments due to various advantages, including delivering drugs at a consistent rate. However, variations in skin hydration can have a significant effect on the permeability of chemicals. Therefore, it is essential to study the changes in skin hydration induced by TDD patches for better control of the delivery rate. In this work, in vivo terahertz (THz) spectroscopy is conducted to quantitatively monitor human skin after the application of patches with different backing materials and propylene glycol concentrations. Changes in skin hydration and skin response to occlusion induced by other patches are investigated and compared. Our work demonstrates the potential application of in vivo THz measurements in label-free, non-invasive evaluation of transdermal patches on human skin and further reveals the mechanism behind the effect.

Tricuspid repair in mitral regurgitation surgery: a systematic review and meta-analysis.

BACKGROUND: Concomitant tricuspid repair in MR surgery is indicated in patients with severa tricuspid regurgitation, however, concomitant repair in less-than-severe TR patients is still a matter of debate. METHODS: In December 2021, we systematically searched PubMed, Embase and Cochrane databases for randomised control trials (RCTs) comparing isolated MR surgery versus MR surgery with concomitant TR annuloplasty. Four studies were included, resulting in 651 patients (323 in the prophylactic tricuspid intervention group and 328 in the no tricuspid intervention group). RESULTS: Our meta-analysis showed a similar all-cause mortality and perioperative mortality for concomitant prophylactic tricuspid repair when compared with no tricuspid intervention (pooled odds ratio (OR), 0.54; 95% confidence interval (CI): 0.25-1.15, P = 0.11; I2 = 0% and pooled OR, 0.54; 95% CI: 0.25-1.15, P = 0.11; I2 = 0%, respectively) in patients undergoing MV surgery. despite a significantly lower TR progression (pooled OR, 0.06; 95% CI: 0.02-0.24, P < 0.01; I2 = 0%). Additionally, similar New York Heart Association (NYHA) classes III and IV were identified in both concomitant prophylactic tricuspid repair and no tricuspid intervention, despite a lower trend in the tricuspid intervention group (pooled OR, 0.63; 95% CI: 0.38-1.06, P = 0.08; I2 = 0%). CONCLUSIONS: Our pooled analyses suggested that TV repair at the time of MV surgery in patients with moderate or less-than-moderate TR did not impact on perioperative or postoperative all-cause mortality, despite reducing TR severity and TR progression following the intervention.

Testing drivers of acoustic divergence in cicadas (Cicadidae: Tettigettalna).

Divergence in acoustic signals may have a crucial role in the speciation process of animals that rely on sound for intra-specific recognition and mate attraction. The acoustic adaptation hypothesis (AAH) postulates that signals should diverge according to the physical properties of the signalling environment. To be efficient, signals should maximize transmission and decrease degradation. To test which drivers of divergence exert the most influence in a speciose group of insects, we used a phylogenetic approach to the evolution of acoustic signals in the cicada genus Tettigettalna, investigating the relationship between acoustic traits (and their mode of evolution) and body size, climate and micro-/macro-habitat usage. Different traits showed different evolutionary paths. While acoustic divergence was generally independent of phylogenetic history, some temporal variables' divergence was associated with genetic drift. We found support for ecological adaptation at the temporal but not the spectral level. Temporal patterns are correlated with micro- and macro-habitat usage and temperature stochasticity in ways that run against the AAH predictions, degrading signals more easily. These traits are likely to have evolved as an anti-predator strategy in conspicuous environments and low-density populations. Our results support a role of ecological selection, not excluding a likely role of sexual selection in the evolution of Tettigettalna calling songs, which should be further investigated in an integrative approach.

Early surgical intervention versus conservative management of asymptomatic severe aortic stenosis: a systematic review and meta-analysis.

OBJECTIVE: Timing of intervention for patients with asymptomatic severe aortic stenosis (AS) remains controversial. To compare the outcomes of early aortic valve replacement (AVR) versus watchful waiting (WW) in patients with asymptomatic severe AS. METHODS: We systematically searched PubMed, Embase and Cochrane databases, in December 2021, for studies comparing early AVR with WW in the treatment of asymptomatic severe AS. Random-effects meta-analysis was performed. RESULTS: Twelve studies were included in which two were randomised clinical trials. A total of 4130 patients were included, providing a 1092 pooled death events. Our meta-analysis showed a significantly lower all-cause mortality for the early AVR compared with WW group, although with a high amount of heterogeneity between studies in the magnitude of the effect (pooled OR 0.40; 95% CI 0.35 to 0.45, p<0.01; I²=61%). An early surgery strategy displayed a significantly lower cardiovascular mortality (pooled OR 0.33; 95% CI 0.19 to 0.56, p<0.01; I²=64%) and heart failure hospitalisation (pooled OR 0.19; 95% CI 0.10 to 0.39, p<0.01, I²=7%). However, both groups had similar rates of stroke (pooled OR 1.30; 95% CI 0.73 to 2.29, p=0.36, I²=0%) and myocardial infarction (pooled OR 0.49; 95% CI 0.19 to 1.27, p=0.14, I²= 0%). CONCLUSIONS: This study suggests that for patients with asymptomatic severe AS an early surgical intervention compared with a conservative WW strategy was associated with a lower heart failure hospitalisation and a similar rate of stroke or myocardial infarction, although with significant risk of bias. PROSPERO REGISTRATION NUMBER: CRD42021291144.

Bridging the gap of axonal regeneration in the central nervous system: A state of the art review on central axonal regeneration.

Neuronal regeneration in the central nervous system (CNS) is an important field of research with relevance to all types of neuronal injuries, including neurodegenerative diseases. The glial scar is a result of the astrocyte response to CNS injury. It is made up of many components creating a complex environment in which astrocytes play various key roles. The glial scar is heterogeneous, diverse and its composition depends upon the injury type and location. The heterogeneity of the glial scar observed in different situations of CNS damage and the consequent implications for axon regeneration have not been reviewed in depth. The gap in this knowledge will be addressed in this review which will also focus on our current understanding of central axonal regeneration and the molecular mechanisms involved. The multifactorial context of CNS regeneration is discussed, and we review newly identified roles for components previously thought to solely play an inhibitory role in central regeneration: astrocytes and p75NTR and discuss their potential and relevance for deciding therapeutic interventions. The article ends with a comprehensive review of promising new therapeutic targets identified for axonal regeneration in CNS and a discussion of novel ways of looking at therapeutic interventions for several brain diseases and injuries.

Renal sympathetic denervation in resistant hypertension: The association between vitamin D and positive early response in systolic blood pressure.

AIMS AND OBJECTIVES: Vitamin D deficiency is a common finding and there is a suggested association with hypertension. Resistant hypertension is a clinical problem observed in 5-30% of hypertensive patients. Renal denervation (RDN) has been used for patients with resistant hypertension and has proven to lower blood pressure. Our primary goal was to assess the vitamin D serum concentration as a predictor of blood pressure response to RDN in highly selected patients. METHODS: This prospective, nonrandomized, single-center study included 24 patients treated with RDN. Based on their one-year response after RDN, patients were classified as responders or non-responders at six months or at 12 months. RESULTS: The median follow-up was 52 months (range, 14-91 months). After RDN, 17 patients (70.8%) had a reduction >5 mmHg in the mean systolic blood pressure, at the first six months of follow-up. At 12 months, 20 patients (83.3%) were responders. Vitamin D levels at baseline (15.1±4.8 vs. 24.2±8.8 ng/ml) and at six months (16.6±7.2 vs. 25±9.2 ng/ml) were lower in early non-responders compared to early responders (p=0.008), without significant variation during follow-up. Even though Vitamin D levels were lower in the total responder's group, no statistically significant differences were found (p=ns). CONCLUSION: In patients with resistant hypertension, low vitamin D concentrations were associated with an absence of early response to RDN.

Lipidomic profiling of the hepatic esterified fatty acid composition in diet-induced nonalcoholic fatty liver disease in genetically diverse Collaborative Cross mice.

Non-alcoholic fatty liver disease (NAFLD), one of the most common forms of chronic liver disease, is characterized by the excessive accumulation of lipid species in hepatocytes. Recent studies have indicated that in addition to the total lipid quantities, changes in lipid composition are a determining factor in hepatic lipotoxicity. Using ultra-high performance liquid chromatography coupled with electrospray tandem mass spectrometry, we analyzed the esterified fatty acid composition in 24 strains of male and female Collaborative Cross (CC) mice fed a high fat/high sucrose (HF/HS) diet for 12 weeks. Changes in lipid composition were found in all strains after the HF/HS diet, most notably characterized by increases in monounsaturated fatty acids (MUFA) and decreases in polyunsaturated fatty acids (PUFA). Similar changes in MUFA and PUFA were observed in a choline- and folate-deficient (CFD) mouse model of NAFLD, as well as in hepatocytes treated in vitro with free fatty acids. Analysis of fatty acid composition revealed that alterations were accompanied by an increase in the estimated activity of MUFA generating SCD1 enzyme and an estimated decrease in the activity of PUFA generating FADS1 and FADS2 enzymes. PUFA/MUFA ratios were inversely correlated with lipid accumulation in male and female CC mice fed the HF/HS diet and with morphological markers of hepatic injury in CFD diet-fed mouse model of NAFLD. These results demonstrate that different models of NAFLD are characterized by similar changes in the esterified fatty acid composition and that alterations in PUFA/MUFA ratios may serve as a diagnostic marker for NAFLD severity.