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Control of cellular proliferation is critical to cell viability. The F-box protein Fbw7 (hAgo/hCdc4/FBXW7) functions as a specificity factor for the Skp1-Cul1-F-box protein (SCF) ubiquitin ligase complex and targets several proteins required for cellular proliferation for ubiquitin-mediated destruction. Fbw7 exists as three splice variants but the mechanistic role of each is not entirely clear. We examined the regulation of the Fbw7-γ isoform, which has been implicated in the degradation of c-Myc. We show here that Fbw7-γ is an unstable protein and that its turnover is proteasome-dependent in transformed cells. Using a two-hybrid screen, we identified a novel interaction partner, SLP-1, which binds the N-terminal domain of Fbw7-γ. Overexpression of SLP-1 inhibits the degradation of Fbw7-γ, suggesting that this interaction can happen in vivo. When Fbw7-γ is stabilized by overexpression of SLP-1, c-Myc protein abundance decreases, suggesting that the SCF(Fbw7-γ) complex maintains activity. We demonstrate that Cdk2 also binds the N-terminal domain of Fbw7-γ as well as SLP-1. Interestingly, co-expression of Cdk2 and SLP-1 does not inhibit Fbw7-γ degradation, suggesting that Cdk2 and SLP-1 may have opposing functions.

Identification of Different MRI Atrophy Progression Trajectories in Epilepsy by Subtype and Stage Inference Xiao F, Caciagli L, Wandschneider B, Sone D, Young AL, Vos SB, Winston GP, Zhang Y, Liu W, An D, Kanber B, Zhou D, Sander JW, Thom M, Duncan JS, Alexander DC, Galovic M, Koepp MJ. Brain. 2023;146(11):4702-4716. doi:10.1093/brain/awad284 Artificial intelligence (AI)-based tools are widely employed, but their use for diagnosis and prognosis of neurological disorders is still evolving. Here we analyse a cross-sectional multicentre structural MRI dataset of 696 people with epilepsy and 118 control subjects. We use an innovative machine-learning algorithm, Subtype and Stage Inference, to develop a novel data-driven disease taxonomy, whereby epilepsy subtypes correspond to distinct patterns of spatiotemporal progression of brain atrophy. In a discovery cohort of 814 individuals, we identify two subtypes common to focal and idiopathic generalized epilepsies, characterized by progression of grey matter atrophy driven by the cortex or the basal ganglia. A third subtype, only detected in focal epilepsies, was characterized by hippocampal atrophy. We corroborate external validity via an independent cohort of 254 people and confirm that the basal ganglia subtype is associated with the most severe epilepsy. Our findings suggest fundamental processes underlying the progression of epilepsy-related brain atrophy. We deliver a novel MRI- and AI-guided epilepsy taxonomy, which could be used for individualized prognostics and targeted therapeutics. [ABSTRACT FROM AUTHOR]

Aims: There are similarities in the pathogenesis of cardiac remodelling and dysfunction in heart failure with preserved ejection fraction (HFpEF) and coarctation of aorta (COA). We hypothesized that clinical HFpEF would be highly prevalent in adults with COA, and that the presence of HFpEF would increase the risk of mortality in this population. The aim of this study was to define the clinical features, haemodynamics, and prognostic implications of HFpEF in COA., Methods and Results: Consecutive adults with repaired COA that underwent right heart catheterization were identified retrospectively. HFpEF was defined as heart failure symptoms (exertional dyspnoea or fatigue), preserved left ventricular ejection fraction ≥50%, and pulmonary artery wedge pressure at rest >15 mmHg. Of 99 COA patients, 32 (32%) had HFpEF. The correlates of HFpEF were obesity (adjusted odds ratio [OR] 4.15, 95% confidence interval [CI] 1.31-13.2), atrial fibrillation (adjusted OR 3.13, 95% CI 1.00-10.7), total arterial compliance index (adjusted OR 0.12, 95% CI 0.06-0.41 per 1 ml/mmHg*m 2 ), and pulmonary artery compliance index (adjusted OR 0.36, 95% CI 0.15-0.56 per 1 ml/mmHg*m 2 ). Of 99 patients, 24 (24%) died and 5 (5%) underwent heart transplant. The 10-year cumulative incidence of death/transplant was higher in COA patients with HFpEF compared with patients without HFpEF (39% vs. 12%, p = 0.001). The presence of HFpEF was associated with increased risk of death/transplant (adjusted hazard ratio 1.68, 95% CI 1.16-3.11)., Conclusions: Heart failure with preserved ejection fraction is common in adults with COA and is associated with greater risk of death/transplant, emphasizing a pressing need for interventions to prevent and treat HFpEF in COA., (© 2024 European Society of Cardiology.)

A large British family was identified with 12 affected individuals that manifested a variety of childhood onset epilepsies. The phenotype in this family included absences, myoclonus, frontal lobe epilepsy and [...]

Aims: Surgical site infection (SSI) after soft-tissue sarcoma (STS) resection is a serious complication. The purpose of this retrospective study was to investigate the risk factors for SSI after STS resection, and to develop a nomogram that allows patient-specific risk assessment., Methods: A total of 547 patients with STS who underwent tumour resection between 2005 and 2021 were divided into a development cohort and a validation cohort. In the development cohort of 402 patients, the least absolute shrinkage and selection operator (LASSO) regression model was used to screen possible risk factors of SSI. To select risk factors and construct the prediction nomogram, multivariate logistic regression was used. The predictive power of the nomogram was evaluated by receiver operating curve (ROC) analysis in the validation cohort of 145 patients., Results: LASSO regression analysis selected possible risk factors for SSI, including age, diabetes, operating time, skin graft or flap, resected tumour size, smoking, and radiation therapy. Multivariate analysis revealed that age, diabetes, smoking during the previous year, operating time, and radiation therapy were independent risk factors for SSI. A nomogram was developed based on the results of multivariate logistic regression analysis. In the development cohort, the incidence of SSI was 4.5% in the low-risk group (risk score < 6.89) and 26.6% in the high-risk group (risk score ≥ 6.89; p < 0.001). In the validation cohort, the incidence of SSI was 2.0% in the low-risk group and 15.9% in the high-risk group (p = 0.004)., Conclusion: Our nomogram will enable surgeons to assess the risk of SSI in patients with STS. In patients with high risk of SSI, frequent monitoring and aggressive interventions should be considered to prevent this., Competing Interests: S. Miwa reports grants (Grant-in-Aid for Scientific Research), paid to Graduate School of Medical Sciences, Kanazawa University, from the Japan Society for the Promotion of Science, related to this study., (© 2024 The British Editorial Society of Bone & Joint Surgery.)

Using longitudinal surveys on married Singaporean women of childbearing ages, we compared self-reported changes to fertility plans among 407 and 345 respondents after the 2016–2017 Zika and 2020 COVID-19 outbreaks, respectively. Zika associated with intentions to delay but not reduce childbearing, while COVID-19 was associated with both. Some women reported accelerating and increasing childbearing during COVID-19, with more intending to bring forward births as the pandemic persisted. Education was more predictive of changes in fertility plans during the pandemic compared to the Zika epidemic, and women who delayed childbearing due to Zika were more likely to further adjust timing of childbearing during COVID-19. We considered three possible explanations for changes to fertility plans: fear of infection, change in subjective wellbeing, and income loss, and find stronger effects of perceptions of the virus on downward revisions of fertility plans after the Zika epidemic but a larger role for stress and income loss during the pandemic, reflecting the latter's wider economic and social impacts. [ABSTRACT FROM AUTHOR]

Background: Steroid-induced osteonecrosis of the femoral head (SONFH) is a challenging and debilitating orthopedic condition with a rising incidence in recent years. Shuanghe Decoction (SHD), a traditional Chinese medicine formula, has shown significant efficacy in treating SONFH, though its underlying mechanisms remain unclear. Purpose: This study aims to elucidate the therapeutic effects and potential mechanisms of SHD on SONFH through in vivo experiments, combined with network pharmacology, metabolomics, and gut microbiota analysis. Materials and methods: Forty male Sprague-Dawley rats (300 ± 20 g) were randomly assigned to four groups: Control, Model, SHD-L, and SHD-H, with 10 rats each. SONFH was induced in all groups except the Control group using lipopolysaccharide and methylprednisolone. The SHD-L and SHD-H groups were treated with Shuanghe decoction at doses of 4.86 g/kg/day and 9.72 g/kg/day, respectively, for eight weeks. Bone morphology, pathological changes, and osteogenic factors were evaluated using Micro-CT, histological staining, and immunohistochemistry. Network pharmacology, metabolomics, and gut microbiota analyses were conducted to explore SHD's mechanisms. Results: SHD improved bone morphology and increased osteogenic factor expression (RUNX2, OCN, COL-I). Network pharmacology indicated that metabolic pathways play a key role in SHD's therapeutic effects. Metabolomic analysis identified 14 differential metabolites, including 21-hydroxypregnenolone and tyramine, which were restored to normal levels by SHD. Gut microbiota analysis revealed that SHD modulated bacterial abundance, particularly Verrucomicrobia, Allobaculum, and Burkholderiales. A comprehensive network identified two key metabolites (tyramine, 21-hydroxypregnenolone), seven targets (CYP19A1, CYP1A2, CYP1B1, CYP2C9, CYP3A4, MIF, and HSD11B1), two metabolic pathways (tyrosine metabolism, steroid hormone biosynthesis), and four bacterial taxa (Jeotgalicoccus, Clostridium, Corynebacterium, rc4-4) as central to SHD against SONFH. Conclusion: SHD alleviates SONFH by reshaping gut microbiota, reversing metabolic imbalances, and enhancing osteogenesis. Our findings provide novel insights into the pharmacological mechanisms of SHD, laying a foundation for its clinical application in treating SONFH. [ABSTRACT FROM AUTHOR]

Background/Objectives: Pre-operative radiation (Pre-RT) decreases local recurrence following soft tissue sarcoma (STS) resection but carries the risk of wound healing complications (WHCs). This study evaluated skin specimens and clinical characteristics of STS patients to (1) compare patients with and without Pre-RT, (2) compare Pre-RT patients with and without WHCs, and (3) explore associations between clinical characteristics and WHCs. Methods: This retrospective study included 54 adults who underwent STS resection with primary closure (Pre-RT n = 30). A pathologist who was blinded to the clinical outcomes evaluated the skin specimens microscopically. Results: Irradiated skin had lower vessel density and was more likely to lack hair follicles and sebaceous glands, consistent with the effects of radiation. Irradiated skin was also more likely to include plasma cells. Irradiated skin demonstrated higher mean TAZ H-scores; however, within the Pre-RT subset, those patients who developed WHCs demonstrated comparatively lower TAZ. Conclusions: This novel finding may suggest that higher TAZ in irradiated skin reflects a response to injury but that comparatively lower TAZ in irradiated skin might contribute to WHCs. Future studies should consider more focused evaluation of TAZ in STS resections with Pre-RT as they may help to predict WHCs when used in combination with other histologic factors and could suggest a therapeutic target. [ABSTRACT FROM AUTHOR]

Osteoporosis is an inflammatory disease characterised by low bone mass and quality, resulting in weaker bone strength and fragility fractures. Periostin is a matricellular protein expressed in the periosteum of bone by osteoblasts. It regulates cell recruitment and differentiation in response to fracture and contributes to extracellular matrix (ECM) formation. The aim of the following study was to determine the splice variants of Periostin expressed in human osteoblasts and Periostin's function in the pathophysiology of osteoporosis. Osteoblasts isolated from femoral heads from 29 patients with or without osteoporosis were utilised. Periostin splice variants were compared by quantitative real-time polymerase chain reaction (qPCR). Furthermore, the effect of Periostin inhibition on osteoblast differentiation was investigated using alizarin red S staining. Lastly, the interaction of IL-6 and Periostin and their effect on osteoprotegerin (OPG) secretion were analysed with the implantation of enzyme-linked immunosorbent assays (ELISAs). It could be demonstrated that human osteoblasts preferentially express Periostin isoform 4, even if splice variant expression was not altered in osteoporosis conditions, indicating that Periostin's functions in bone are primarily attributable to this isoform. The inhibition of Periostin resulted in significantly reduced osteoblast differentiation. However, Periostin was secreted in significantly higher amounts in osteoblasts from patients with osteoporosis. Additionally, Periostin significantly reduces OPG secretion and, thereby, rather promotes bone resorption. Furthermore, it could be determined that Periostin and IL-6 induce each other, and both significantly decrease OPG secretion. A positive feedback loop exacerbates the dysregulation found in human osteoblasts from patients with osteoporosis, thereby contributing to bone loss. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis (OP) frequently occurs in post-menopausal women, increasing the risk of fracture. Early screening OP could improve the prevention of fractures.This study focused on the significance of miR-208a-3p in diagnosing OP and development regulation, aiming to explore a novel biomarker and therapeutic target for OP. Methods: The study enrolled a total of 154 post-menopausal women and grouping was performed based on the incidence of OP and fracture. The significance of miR-208a-3p was evaluated from the perspectives of menopausal correlation, OP diagnosis, and fracture prediction. In mechanism, the regulatory effect and mechanism of miR-208a-3p on osteoclast activation was investigated. Results: miR-208a-3p was menopause-related showing a negative correlation with E2 and positive correlations with FSH and LH. Significant upregulation of miR-208a-3p was observed in post-menopausal women with OP and showed significant diagnostic potential. Increasing miR-208a-3p was positively correlated with bone metabolism markers and negatively correlated with BMD of post-menopausal women with OP. Moreover, miR-208a-3p was also identified as a risk factor for fracture. STC1 was identified as a direct target of miR-208a-3p and was negatively regulated by miR-208a-3p. Silencing miR-208a-3p significantly alleviated macrophage inflammation and osteoblast activation, which was reversed by the knockdown of STC1. Conclusion: Serum miR-208a-3p served as a diagnostic biomarker for OP and a risk factor for fracture in post-menopausal women. miR-208a-3p regulated macrophage inflammation and further mediated osteoclast activation via targeting STC1. [ABSTRACT FROM AUTHOR]

Background: For patients with epilepsy, antiseizure medication remains the primary treatment; however, it is ineffective in approximately 30% of cases. These patients experience progressive neuronal damage and poor outcomes. Therefore, there is an urgent need for disease-modifying therapy (DMT) that targets the pathogenesis of epilepsy. Glycyrrhizin has shown potential as a DMT in epilepsy due to its multiple targets and diverse mechanisms. Previous studies suggest that glycyrrhizin may regulate key processes involved in epilepsy pathogenesis, such as neuroinflammation and cell death, but its effects on pyroptosis have not been reported. Methods: This study employed bioinformatics techniques to identify potential molecular targets for glycyrrhizin in epilepsy treatment and then validated using a kainic acid-induced status epilepticus mouse model. Results: Glycyrrhizin treatment significantly prolonged seizure latency, reduced seizure duration, and alleviated neuronal damage in the status epilepticus mouse model. Molecular experiments indicated that glycyrrhizin may regulate pyroptosis through mediation of the high mobility group box 1 (HMGB1)/Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling pathway. Conclusion: Glycyrrhizin exerts neuroprotective and anticonvulsant effects in epilepsy by regulating pyroptosis via the HMGB1/TLR4/NF-κB signaling pathway, offering novel insights into its potential as a DMT for epilepsy. [ABSTRACT FROM AUTHOR]

Introduction: Neoadjuvant radiotherapy (NART) is often used in the treatment of extremity soft tissue sarcomas (STS) including myxoid liposarcoma (MLS). Postoperative major wound complications (WC) are a well-recognised problem following NART. Aims: A review of the literature regarding the definition and incidence of WC following NART and surgery for STS and a retrospective review of a single surgeon series of 25 MLS. Methods: A literature search for papers focusing on MLS, NART and WC was performed, with 12 papers being reviewed. Retrospective data from a single surgeon series of 25 patients with MLS, treated with NART and surgery, were reviewed, focussing on WC. Results: The average rate of WC from the 12 papers included was 29·4% (20–47%), and the average rate of reoperation was 15·6% (7·3–24%). There were a range of definitions used for WC, most commonly O'Sullivan's definition. In the single surgeon series, two patients (8%) developed WC and were treated conservatively, and there were no reoperations within 120 days. Conclusion: This literature review identified that there was a lack of consistency between the definitions used for major WC. The single surgeon series of MLS showed WC that were lower when compared to the reviewed literature (8% versus 29·4%). [ABSTRACT FROM AUTHOR]

The autonomic regulation of the pulmonary vasculature has been under‐appreciated despite the presence of sympathetic and parasympathetic neural innervation and adrenergic and cholinergic receptors on pulmonary vessels. Recent clinical trials targeting this innervation have demonstrated promising effects in pulmonary hypertension, and in this context of reignited interest, we review autonomic pulmonary vascular regulation, its integration with other pulmonary vascular regulatory mechanisms, systemic homeostatic reflexes and their clinical relevance in pulmonary hypertension. The sympathetic and parasympathetic nervous systems can affect pulmonary vascular tone and pulmonary vascular stiffness. Local afferents in the pulmonary vasculature are activated by elevations in pressure and distension and lead to distinct pulmonary baroreflex responses, including pulmonary vasoconstriction, increased sympathetic outflow, systemic vasoconstriction and increased respiratory drive. Autonomic pulmonary vascular control interacts with, and potentially makes a functional contribution to, systemic homeostatic reflexes, such as the arterial baroreflex. New experimental therapeutic applications, including pulmonary artery denervation, pharmacological cholinergic potentiation, vagal nerve stimulation and carotid baroreflex stimulation, have shown some promise in the treatment of pulmonary hypertension. What is the topic of this review?This review examines our understanding of the autonomic control of pulmonary circulation, with an emphasis on its clinical relevance and potential therapeutic targeting in pulmonary hypertension.What advances does it highlight?The sympathetic and parasympathetic nervous systems both regulate pulmonary vascular tone and stiffness, in integration with systemic autonomic homeostasis. Pulmonary vascular afferents responsive to pulmonary arterial pressure produce distinct pulmonary baroreflex responses. Dysfunction in autonomic control both to and from the pulmonary vasculature might contribute to pulmonary hypertension, and new approaches targeting this have demonstrated early success. [ABSTRACT FROM AUTHOR]

The past two decades have witnessed a wide range of studies investigating genetic variants of voltage‐gated sodium (NaV) channels, which are involved in a broad spectrum of diseases, including several types of epilepsy. We have reviewed here phenotypes and pathological mechanisms of genetic epilepsies caused by variants in NaV α and β subunits, as well as of some relevant interacting proteins (FGF12/FHF1, PRRT2, and Ankyrin‐G). Notably, variants of all these genes can induce either gain‐ or loss‐of‐function of NaV leading to either neuronal hyperexcitability or hypoexcitability. We present the results of functional studies obtained with different experimental models, highlighting that they should be interpreted considering the features of the experimental system used. These systems are models, but they have allowed us to better understand pathophysiological issues, ameliorate diagnostics, orientate genetic counseling, and select/develop therapies within a precision medicine framework. These studies have also allowed us to gain insights into the physiological roles of different NaV channels and of the cells that express them. Overall, our review shows the progress that has been made, but also the need for further studies on aspects that have not yet been clarified. Finally, we conclude by highlighting some significant themes of general interest that can be gleaned from the results of the work of the last two decades. [ABSTRACT FROM AUTHOR]

Background and Objectives: Children with congenital heart diseases (CHDs) have an increased risk of developing neurologic deficits, even in the absence of apparent brain pathology. The aim of this work was to compare quantitative macro- and microstructural properties of subcortical gray matter structures of pediatric CHD patients with normal appearing brain magnetic resonance imaging to healthy controls. Methods: We retrospectively reviewed children with coarctation of the aorta (COA) and hypoplastic left heart syndrome (HLHS) admitted to our hospital. We identified 24 pediatric CHD patients (17 COA, 7 HLHS) with normal-appearing brain MRI. Using an atlas-based approach, the volume and apparent diffusion coefficient (ADC) were determined for the thalamus, caudate, putamen, pallidum, hippocampus, amygdala, nucleus accumbens, cerebral white matter, cerebral cortex, and brainstem. Multivariate statistics were used to compare the extracted values to reference values from 100 typically developing children without any known cardiac or neurological diseases. Results: Multivariate analysis of covariance using the regional ADC and volume values as dependent variables and age and sex as co-variates revealed a significant difference between pediatric CHD patients and healthy controls (p < 0.001). Post-hoc comparisons demonstrated significantly reduced brain volumes in most subcortical brain regions investigated and elevated ADC values in the thalamus for children with CHD. No significant differences were found comparing children with COA and HLHS. Conclusions: Despite normal appearing brain MRI, children with CHD exhibit wide-spread macro-structural and regional micro-structural differences of subcortical brain structures compared to healthy controls, which could negatively impact neurodevelopment, leading to neurological deficits in childhood and beyond. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) is a multifarious syndrome, accounting for over half of heart failure (HF) patients receiving clinical treatment. The prevalence of HFpEF is rapidly increasing in the coming decades as the global population ages. It is becoming clearer that HFpEF has a lot of different causes, which makes it challenging to find effective treatments. Currently, there are no proven treatments for people with deteriorating HF or HFpEF. Although the pathophysiologic foundations of HFpEF are complex, excessive reactive oxygen species (ROS) generation and increased oxidative stress caused by mitochondrial dysfunction seem to play a critical role in the pathogenesis of HFpEF. Emerging evidence from animal models and human myocardial tissues from failed hearts shows that mitochondrial aberrations cause a marked increase in mitochondrial ROS (mtROS) production and oxidative stress. Furthermore, studies have reported that common HF medications like beta blockers, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and mineralocorticoid receptor antagonists indirectly reduce the production of mtROS. Despite the harmful effects of ROS on cardiac remodeling, maintaining mitochondrial homeostasis and cardiac functions requires small amounts of ROS. In this review, we will provide an overview and discussion of the recent findings on mtROS production, its threshold for imbalance, and the subsequent dysfunction that leads to related cardiac and systemic phenotypes in the context of HFpEF. We will also focus on newly discovered cellular and molecular mechanisms underlying ROS dysregulation, current therapeutic options, and future perspectives for treating HFpEF by targeting mtROS and the associated signal molecules. [ABSTRACT FROM AUTHOR]

Introduction: Surgical site infections (SSI) are one of the most common complications after extensive sarcoma resections and represent a daily challenge. SSI occur in up to 50% of cases particularly in the peripelvic area. One possible approach to reduce infection rate is perioperative antibiotic prophylaxis. The aim of this study therefore was to investigate the influence of perioperative antibiotic prophylaxis on the infection rate and the possible influence of location-specific antibiotic prophylaxis with ampicillin/sulbactam. Methods: This monocentric retrospective study included 366 patients who underwent sarcoma resections in the groin, proximal thigh, or gluteal region. All patients were operated on by 2 surgeons after neoadjuvant pretreatment if necessary. 3 groups of patients were defined. Group 1: In 60.4% of all cases, antibiotic prophylaxis was administered with cephalosporins (also clindamycin in case of penicillin allergy). Group2: In 9.8% of cases, ampicillin/sulbactam was used. Group 3: 29.8% of patients did not receive any antibiotic prophylaxis. Results: In 31.1% of treated cases, antibiotic therapy was prolonged due to extended tumor resections. Postoperative infections occurred in 23.2% (85 cases), in 77 cases within the first 90 days (on average after 20 days). The median operating time, blood loss was higher, and tumor size were significantly larger in cases with infections, compared to patients without infection. In group 1 and 2 with perioperative single-shot prophylaxis, infection occurred in 24.1% of cases, compared to 13.5% of cases without prophylaxis (group 3) (p= 0.032). In the patients with prolonged antibiotic therapy, infection occurred in 31.6% of cases, compared to 16.3% of cases without prolongation (p< 0.001). In the group 2, infection occurred in 19.4% of cases compared to 24.9% of cases in the group 1 (p= 0.479). In the multivariate analysis, surgery time longer 80 min, blood substitution, neoadjuvant radio- and chemotherapy proved to be a risk factor for SSI. Discussion: Region adapted perioperative antibiotic prophylaxis may reduce the risk of infection after extended sarcoma resection in the peripelvic area. However, the particular bacterial spectrum of this anatomic region should be taken into account when deciding which antibiotics to use. [ABSTRACT FROM AUTHOR]

Regulated cell cycle progression ensures homeostasis and prevents cancer. In proliferating cells, premature S phase entry is avoided by the E3 ubiquitin ligase anaphasepromoting complex/cyclosome (APC/C), although the APC/C substrates whose degradation restrains G1 -S progression are not fully known. The APC/C is also active in arrested cells that exited the cell cycle, but it is not clear whether APC/C maintains all types of arrest. Here, by expressing the APC/C inhibitor, EMI1, we show that APC/C activity is essential to prevent S phase entry in cells arrested by pharmacological cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition (Palbociclib). Thus, active protein degradation is required for arrest alongside repressed cell cycle gene expression. The mechanism of rapid and robust arrest bypass from inhibiting APC/C involves CDKs acting in an atypical order to inactivate retinoblastoma-mediated E2F repression. Inactivating APC/C first causes mitotic cyclin B accumulation which then promotes cyclin A expression. We propose that cyclin A is the key substrate for maintaining arrest because APC/C-resistant cyclin A, but not cyclin B, is sufficient to induce S phase entry. Cells bypassing arrest from CDK4/6 inhibition initiate DNA replication with severely reduced origin licensing. The simultaneous accumulation of S phase licensing inhibitors, such as cyclin A and geminin, with G1 licensing activators disrupts the normal order of G1-S progression. As a result, DNA synthesis and cell proliferation are profoundly impaired. Our findings predict that cancers with elevated EMI1 expression will tend to escape CDK4/6 inhibition into a premature, underlicensed S phase and suffer enhanced genome instability. [ABSTRACT FROM AUTHOR]

Objective: Pediatric epilepsy surgery effectively controls seizures but may risk cognitive, language, or memory decline. Historically, the intra-carotid anesthetic procedure (IAP or Wada Test) was pivotal for language and memory function. However, advancements in noninvasive mapping, notably functional magnetic resonance imaging (fMRI), have transformed clinical practice, reducing IAP's role in presurgical evaluations. Method: We conducted a critical narrative review on mapping technologies, including factors to consider for discordance. Results: Neuropsychological findings suggest that if pre-surgery function remains intact and the surgery targets the eloquent cortex, there is a high chance for decline. Memory and language decline are particularly pronounced post-left anterior temporal lobe resection (ATL), making presurgical cognitive assessment crucial for predicting postoperative outcomes. However, the risk of functional decline is not always clear – particularly with higher rates of atypical organization in pediatric epilepsy patients and discordant findings from cognitive mapping. We found little research to date on the use of IAP and other newer technologies for lateralization/localization in pediatric epilepsy. Based on this review, we introduce an IAP decision tree to systematically navigate discordance in IAP decisions for epilepsy presurgical workup. Conclusions: Future research should be aimed at pediatric populations to improve the precision of functional mapping, determine which methods predict post-surgical deficits and then create evidence-based practice guidelines to standardize mapping procedures. Explicit directives are needed for resolving conflicts between developing mapping procedures and established clinical measures. The proposed decision tree is the first step to standardize when to consider IAP or invasive mapping, in coordination with the multidisciplinary epilepsy surgical team. [ABSTRACT FROM AUTHOR]

Excising epileptic foci (EF) is the most efficient approach for treating drug-resistant epilepsy (DRE). However, owing to the vast heterogeneity of epilepsies, EF in one-third of patients cannot be accurately located, even after exhausting all current diagnostic strategies. Therefore, identifying biomarkers that truly represent the status of epilepsy and fabricating probes with high targeting specificity are prerequisites for identifying the "concealed" EF. However, no systematic summary of this topic has been published. Herein, the potential biomarkers of EF are first summarized and classified into three categories: functional, molecular, and structural aberrances during epileptogenesis, a procedure of nonepileptic brain biasing toward epileptic tissue. The materials used to fabricate these imaging probes and their performance in defining the EF in preclinical and clinical studies are highlighted. Finally, perspectives for developing the next generation of probes and their challenges in clinical translation are discussed. In general, this review can be helpful in guiding the development of imaging probes defining EF with improved accuracy and holds promise for increasing the number of DRE patients who are eligible for surgical intervention., (© 2022 Wiley-VCH GmbH.)

Purpose of Review: Chronic axial spinal pain is a leading cause of disability and healthcare spending in the United States. A common source of axial spinal pain is the facet joint. Current treatments for facet joint-mediated pain include conservative treatments and interventions such as intra-articular facet joint injections (FJI), medial branch blocks (MBB), and radiofrequency ablation (RFA). While facet joint interventions are one of the most common spinal procedures, current scientific literature demonstrates conflicting results regarding the use of corticosteroids in these interventions., Recent Findings: A systematic review was conducted to determine the efficacy of local corticosteroid usage in facet joint interventions for treating chronic axial spinal pain. Separate literature searches were performed using PubMed, Google Scholar, Embase, and Cochrane Library to evaluate the use of local corticosteroids in intra-articular FJI, MBB, and for the prevention of post-neurotomy neuritis (PNN). Inclusion criteria included a randomized clinical trial (RCT) or control trial while unique inclusion criteria was used for the differing uses of local corticosteroids. The exclusion criteria for studies included (i) studies written in a non-English language; (ii) articles without full-text access or abstract-only papers; (iii) and studies focused on non-human subjects. Final literature searches were conducted in August 2024. Two studies with 131 patients, four studies with 440 patients, and two studies with 203 patients were selected for the assessment of local corticosteroid use on intra-articular FJI, MBB, and PNN, respectively. A quality assessment tool recommended by The Cochrane Collaboration was used to assess bias risk in included studies. Results were synthesized through a meta-analysis to evaluate intra-articular FJI while a literature analysis was completed to investigate MBB and PNN. This study found that the use of corticosteroid intra-articular FJI and MBB provides significant improvement in pain relief and functionality from baseline for the treatment of lower back pain and chronic axial spinal pain, respectively. However, the use of corticosteroids post-RFA has not been proven to reduce the occurrence of PNN. Limitations to the studies used included blinding bias, absence of placebo groups, subjective inclusion criteria, limited generalizability and small sample sizes., Competing Interests: Declarations. Ethics Approval: This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. Competing interests: ADK is the Editor-in-chief of CPHRs. Human and Animal Rights and Informed Consent: This article does not contain any studies with human or animal subjects performed by any of the authors., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Heart failure (HF) with preserved ejection fraction (HFpEF) is a complex syndrome characterized by symptoms of HF despite normal left ventricular function. It now accounts for >50% of all HF cases, with the only effective treatment (morbidity benefit) so far being sodium-glucose co-transporter-2 inhibitors, finerenone and tirzepatide. Recently, vascular dysfunction has been highlighted as one of the main pathophysiological mechanisms of HFpEF. Recently, a 'two-hit' experimental model of HFpEF was described in which mice fed a high-fat diet (HFD) and l-NAME developed a phenotype that mimics human HFpEF. We further characterize this model by assessing vascular remodelling in the aorta, carotid and femoral arteries. C57BL/6N mice aged 11-12 weeks were fed a HFD and water supplemented with l-NAME 1.5 g/L for 15 weeks. These mice manifested increased body weight and blood pressure, glucose and exercise intolerance, and cardiac structural and functional alterations consistent with HFpEF. Morphometric analyses were performed in the aorta, carotid and femoral arteries, revealing increased media thickness and media-to-lumen ratios. Moreover, we detected evidence of fibrosis in the middle layer of the aorta. A correlation between increased aortic remodelling and fibrosis with diastolic dysfunction was observed. Vascular reactivity studies using wire myography uncovered impaired vasoconstriction and vasodilatation responses, suggesting aortic stiffness. We also detected the presence of a senescence-like phenotype in the aortic wall. Together, these data offer valuable contributions to understanding the vascular mechanisms underlying HFpEF. KEY POINTS: Heart failure with preserved ejection fraction (HFpEF) represents >50% of heart failure patients. Despite its growing prevalence, the aetiology of HFpEF continues to be incompletely understood, mainly due to the lack of reliable animal models. An HFpEF mouse model, obtained by feeding mice a high-fat diet and exposing them to l-NAME, reproduces the majority of the clinical features observed in HFpEF patients. Possible vascular alterations elicited by this model remain unknown. Here, we report that HFpEF mice manifest aortic, carotid and femoral artery remodelling. The aorta also harboured fibrosis plus impaired vasodilatation and vasoconstriction responses. Aortic remodelling and fibrosis correlated with diastolic dysfunction. The aorta from HFpEF mice harboured increased p53, IL-6 and VCAM-1 protein levels, suggesting a senescence-like phenotype. These data reveal that this HFpEF mouse model displays vascular alterations similar to those reported in HFpEF patients. These findings unveil novel insights into the vascular remodelling of HFpEF and, furthermore, validate a reliable animal model that can be used to study HFpEF aetiology and potentially develop future therapeutic approaches., (© 2025 The Authors. The Journal of Physiology © 2025 The Physiological Society.)

Epilepsy which is a chronic neurological disorder is characterized by recurrent seizure poses a significant challenge to healthcare professionals worldwide. Most of antiepileptic drugs have serious side effects that might affect the quality of life such as fatigue, dizziness, weight gain and cognitive impairments. In this context, the search for more effective and potential antiepileptic drug candidate has led to a growing interest in the field of synthesis of heterocyclic compounds. This review will focus on the utilization of heterocyclic moieties including imidazole, indole, thiazole, triazine, quinazoline and oxazole which show remarkable anticonvulsant properties. Furthermore, the exploration of various methodologies for the synthesis of heterocyclic anticonvulsant drugs such as green methodologies and microwave assisted protocols have contributed to the development of environment friendly, more efficient and potential approaches. The review will distinguish from previous ones by specifically focusing on innovative synthetic methodologies, including greener methodologies and micro-assisted techniques, that contribute to eco-friendly and environment benign approaches during 2019-2024. In addition to this, the review will focus on the Structure Activity Relationship (SAR) studies of heterocyclic compounds in order to offer insight into the design of next generation antiepileptic drugs with improved efficacy and reduced side effects., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Proteasomes are the catalytic complexes in eukaryotic cells that decide the fate of proteins involved in various cellular processes in an energy-dependent manner. The proteasomal system performs its function by selectively destroying the proteins labelled with the small protein ubiquitin. Dysfunctional proteasomal activity is allegedly involved in various clinical disorders such as cancer, neurodegenerative disorders, ageing, and so forth, making it an important therapeutic target. Notably, compared to healthy cells, cancer cells have a higher protein homeostasis requirement and a faster protein turnover rate. The ubiquitin-proteasome system (UPS) helps cancer cells increase rapidly and experience less apoptotic cell death. Therefore, understanding UPS is essential to design and discover some effective inhibitors for cancer therapy. Hereby, we have focused on the role of the 26S proteasome complex, mainly the UPS, in carcinogenesis and seeking potential therapeutic targets in treating numerous cancers., (© 2025 Wiley Periodicals LLC.)

On behalf of the SNS, we are pleased to present the Abstracts of the Annual Meeting which is held at the Congress Center in Basel, Switzerland, from 6–7 June 2024. In total, 83 abstracts were selected, whereof we include 8 abstracts for the Plenary Sessions, 6 abstracts for the SAYN GemSession, 30 abstracts for Poster flash presentations, and 39 abstracts as ePosters. We congratulate all the presenters on their research work and contributions. [ABSTRACT FROM AUTHOR]

ATP-binding cassette (ABC) transporters play a crucial role for the efflux of a wide range of substrates across different cellular membranes. In the central nervous system (CNS), ABC transporters have recently gathered significant attention due to their pivotal involvement in brain physiology and neurodegenerative disorders, such as Alzheimer's disease (AD). Glial cells are fundamental for normal CNS function and engage with several ABC transporters in different ways. Here, we specifically highlight ABC transporters involved in the maintenance of brain homeostasis and their implications in its metabolic regulation. We also show new aspects related to ABC transporter function found in less recognized diseases, such as Huntington's disease (HD) and experimental autoimmune encephalomyelitis (EAE), as a model for multiple sclerosis (MS). Understanding both their impact on the physiological regulation of the CNS and their roles in brain diseases holds promise for uncovering new therapeutic options. Further investigations and preclinical studies are warranted to elucidate the complex interplay between glial ABC transporters and physiological brain functions, potentially leading to effective therapeutic interventions also for rare CNS disorders. [ABSTRACT FROM AUTHOR]

Background: Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have a higher risk of osteoporosis/fractures; however, the causal relationship remains unclear. Methods: Publicly available genome‐wide association studies (GWASs) were used for Mendelian randomization (MR) analysis. GWASs of NAFLD and fractures were obtained from the FinnGen Consortium. GWASs of bone mineral density (BMD) were derived from a meta‐analysis. GWASs of obesity, diabetes, liver function, and serum lipid‐related metrics were used to clarify whether the accompanying NAFLD symptoms contributed to fractures. Moreover, two additional GWASs of NAFLD were applied. Results: A causal association was not observed between NAFLD and BMD using GWASs from the FinnGen Consortium. However, a causal relationship between NAFLD and femoral neck‐BMD (FN‐BMD), a suggestive relationship between fibrosis and FN‐BMD, and between NAFLD and osteoporosis were identified in replication GWASs. Genetically proxied body mass index (BMI), high‐density lipoprotein (HDL), and hip circumference increased the likelihood of lower limb fractures. The waist‐to‐hip ratio decreased, whereas glycated hemoglobin (HbA1C) and homeostasis model assessment of β‐cell function (HOMA‐B) increased the risk of forearm fractures. Low‐density lipoprotein (LDL) reduced, whereas HbA1C increased the incidence of femoral fractures. Alkaline phosphatase (ALP) raised the risk of foot fractures. However, after a multivariate MR analysis (adjusted for BMI), all the relationships became insignificant. Conclusions: NAFLD caused reduced BMD, and genetically predicted HDL, LDL, HbA1C, HOMA‐B, ALP, hip circumference, and waist‐to‐hip ratio causally increased the risk of fractures. BMI may mediate causal relationships. Larger GWASs are required to verify this finding. [ABSTRACT FROM AUTHOR]

Objectives: Osteoprotegerin (OPG) is a member of the tumor necrosis factor receptor family involved in processes in many inflammatory states. OPG concentration is enhanced in the majority of chronic kidney disease (CKD) patients and those undergoing renal replacement therapy. The aim of the study was to assess the relation of OPG and chronic inflammation in peritoneal dialysis (PD) patients and to evaluate whether OPG concentrations in plasma and dialysate were related to plasma and dialysate levels of proinflammatory mediators (interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP), interleukin 33 (IL-33) and interleukin 1 receptor-like 1IL-1RL1 (IL-1RL1, sST2)). Methods: The study included 37 patients of the Peritoneal Dialysis Center, Department of Nephrology, Transplantology and Internal Medicine, Szczecin, Poland, 4–6 weeks after the onset of peritoneal dialysis therapy. During a peritoneal equilibration test, plasma (at 2 h) and dialysate (at 4 h) OPG, IL-33, 1IL-1RL1 (sST2), IL-6 and hsCRP concentrations were determined. Results: Plasma concentration of OPG did not correlate with dialysate OPG level (Rs = 0.04, p = 0.8). There was a strong positive correlation between plasma OPG concentrations and plasma IL-1RL1 (sST2) (Rs = 0.41; p = 0.01), plasma IL-6 (Rs = 0.38; p = 0.01) and plasma hsCRP (Rs = 0.35; p = 0.02). Dialysate OPG concentrations were positively associated with dialysate IL-1RL1 (sST2) (Rs = 0.37; p = 0.02) and dialysate IL-6 levels (Rs = 0.44; p = 0.005). Multivariate analysis showed that higher IL-1RL1 (sST2) (ß = +0.38, p = 0.006), higher plasma hsCRP (ß = +0.32, p = 0.02) and older age (ß = +0.35, p = 0.01) were independent determinants of higher plasma OPG concentration and that higher concentrations of dialysate IL-6 (ß = +0.37, p = 0.02) were independent determinants of higher dialysate OPG concentration. Conclusions: Both plasma and dialysate OPG levels are associated with the severity of systemic and local inflammation illustrated by the plasma and dialysate concentrations of IL-1RL1 (sST2), hsCRP and IL-6, suggesting that OPG might have a pivotal role in explaining the milieu of systemic and intraperitoneal inflammation. [ABSTRACT FROM AUTHOR]

Objective: To explore the changes of a series of cytokines before and after percutaneous balloon kyphoplasty (PKP) and prognostic markers for response to PKP. Methods: From 1 January 2019 to 31 May 2019, all single-level lumbar osteoporotic vertebral compression fracture (OVCF) patients diagnosed by MRI who matched the inclusion and exclusion criteria were enrolled in this study. They were classified into the effective group and the ineffective group based on the outcome after PKP. The levels of a series of inflammatory factors and indices of spinal functions were obtained before and after PKP. Results: A total of 72 patients were included in this study, 59 in the effective group and 13 in the ineffective group. The anterior height (AH) and posterior height (PH) were 77.3 ± 11.2% and 91.2 ± 9.3%, respectively, in the effective group after PKP, which were higher than that in the ineffective group (p<.001). While, the Kyphotic angle, visual analog scale (VAS), and Oswestry Disability Index (ODI) score were 9.1 ± 4.3°, 3.1 ± 1.9, and 19.2 ± 4.1 in the effective group, which was lower than that in ineffective group (p<.001). The serum levels of IL-1β, IL-6, and TNF-α were found significantly decreased after treatment in the effective group (p<.05). The logistic regression showed that the levels of IL-6 TNF-α and AH were significant predictor of outcome. Conclusions: Our results demonstrated that PKP can reduce the serum levels of IL-6, IL-1β, and TNF-α, moreover, the IL-6, TNF-α, and AH were significant predictors of outcome. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) accounts for over 50% of all heart failure cases nationwide and continues to rise in its prevalence. The complex, multi‐organ involvement of the HFpEF clinical syndrome requires clinicians and investigators to adopt an integrative approach that considers the contribution of both cardiac and non‐cardiac function to HFpEF pathophysiology. Thus, this symposium review outlines the key points from presentations covering the contributions of disease‐related changes in cardiac function, arterial stiffness, peripheral vascular function, and oxygen delivery and utilization to exercise tolerance in patients with HFpEF. While many aspects of HFpEF pathophysiology remain poorly understood, there is accumulating evidence for a decline in vascular health in this patient group that may be remediable through pharmacological and lifestyle interventions and could improve outcomes and clinical status in this ever‐growing patient population. What is the topic of this review?This symposium review provides an integrative view of how disease‐related changes in cardiac, vascular and skeletal muscle function contribute to exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF).What advances does it highlight?Emerging evidence continues to highlight the importance of considering both cardiac and non‐cardiac abnormalities in patients with HFpEF, with accumulating evidence for 'plasticity' in vascular function that emphasizes the need for a greater focus on strategies targeting the peripheral circulation as a means to improve exercise intolerance. [ABSTRACT FROM AUTHOR]

Background: Wound healing after resection of large soft-tissue tumors is often impaired by large dead space and fluid collection. Recently, the authors were able to show an association of wound complications with worse oncologic outcome in soft-tissue sarcomas. The aim of the study was to examine the value of closed-incision negative pressure wound therapy on postoperative wound drainage and wound complications after soft-tissue tumor resection., Methods: Patients for whom resection is planned of a soft-tissue tumor larger than 10 cm in diameter of the extremities or the trunk were allocated randomly to one of two groups. After wound closure, patients in the study group received closed-incision negative-pressure wound therapy for a duration of 5 days, whereas those in the control group received regular dressings. The amount of drainage fluid, course of wound healing, length of hospital stay, and wound edge perfusion at postoperative day 5 measured by white-light infrared spectroscopy were compared., Results: Sixty patients could be included in the study with even distribution to both study arms, meeting the goal. The postoperative course of wound drainage volume was significantly lower in the study group, and hospital stay was significantly shorter, with 9.1 ± 3.8 days versus 13.9 ± 11.8 days. The occurrence of wound complications was significantly lower in the study group on time-to-event analysis (one versus six). Tissue spectroscopy revealed a significantly higher oxygen saturation increase in the wound edge for the study group versus the control group., Conclusion: Closed-incision negative-pressure wound therapy should be considered for patients undergoing resection of large soft-tissue tumors., Clinical Question/level of Evidence: Therapeutic, II., (Copyright © 2022 by the American Society of Plastic Surgeons.)

FBXW7 is an E3 ubiquitin ligase that targets proteins for proteasome-mediated degradation and is mutated in various cancer types. Here, we use CRISPR base editors to introduce different FBXW7 hotspot mutations in human colon organoids. Functionally, FBXW7 mutation reduces EGF dependency of organoid growth by ~10,000-fold. Combined transcriptomic and proteomic analyses revealed increased EGFR protein stability in FBXW7 mutants. Two distinct phosphodegron motifs reside in the cytoplasmic tail of EGFR. Mutations in these phosphodegron motifs occur in human cancer. CRISPR-mediated disruption of the phosphodegron motif at T693 reduced EGFR degradation and EGF growth factor dependency. FBXW7 mutant organoids showed reduced sensitivity to EGFR-MAPK inhibitors. These observations were further strengthened in CRC-derived organoid lines and validated in a cohort of patients treated with panitumumab. Our data imply that FBXW7 mutations reduce EGF dependency by disabling EGFR turnover. [ABSTRACT FROM AUTHOR]

The prevalence of heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of the total heart failure population, and with the aging of the population and the increasing prevalence of hypertension, obesity, and type 2 diabetes (T2DM), the incidence of HFpEF continues to rise and has become the most common subtype of heart failure. Compared with heart failure with reduced ejection fraction, HFpEF has a more complex pathophysiology and is more often associated with hypertension, T2DM, obesity, atrial fibrillation, renal insufficiency, pulmonary hypertension, obstructive sleep apnea, and other comorbidities. HFpEF has generally been considered a syndrome with high phenotypic heterogeneity, and no effective treatments have been shown to reduce mortality to date. Diuretics and comorbidity management are traditional treatments for HFpEF; however, they are mostly empirical due to a lack of clinical evidence in the setting of HFpEF. With the EMPEROR-Preserved and DELIVER results, sodium-glucose cotransporter 2 inhibitors become the first evidence-based therapies to reduce rehospitalization for heart failure. Subgroup analyses of the PARAGON-HF, TOPCAT, and CHARM-Preserved trials suggest that angiotensin receptor-neprilysin inhibitors, spironolactone, and angiotensin II receptor blockers may be beneficial in patients at the lower end of the ejection fraction spectrum. Other potential pharmacotherapies represented by non-steroidal mineralocorticoid receptor antagonists finerenone and antifibrotic agent pirfenidone also hold promise for the treatment of HFpEF. This article intends to review the clinical evidence on current pharmacotherapies of HFpEF, as well as the comorbidities management of atrial fibrillation, hypertension, T2DM, obesity, pulmonary hypertension, renal insufficiency, obstructive sleep apnea, and iron deficiency, to optimize the clinical management of HFpEF. [ABSTRACT FROM AUTHOR]

Aims: We aimed to clarify the extent to which cardiac and peripheral impairments to oxygen delivery and utilization contribute to exercise intolerance and risk for adverse events, and how this relates to diversity and multiplicity in pathophysiologic traits. Methods and results: Individuals with heart failure with preserved ejection fraction (HFpEF) and non‐cardiac dyspnoea (controls) underwent invasive cardiopulmonary exercise testing and clinical follow‐up. Haemodynamics and oxygen transport responses were compared. HFpEF patients were then categorized a priori into previously‐proposed, non‐exclusive descriptive clinical trait phenogroups, including cardiometabolic, pulmonary vascular disease, left atrial myopathy, and vascular stiffening phenogroups based on clinical and haemodynamic profiles to contrast pathophysiology and clinical risk. Overall, patients with HFpEF (n = 643) had impaired cardiac output reserve with exercise (2.3 vs. 2.8 L/min, p = 0.025) and greater reliance on peripheral oxygen extraction augmentation (4.5 vs. 3.8 ml/dl, p < 0.001) compared to dyspnoeic controls (n = 219). Most (94%) patients with HFpEF met criteria for at least one clinical phenogroup, and 67% fulfilled criteria for multiple overlapping phenogroups. There was greater impairment in peripheral limitations in the cardiometabolic group and greater cardiac output limitations and higher pulmonary vascular resistance during exertion in the other phenogroups. Increasing trait multiplicity within a given patient was associated with worse exercise haemodynamics, poorer exercise capacity, lower cardiac output reserve, and greater risk for heart failure hospitalization or death (hazard ratio 1.74, 95% confidence interval 1.08–2.79 for 0–1 vs. ≥2 phenogroup traits present). Conclusions: Though cardiac output response to exercise is limited in patients with HFpEF compared to those with non‐cardiac dyspnoea, the relative contributions of cardiac and peripheral limitations vary with differing numbers and types of clinical phenotypic traits present. Patients fulfilling criteria for greater multiplicity and diversity of HFpEF phenogroup traits have poorer exercise capacity, worsening haemodynamic perturbations, and greater risk for adverse outcome. [ABSTRACT FROM AUTHOR]

Aims Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by multiple cardiac reserve limitations during exercise. Cardiac power output (CPO) is an index of global cardiac performance and can be estimated non-invasively by echocardiography. We hypothesized that CPO reserve during exercise would be associated with impaired cardiovascular reserve, exercise intolerance, and adverse outcomes in HFpEF. Methods and results Exercise stress echocardiography was performed in 425 dyspnoeic patients [217 HFpEF and 208 non-heart failure (HF) controls] to estimate CPO at rest and during exercise. We classified patients with HFpEF based on the median value of changes in CPO from rest to peak exercise (ΔCPO >0.49 W/100 g). Patients with HFpEF and a lower CPO reserve had poorer biventricular systolic function, impaired chronotropic response during exercise, and worse aerobic capacity than controls and those with a higher CPO reserve. During a median follow-up of 358 days, a composite outcome of all-cause mortality or HF events occurred in 30 patients. Patients with a lower CPO reserve had four-fold and nearly 10-fold increased risks of the outcomes compared with those with a higher CPO reserve and controls, respectively [hazard ratio (HR) 4.05, 95% confidence interval (CI) 1.16–10.1, P = 0.003 and HR 9.61, 95% CI 3.58–25.8, P < 0.0001]. We further found that a lower CPO reserve had an incremental prognostic value over the H2FPEF score and exercise duration. In contrast, resting CPO did not predict clinical outcomes in patients with HFpEF. Conclusion A lower CPO reserve was associated with biventricular systolic dysfunction, chronotropic incompetence, exercise intolerance, and adverse outcomes in patients with HFpEF. [ABSTRACT FROM AUTHOR]

Despite remarkable improvements in the management of heart failure (HF), HF remains one of the most rapidly growing cardiovascular condition resulting in a substantial burden on healthcare systems worldwide. In clinical practice, however, a relevant proportion of patients are treated with suboptimal combinations and doses lower than those recommended in the current guidelines. Against this background, it remains important to identify new targets and investigate additional therapeutic options to alleviate symptoms and potentially improve prognosis in HF. Therefore, non‐pharmacological interventions targeting autonomic imbalance in HF have been evaluated. This paper aims to review the physiology, available clinical data, and potential therapeutic role of device‐based neuromodulation in HF. [ABSTRACT FROM AUTHOR]

Background: In tobacco-exposed persons with preserved spirometry (active smoking or secondhand smoke [SHS] exposure), air trapping can identify a subset with worse symptoms and exercise capacity. The physiologic nature of air trapping in the absence of spirometric airflow obstruction remains unclear. The aim of this study was to examine the underlying pathophysiology of air trapping in the context of preserved spirometry and to determine the utility of bronchodilators in SHS tobacco-exposed persons with preserved spirometry and air trapping. Methods: We performed a double-blinded placebo-controlled crossover randomized clinical trial in nonsmoking individuals at risk for COPD due to exposure to occupational SHS who had preserved spirometry and air trapping defined as either a residual volume-to-total lung capacity ratio (RV/TLC) > 0.35 or presence of expiratory flow limitation (EFL, overlap of tidal breathing on maximum expiratory flow-volume loop) on spirometry at rest or during cardiopulmonary exercise testing (CPET). Those with asthma or obesity were excluded. Participants underwent CPET at baseline and after 4-week trials of twice daily inhalation of 180 mcg of albuterol or placebo separated by a 2-week washout period. The primary outcome was peak oxygen consumption (VO2) on CPET. Data was analyzed by both intention-to-treat and per-protocol based on adherence to treatment prescribed. Results: Overall, 42 participants completed the entire study (66 ± 8 years old, 91% female; forced expiratory volume in 1 s [FEV1] = 103 ± 16% predicted; FEV1 to forced vital capacity [FVC] ratio = 0.75 ± 0.05; RV/TLC = 0.39 ± 0.07; 85.7% with EFL). Adherence was high with 87% and 93% of prescribed doses taken in the treatment and placebo arms of the study, respectively (P = 0.349 for comparison between the two arms). There was no significant improvement in the primary or secondary outcomes by intention-to-treat or per-protocol analysis. In per-protocol subgroup analysis of those with RV/TLC > 0.35 and ≥ 90% adherence (n = 27), albuterol caused an improvement in peak VO2 (parameter estimate [95% confidence interval] = 0.108 [0.014, 0.202]; P = 0.037), tidal volume, minute ventilation, dynamic hyperinflation, and oxygen-pulse (all P < 0.05), but no change in symptoms or physical activity. Conclusions: Albuterol may improve exercise capacity in the subgroup of SHS tobacco-exposed persons with preserved spirometry and substantial air trapping. These findings suggest that air trapping in pre-COPD may be related to small airway disease that is not considered significant by spirometric indices of airflow obstruction. Key messages: What is already known on this topic? Many people who have been exposed to tobacco smoke (direct or indirect) but have preserved spirometry show abnormal lung volumes suggestive of presence of air trapping. The physiologic nature of air trapping in the absence of spirometric airflow obstruction remains unclear. What this study adds? Albuterol may improve ventilation and exercise capacity in secondhand tobacco-exposed persons with preserved spirometry and lung volumes suggestive of air trapping. How this study might affect research, practice, or policy? Air trapping in pre-COPD may be related to small airway disease that is not considered significant by spirometric indices of airflow obstruction. Stratification of the tobacco-exposed persons with preserved spirometry by lung volumes and air trapping may help in identifying a subset who do benefit from the use of bronchodilators. [ABSTRACT FROM AUTHOR]

Results of experimental studies have shown that β-aminoisobutyric acid (BAIBA), an exercise-induced myokine-like molecule, is an endogenous negative regulator of fat mass in mice, but it remains unclear whether that is the case in humans, though an enhanced BAIBA concentration in patients receiving sodium–glucose cotransporter 2 inhibitors was found in our recent study. The objective of this study was to analyze the determinants of circulating BAIBA concentration in humans, with focus on the possible link between circulating BAIBA and body composition including fat mass. Data for 188 consecutive patients with heart failure (HF, 64 ± 13 years; 70% male) who received a dual energy X ray absorptiometry (DEXA) scan for assessment of body composition including fat mass index (FMI) and appendicular skeletal muscle mass index (ASMI) were used in this study. Plasma BAIBA concentration in a fasting state after stabilization of HF was determined using ultraperformance liquid chromatography. Plasma BAIBA was detected in 66% of the patients. In simple linear regression analyses of data from patients in whom plasma BAIBA was detected, plasma BAIBA concentration was positively correlated with uric acid and was negatively correlated with body mass index (BMI), estimated glomerular filtration rate (eGFR), FMI, and % body fat. There were no correlations between plasma BAIBA concentration and indexes of muscle mass and bone mass. The results of multiple linear regression analyses showed that FMI and % body fat in addition to BMI, but not ASMI, were independent explanatory factors for plasma BAIBA concentration. In conclusion, plasma BAIBA concentration is inversely correlated with indexes of fat mass, indicating that BAIBA may be a therapeutic target for excessive fat accumulation. [ABSTRACT FROM AUTHOR]

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The use of sulfonium salts in organic synthesis has experienced a dramatic increase during the last years that can arguably be attributed to three main factors; the development of more direct and efficient synthetic methods that make easily available sulfonium reagents of a wide structural variety, their intrinsic thermal stability, which facilitates their structural modification, handling and purification even on large scale, and the recognition that their reactivity resembles that of hypervalent iodine compounds and therefore, they can be used as replacement of such reagents for most of their uses. This renewed interest has led to the improvement of already existing reactions, as well as to the discovery of unprecedented transformations; in particular, by the implementation of photocatalytic protocols. This review aims to summarize the most recent advancements on the area focusing on the work published during and after 2020. The scope of the methods developed will be highlighted and their limitations critically evaluated., (© 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH.)