Predictability of varicocele repair success: preliminary results of a machine learning-based approach.

Varicocele is a prevalent condition in the infertile male population. However, to date, which patients may benefit most from varicocele repair is still a matter of debate. The purpose of this study was to evaluate whether certain preintervention sperm parameters are predictive of successful varicocele repair, defined as an improvement in total motile sperm count (TMSC). We performed a retrospective study on 111 patients with varicocele who had undergone varicocele repair, collected from the Department of Endocrinology, Metabolic Diseases and Nutrition, University of Catania (Catania, Italy), and the Unit of Urology at the Selcuk University School of Medicine (Konya, Türkiye). The predictive analysis was conducted through the use of the Brain Project, an innovative tool that allows a complete and totally unbiased search of mathematical expressions that relate the object of study to the various parameters available. Varicocele repair was considered successful when TMSC increased by at least 50% of the preintervention value. For patients with preintervention TMSC below 5 × 106, improvement was considered clinically relevant when the increase exceeded 50% and the absolute TMSC value was >5 × 106. From the preintervention TMSC alone, we found a model that predicts patients who appear to benefit little from varicocele repair with a sensitivity of 50.0% and a specificity of 81.8%. Varicocele grade and serum follicle-stimulating hormone (FSH) levels did not play a predictive role, but it should be noted that all patients enrolled in this study were selected with intermediate- or high-grade varicocele and normal FSH levels. In conclusion, preintervention TMSC is predictive of the success of varicocele repair in terms of TMSC improvement in patients with intermediate- or high-grade varicoceles and normal FSH levels.

SURgical vs. PERcutaneous ACCESS in Transfemoral Transcatheter Aortic Valve Implantation (SU-PER-ACCESS Study).

Background: The transfemoral (TF) approach is the most common route in TAVI, but it is still associated with a risk of bleeding and vascular complications. The aim of this study was to compare the clinical outcomes between surgical cut-down (SC) and percutaneous (PC) approach. (2) Methods: Between January 2018 and June 2022, 774 patients underwent a transfemoral TAVI procedure. After propensity matching, 323 patients underwent TAVI in each group. (3) Results: In the matched population, 15 patients (4.6%) in the SC group vs. 34 patients in the PC group (11%) experienced minor vascular complications (p = 0.02), while no difference for major vascular complication (1.5% vs. 1.9%) were reported. The rate of minor bleeding events was higher in the percutaneous group (11% vs. 3.1%, p <.001). The SC group experienced a higher rate of non-vascular-related access complications (minor 8% vs. 1.2%; major 2.2% vs. 1.2%; p < 0.001). (4) Conclusions: SC for TF-TAVI did not alter the mortality rate at 30 days and was associated with reduced minor vascular complication and bleeding. PC showed a lower rate of non-vascular-related access complications and a lower length of stay. The specific approach should be tailored to the patient's clinical characteristics.

Appendicular Skeletal Muscle Mass in Older Adults Can Be Estimated With a Simple Equation Using a Few Zero-Cost Variables.

BACKGROUND AND PURPOSE: Assessing appendicular skeletal muscle (ASM) mass is crucial for the diagnosis of numerous pathologies related to the decline of muscle mass in old age, such as sarcopenia, malnutrition, or cachexia. The dual-energy X-ray absorptiometer (DEXA) radiological technique, which is the gold standard for its assessment, is particularly costly and not routinely used in clinical practice. The aim of this study was to derive computationally simple equations capable of estimating the DEXA-measured ASM at zero cost in older adult populations. METHODS: We used the cross-sectional data collected by the National Health and Nutrition Examination Survey (NHANES) over 7 years (1999-2006). The study sample included 16,477 individuals aged 18 years and over, of which 4401 were over 60 years old. We considered 38 nonlaboratory variables. For the derivation of the equations, we employed the Brain Project, an innovative artificial intelligence tool that combines genetic programming and neural networks. The approach searches simultaneously for the mathematical expression and the variables to use in the equation. The derived equations are useful to estimate the DEXA-measured ASM. RESULTS AND DISCUSSION: A simple equation that includes the body weight of the patient as the sole variable can estimate the outcome of DEXA with an accuracy equivalent to previously published equations. When used to identify individuals over 60 years old with muscle mass loss, it achieved an area under the curve (AUC) value of 0.85 for both males and females. The inclusion of sex and anthropometric data (thigh and arm circumference) improved the accuracy for male individuals (AUC 0.89). The model is also suitable to be applied to the general adult population of 18 years of age or older. Using more than 3 variables does not lead to better accuracy. CONCLUSIONS: The newly proposed equations have better diagnostic accuracy than previous equations for the estimation of DEXA-measured ASM. They are readily applicable in clinical practice for the screening of muscle mass loss in the over 60-year-old population with nearly zero-cost variables. The most complex model proposed in this study requires only the inspection of a simple diagnostic chart to estimate the status of muscle mass loss.

Robotic Mitral Valve Repair: Impact of Experience on Results and Complex Mitral Disease Treatment.

Background/Objectives: Robotically assisted mitral valve (MV) surgery is the least invasive surgical approach to the MV. The aim of the present study is to report our experience with robotically assisted MV repair, trying to define how experience could impact on postoperative results. Methods: This is a retrospective study on 144 patients who underwent robotic MV repair from November 2011 to March 2023. Patients were divided in two groups: Group 1, including 39 patients (November 2011-January 2013) operated using the Da Vinci Si system, and Group 2, including 105 patients operated (February 2020-March 2023) using the new Da Vinci Xi system. Results: Mean age was 58 ± 10 years. Increased use of external aortic clamp was observed in Group 2. A significant reduction of surgical times was observed: cardiopulmonary bypass time was 155 ± 44 min in Group 1 and 121 ± 36 min in Group 2 (p = 0.002), whereas cross-clamp time was 112 ± 25 min in Group 1 and 68 ± 39 min in Group 2 (p < 0.001). In-hospital mortality was 0.7%, and 10-year survival was 96 ± 2%. Freedom from reoperation was 100%. A higher percentage of complex and most complex MV repairs were performed in Group 2 (36% in Group 1 vs. 52% in Group 2, p = 0.001). Conclusions: Robotic-assisted MV repair is associated with excellent results. Experience is a key element to overcome the limitations of this technology. Finally, the robotic platform could improve results in difficult MV repair.

[Surgical treatment of isolated tricuspid valve disease: indications, new evidence, and risk stratification]. / Trattamento cardiochirurgico della patologia tricuspidale isolata: indicazioni, nuove evidenze e stratificazione del rischio.

The tricuspid valve, long neglected as a passive structure and often termed the "forgotten valve", has recently gained attention from the international medical and cardiological community due to the association of tricuspid regurgitation with an unfavorable prognosis. Isolated tricuspid regurgitation represents a relatively unknown and variable condition, closely linked to the shape and function of the right ventricle and the state of the pulmonary circulation. Currently, guidelines are not clear regarding the optimal treatment strategy, the process of patient selection, and the surgical or transcatheter procedural timing, nor for predicting patient outcomes. Surgical procedures specifically aimed at correcting isolated tricuspid regurgitation, without other concomitant indications for open-heart surgery, have been considered complex and risky, with a high rate of postoperative complications and a poorly understood impact on patient survival and life expectancy. In this review, we will attempt to examine tricuspid valve pathology by analyzing preoperative assessment, essential for risk stratification, various surgical techniques, and outcomes.

[Total artificial heart: past, present, and future]. / Cuore artificiale totale: passato, presente e futuro.

Every year, approximately 5 out of 1000 patients receive a diagnosis of advanced heart failure, with a prevalence of 1-2% in the adult population. This figure is likely underestimated, considering undiagnosed cases. Despite significant progress in medical therapy for heart failure, mortality rates persist around 20% within the first year, reaching 50-60% at 5 years from the initial diagnosis. For patients with severe end-stage heart failure, the 1-year mortality rate can reach up to 70%. Heart transplantation remains the preferred treatment for terminal stages of the disease; however, the significant challenge lies in the mismatch between available donors and recipients. Given this dilemma, both short-term solutions including extracorporeal membrane oxygenation and long-term options such as left ventricular assist devices have gained prominence. These mechanical circulatory support systems become crucial for patients in critical conditions, temporarily ineligible for heart transplantation, such as those with severe irreversible pulmonary hypertension or acute organ failure. Despite these advancements, a growing number of patients on the waiting list develops severe biventricular dysfunction, precluding the use of a left ventricular assist device as a bridge to transplant. In such cases, a total artificial heart emerges as a viable therapeutic option.

TNF-NF-κB-p53 axis restricts in vivo survival of hPSC-derived dopamine neurons.

Ongoing, early-stage clinical trials illustrate the translational potential of human pluripotent stem cell (hPSC)-based cell therapies in Parkinson's disease (PD). However, an unresolved challenge is the extensive cell death following transplantation. Here, we performed a pooled CRISPR-Cas9 screen to enhance postmitotic dopamine neuron survival in vivo. We identified p53-mediated apoptotic cell death as a major contributor to dopamine neuron loss and uncovered a causal link of tumor necrosis factor alpha (TNF-α)-nuclear factor κB (NF-κB) signaling in limiting cell survival. As a translationally relevant strategy to purify postmitotic dopamine neurons, we identified cell surface markers that enable purification without the need for genetic reporters. Combining cell sorting and treatment with adalimumab, a clinically approved TNF-α inhibitor, enabled efficient engraftment of postmitotic dopamine neurons with extensive reinnervation and functional recovery in a preclinical PD mouse model. Thus, transient TNF-α inhibition presents a clinically relevant strategy to enhance survival and enable engraftment of postmitotic hPSC-derived dopamine neurons in PD.

Human DNA topoisomerase I poisoning causes R loop-mediated genome instability attenuated by transcription factor IIS.

DNA topoisomerase I can contribute to cancer genome instability. During catalytic activity, topoisomerase I forms a transient intermediate, topoisomerase I-DNA cleavage complex (Top1cc) to allow strand rotation and duplex relaxation, which can lead to elevated levels of DNA-RNA hybrids and micronuclei. To comprehend the underlying mechanisms, we have integrated genomic data of Top1cc-triggered hybrids and DNA double-strand breaks (DSBs) shortly after Top1cc induction, revealing that Top1ccs increase hybrid levels with different mechanisms. DSBs are at highly transcribed genes in early replicating initiation zones and overlap with hybrids downstream of accumulated RNA polymerase II (RNAPII) at gene 5'-ends. A transcription factor IIS mutant impairing transcription elongation further increased RNAPII accumulation likely due to backtracking. Moreover, Top1ccs can trigger micronuclei when occurring during late G1 or early/mid S, but not during late S. As micronuclei and transcription-replication conflicts are attenuated by transcription factor IIS, our results support a role of RNAPII arrest in Top1cc-induced transcription-replication conflicts leading to DSBs and micronuclei.

Intervention for critical aortic stenosis in Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare genetic premature aging disease that is historically fatal in teenage years, secondary to severe accelerated atherosclerosis. The only approved treatment is the farnesyltransferase inhibitor lonafarnib, which improves vascular structure and function, extending average untreated lifespan of 14.5 years by 4.3 years (30%). With this longer lifespan, calcific aortic stenosis (AS) was identified as an emerging critical risk factor for cardiac death in older patients. Intervention to relieve critical AS has the potential for immediate improvement in healthspan and lifespan. However, HGPS patient-device size mismatch, pervasive peripheral arterial disease, skin and bone abnormalities, and lifelong failure to thrive present unique challenges to intervention. An international group of experts in HGPS, pediatric and adult cardiology, cardiac surgery, and pediatric critical care convened to identify strategies for successful treatment. Candidate procedures were evaluated by in-depth examination of 4 cases that typify HGPS clinical pathology. Modified transcatheter aortic valve replacement (TAVR) and left ventricular Apico-Aortic Conduit (AAC) placement were deemed high risk but viable options. Two cases received TAVR and 2 received AAC post-summit. Three were successful and 1 patient died perioperatively due to cardiovascular disease severity, highlighting the importance of intervention timing and comparative risk stratification. These breakthrough interventions for treating critical aortic stenosis in HGPS patients could rewrite the current clinical perspective on disease course by greatly improving late-stage quality of life and increasing lifespan. Expanding worldwide medical and surgical competency for this ultra-rare disease through expert information-sharing could have high impact on treatment success.

TDP1 mutation causing SCAN1 neurodegenerative syndrome hampers the repair of transcriptional DNA double-strand breaks.

TDP1 removes transcription-blocking topoisomerase I cleavage complexes (TOP1ccs), and its inactivating H493R mutation causes the neurodegenerative syndrome SCAN1. However, the molecular mechanism underlying the SCAN1 phenotype is unclear. Here, we generate human SCAN1 cell models using CRISPR-Cas9 and show that they accumulate TOP1ccs along with changes in gene expression and genomic distribution of R-loops. SCAN1 cells also accumulate transcriptional DNA double-strand breaks (DSBs) specifically in the G1 cell population due to increased DSB formation and lack of repair, both resulting from abortive removal of transcription-blocking TOP1ccs. Deficient TDP1 activity causes increased DSB production, and the presence of mutated TDP1 protein hampers DSB repair by a TDP2-dependent backup pathway. This study provides powerful models to study TDP1 functions under physiological and pathological conditions and unravels that a gain of function of the mutated TDP1 protein, which prevents DSB repair, rather than a loss of TDP1 activity itself, could contribute to SCAN1 pathogenesis.

Clusters of adipose tissue dysfunction in adults with type 2 diabetes identify those with worse lipidomic profile despite similar glycaemic control.

AIMS: To investigate clusters of adipose tissue dysfunction, that is, with adipose tissue insulin resistance (ADIPO-IR) and large waist circumference (WC), identify a worse lipidomic profile characterised by a high proportion of lipids rich in saturated fatty acids (SFA). MATERIALS AND METHODS: Hierarchical clustering based on WC and ADIPO-IR (calculated as fasting plasma non-esterified fatty acids times fasting plasma insulin, FFA×INS), was performed in 192 adults with overweight/obesity and type 2 diabetes (T2D) treated with metformin (HbA1c = 7.8%). Free fatty acid composition and lipidomic profile were measured by mass spectrometry (GC-MS and LC-MSQTOF). Indexes of fatty acid desaturation (stearoyl-coA desaturase-1 activity, SCD116 = palmitoleic acid/palmitic acid and SCD118 = oleic acid/stearic acid) and of insulin resistance (HOMA-IR) were also calculated. RESULTS: Three clusters were identified: CL1 (ADIPO-IR = 4.9 ± 2.4 and WC = 96±7 cm, mean ± SD), CL2 (ADIPO-IR = 6.5 ± 2.5 and WC = 114 ± 7 cm), and CL3 (ADIPO-IR = 15.0 ± 4.7 and WC = 107 ± 8 cm). Insulin concentrations, ADIPO-IR, and HOMA-IR significantly increased from CL1 to CL3 (all p < 0.001), while fasting glucose concentrations, HbA1c, dietary lipids and caloric intake were similar. Moreover, CL3 showed significantly higher concentrations of monounsaturated free fatty acids, oleic and palmitoleic acids, triglycerides (TAG) rich in saturated FA and associated with de novo lipogenesis (i.e., TAG 46-50), higher SCD116, SCD118, ceramide (d18:0/18:0), and phosphatidylcholine aa(36:5) compared with CL1/CL2 (all p < 0.005). CONCLUSIONS: High ADIPO-IR and large WC identify a worse lipid profile in T2D characterised by complex lipids rich in SFA, likely due to de novo synthesis given higher plasma monounsaturated FFA and increased desaturase activity indexes. REGISTRATION NUMBER TRIAL: ID NCT00700856 https://clinicaltrials.gov.

Altered microbial bile acid metabolism exacerbates T cell-driven inflammation during graft-versus-host disease.

Microbial transformation of bile acids affects intestinal immune homoeostasis but its impact on inflammatory pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that T cell-driven inflammation decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of unconjugated and microbe-derived bile acids. Several microbe-derived bile acids attenuated farnesoid X receptor (FXR) activation, suggesting that loss of these metabolites during inflammation may increase FXR activity and exacerbate the course of disease. Indeed, mortality increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells during mouse GVHD. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and microbe-derived bile acids. In addition, the FXR antagonist ursodeoxycholic acid reduced the proliferation of human T cells and was associated with a lower risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of microbe-derived bile acids during inflammation may be an important mechanism to amplify T cell-mediated diseases.

Digital postprocessing analysis of prostatic perfusion in neutered dogs.

B-mode ultrasound is routinely performed to evaluate the prostate gland in neutered dogs, although, the detection of malignancies may be challenging. Contrast-enhanced ultrasound (CEUS) has shown to be useful for the assessment of prostatic perfusion in normal and diseased dogs, although the interpretation of contrast ultrasonographic features may still be subjective. A quantitative tool for evaluating prostatic perfusion might improve the reliability of the results in terms of early detection of prostate neoplasia in neutered dogs. The present study aimed to evaluate the applicability of a postprocessing analysis tool to CEUS of the prostate in healthy neutered dogs, to provide quantitative measurements, and to study the influence of individual characteristics on prostatic regression. Twenty-three neutered dogs underwent a B-mode and CEUS examination of the prostate to acquire data about prostatic morphology and microcirculation. The prostate was imaged using a 5-7.5 MHz linear transducer and contrast was administered intravenously. Videoclips were analyzed by using Qontrast software and a postprocessing digital analysis tool (ImageJ) to measure perfusion peak intensity, time to peak, and vascularization ratio at the moment of the peak, which were then related to body weight, age, and time elapsed since orchiectomy. Correlation tests revealed higher vascularization in younger compared with older dogs (P < .05) and in smaller compared with larger dogs (P < .05). Time elapsed since orchiectomy (P > .05) did not affect prostatic perfusion. Contrast-enhanced ultrasound and the postprocessing analysis tool ImageJ allowed analysis of vascular perfusion in all dogs and have the potential to improve the diagnostic possibilities for andrological examination.

Extended septal myectomy for obstructive hypertrophic cardiomyopathy and its impact on mitral valve function.

AIMS: Septal myectomy is the treatment of choice for hypertrophic obstructive cardiomyopathy (HOCM). Around 30-60% of patients with HOCM have a secondary mitral valve regurgitation due to systolic anterior motion (SAM). We report our experience with extended septal myectomy and its impact on the incidence of concomitant mitral valve procedures. METHODS: This is a retrospective study on 84 patients who underwent SM from January 2008 to February 2022. Surgical procedure was performed according to the concept of 'extended myectomy' described by Messmer in 1994. Follow-up outcomes in terms of survival, hospital admissions for heart failure or MV disease, cardiac reoperations, and pacemaker (PMK) implantation were recorded. RESULTS: Mean age was 61 ±â€Š15 years. Mitral valve surgery was performed in seven cases (8%); particularly only one patient without degenerative mitral valve disease underwent mitral valve surgery, with a plicature of the posterior leaflet. In-hospital mortality was 5%. Mitral valve regurgitation greater than mild was present in four patients (5%) at discharge. Twelve-year survival was 78 ±â€Š22%. Cumulative incidence of rehospitalization for heart failure and rehospitalization for mitral valve disease was 10 ±â€Š4 and 2.5 ±â€Š2.5%, respectively. PMK implantation was 5% at discharge, with a cumulative incidence of 15 ±â€Š7%. Freedom from cardiac reoperations was 100%. CONCLUSION: Septal myectomy for HOCM is associated with good outcomes. Although concomitant surgery on the mitral valve to address SAM and associated regurgitation has been advocated, these procedures were needed in our practice only in patients with intrinsic mitral valve disease. Adequate myectomy addresses the underlying pathophysiology in most patients.

G Protein-Coupled Estrogen Receptor (GPER) and ERs Are Modulated in the Testis-Epididymal Complex in the Normal and Cryptorchid Dog.

There is growing evidence by the literature that the unbalance between androgens and estrogens is a relevant condition associated with a common canine reproductive disorder known as cryptorchidism. The role of estrogens in regulating testicular cell function and reproductive events is supposedly due to the wide expression of two nuclear estrogen receptors (ERs), ER-alpha and ER-beta and a trans-membrane G protein-coupled estrogen receptor (GPER) in the testis. In this study, immunohistochemistry, Western blotting and qRT-PCR were used to assess the distribution and expression of GPER in the testis-epididymal complex in the normal and cryptorchid dog. ER-alpha and ER-beta were also evaluated to better characterize the relative abundances of all three receptors. In addition, in these tissues, the expression level of two proteins as SOD1 and Nrf2 normally associated with oxidative stress was investigated to evaluate a possible relationship with ERs. Our data revealed changes in the distribution and expression of the GPER between the normal and cryptorchid dog. In particular, dogs affected by cryptorchidism showed an upregulation of GPER at level of the examined reproductive tract. Also considering the obtained result of a modulation of SOD1 and Nrf2 expression, we could hypothesize the involvement of GPER in the cryptorchid condition. Further studies are, however, necessary to characterize the role of GPER and its specific signaling mechanisms.

Current Prostheses for Transcatheter Heart Valve Replacement: A Technical and Clinical Review.

Transcatheter aortic valve replacement (TAVR) has become a cornerstone in today's treatment of aortic stenosis. Modern transcatheter prostheses are continuously evolving and each one features different design traits. In this review, the authors provide insight in the technical differences of current prostheses and TAVR related clinical decision pathways, preferably useful for the beginners but also for advanced operators. Additionally, procedural considerations and comparative outcomes of the prostheses are discussed. In doing so, the authors aim to facilitate the choice of the ideal transcatheter valve procedure for each individual.