Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington's disease.

Evidence that Huntington's disease (HD) is characterized by impaired cholesterol biosynthesis in the brain has led to strategies to increase its level in the brain of the rapidly progressing R6/2 mouse model, with a positive therapeutic outcome. Here we tested the long-term efficacy of chronic administration of cholesterol to the brain of the slowly progressing zQ175DN knock-in HD mice in preventing ("early treatment") or reversing ("late treatment") HD symptoms. To do this we used the most advanced formulation of cholesterol loaded brain-permeable nanoparticles (NPs), termed hybrid-g7-NPs-chol, which were injected intraperitoneally. We show that one cycle of treatment with hybrid-g7-NPs-chol, administered in the presymptomatic ("early treatment") or symptomatic ("late treatment") stages is sufficient to normalize cognitive defects up to 5 months, as well as to improve other behavioral and neuropathological parameters. A multiple cycle treatment combining both early and late treatments ("2 cycle treatment") lasting 6 months generates therapeutic effects for more than 11 months, without severe adverse reactions. Sustained cholesterol delivery to the brain of zQ175DN mice also reduces mutant Huntingtin aggregates in both the striatum and cortex and completely normalizes synaptic communication in the striatal medium spiny neurons compared to saline-treated HD mice. Furthermore, through a meta-analysis of published and current data, we demonstrated the power of hybrid-g7-NPs-chol and other strategies able to increase brain cholesterol biosynthesis, to reverse cognitive decline and counteract the formation of mutant Huntingtin aggregates. These results demonstrate that cholesterol delivery via brain-permeable NPs is a therapeutic option to sustainably reverse HD-related behavioral decline and neuropathological signs over time, highlighting the therapeutic potential of cholesterol-based strategies in HD patients. DATA AVAILABILITY: This study does not include data deposited in public repositories. Data are available on request to the corresponding authors.

Transapical Transcatheter Mitral Valve Implantation with the Tendyne Valve: The Swiss Experience.

BACKGROUND: The aim of this study was to report outcomes of all patients undergoing transcatheter mitral valve implantation with the Tendyne Mitral Valve System (Tendyne) in Switzerland. METHODS: We retrospectively analyzed preoperative echocardiographic and computed tomography (CT) data, procedural findings, and 30-day and 1-year follow-up echocardiographic and clinical data of patients who underwent transcatheter mitral valve implantation with Tendyne in Switzerland. RESULTS: A total of 24 patients (age, 74.8 ± 7.8 years; 67% male) underwent transapical transcatheter mitral valve implantation with Tendyne between June 2020 and October 2022. Technical success rate was 96%. In five patients, concomitant interventions in the form of transcatheter aortic valve implantation (one patient), minimally invasive direct coronary artery bypass (one patient), and transcatheter edge-to-edge repair (three patients) were performed prior to or after the index procedure. There was one device embolization, and two patients required valve retrieval. In-hospital outcomes included one stroke and three major bleeding events. None of the patients died within 30 days. Two patients were rehospitalized for decompensated heart failure. At 1-year follow-up, there were three noncardiovascular-related deaths. CONCLUSION: Transcatheter mitral valve implantation with Tendyne is feasible to treat polymorbid patients suffering from complex mitral valve disease as well as patients with previous mitral interventions. Perioperative risk was acceptable and procedural success high.

Right ventricular function in Marfan patients remains stable despite multiple cardiac interventions.

OBJECTIVES: Mitral valve regurgitation and left ventricular dysfunction are cardiovascular symptoms of Marfan syndrome. There is a paucity of information on tricuspid valve regurgitation and right ventricular function. In patients with Marfan syndrome, we looked at long-term changes in right ventricular function, tricuspid valve regurgitation and freedom from tricuspid valve repair. METHODS: Retrospective-observational single-centre analysis on right ventricular function and tricuspid regurgitation in Marfan patients who underwent surgery with cardioplegic arrest between 1995 and 2020. Patients were followed-up from 1st operation until death, with echocardiographic changes analysed longitudinally. Composite end point was tricuspid annular plane systolic excursion (TAPSE) ≤16 mm, severe tricuspid regurgitation or tricuspid repair. RESULTS: The study included 135 patients who underwent 193 operations, 58 of those were reoperations in 40 patients. Median age at 1st operation was 35 years [interquartile range (IQR) 26-46], median follow-up was 8.0 years (IQR 3.0-16.0) and median time to 1st reoperation was 7.5 years (IQR 3.4-12.5). The composite end point occurred in 81 observations in 40 patients, mostly as a recurrent event, after median 7.0 years (IQR 1.0-13.0). Ten-year cumulative incidence for composite end point was 22.0% (95% CI 15-31) and 9.0% (95% CI 4.4-16) for new-onset TAPSE ≤16 mm, but no significant change in TAPSE was observed at 10 years. Tricuspid regurgitation was associated with increased risk of annual progression (P < 0.001), but not clinically relevant at 10 years. Actuarial 10-year survival was 91.1%. CONCLUSIONS: In Marfan patients with a history of cardiac surgery and subsequent reoperations, the right ventricular function remains stable. The incidence of severe tricuspid regurgitation and tricuspid repair remain low.

Endovascular aortic repair in patients with Marfan and Loeys-Dietz syndrome is safe and durable when employed by a multi-disciplinary aortic team.

OBJECTIVES: The aim of this study was to report on mid-term outcomes after endovascular aortic repair (EVAR) in patients with Marfan (MFS) or Loeys-Dietz (LDS) syndrome. METHODS: We analysed data from 2 European centres of patients with MFS and LDS undergoing EVAR. Patients were analysed based on (i) timing of the procedure (planned versus emergency procedure) and (ii) the nature of the landing zone (safe versus non-safe). The primary end-point was freedom from reintervention. Secondary end-points were freedom from stroke, bleeding and death. RESULTS: A population of 419 patients with MFS (n = 352) or LDS (n = 67) was analysed for the purpose of this study. Thirty-nine patients (9%) underwent EVAR. Indications for thoracic endovascular aortic repair or EVAR were aortic dissection in 13 (33%) patients, aortic aneurysm in 22 (57%) patients and others (intercostal patch aneurysm, penetrating atherosclerotic ulcer, pseudoaneurysm, kinking of frozen elephant trunk (FET)) in 4 (10%) patients. Thoracic endovascular repair was performed in 34 patients, and abdominal endovascular aortic repair was performed in 5 patients. Mean age at 1st thoracic endovascular aortic repair/EVAR was 48.5 ± 15.4 years. Mean follow-up after 1st thoracic endovascular aortic repair/EVAR was 5.9 ± 4.4 years. There was no statistically significant difference in the rate of reinterventions between patients with non-safe landing zone and the patients with safe proximal landing zone (P = 0.609). Furthermore, there was no increased probability for reintervention after planned endovascular intervention compared to emergency procedures (P = 0.916). Mean time to reintervention, either open surgical or endovascular, after planned endovascular intervention was in median 3.9 years (95% confidence interval 2.0-5.9 years) and 2.0 years (95% confidence interval -1.1 to 5.1 years) (P = 0.23) after emergency procedures. CONCLUSIONS: EVAR in patients with MFS and LDS and a safe landing zone is feasible and safe. Endovascular treatment is a viable option when employed by a multi-disciplinary aortic team even if the landing zone is in native tissue.

The non to moderately dilated root in acute type A aortic dissection: outcomes of the PENN-BERN registry in young, non-syndromic patients.

OBJECTIVES: There is an ongoing debate regarding whether patients benefit more from root replacement compared to a reconstruction of the sinuses of Valsalva in acute type A aortic dissection (aTAAD). In those with known or suspected connective tissue disorders, root replacement is considered appropriate. However, there are currently no diameter-based guidelines regarding the best approach in patients with minimally to moderately dilated root and no connective tissue disorders. METHODS: From January 2005 to December 2022, a two-centre registry of aTAAD was created. Patients were included based on their age (≤60 years), the absence of root entry and dilatation >50 mm and the absence of syndromic hereditable aortic disease. Patients were divided into 2 groups based on the proximal procedure, root reconstruction and root replacement. Propensity score pair matching was performed based on preoperative characteristics. RESULTS: Cumulative incidence of reintervention at 10 years was slightly higher after root reconstruction 13% vs 3.9% in the matched group (P = 0.040). Survival at 10 years was not affected by the procedure independently of the matching 72.1% vs 71.4% (P = 0.2). Uni- and multivariate Cox regressions showed that a root diameter of >40 mm was associated with a hazard ratio of 7.7 (95% confidence interval 2.6-23) and 5.4 (7-17), respectively, for reoperation for aneurysm and pseudoaneurysm. CONCLUSIONS: Rate of reoperation due to proximal pseudoaneurysm and aneurysm could be significantly reduced with a lower threshold of 40 mm to replace the aortic root in aTAAD than in elective cases.

Huntington's disease cellular phenotypes are rescued non-cell autonomously by healthy cells in mosaic telencephalic organoids.

Huntington's disease (HD) causes selective degeneration of striatal and cortical neurons, resulting in cell mosaicism of coexisting still functional and dysfunctional cells. The impact of non-cell autonomous mechanisms between these cellular states is poorly understood. Here we generated telencephalic organoids with healthy or HD cells, grown separately or as mosaics of the two genotypes. Single-cell RNA sequencing revealed neurodevelopmental abnormalities in the ventral fate acquisition of HD organoids, confirmed by cytoarchitectural and transcriptional defects leading to fewer GABAergic neurons, while dorsal populations showed milder phenotypes mainly in maturation trajectory. Healthy cells in mosaic organoids restored HD cell identity, trajectories, synaptic density, and communication pathways upon cell-cell contact, while showing no significant alterations when grown with HD cells. These findings highlight cell-type-specific alterations in HD and beneficial non-cell autonomous effects of healthy cells, emphasizing the therapeutic potential of modulating cell-cell communication in disease progression and treatment.

Impact of surgically placed radiopaque markers during aortic root surgery on facilitating secondary diagnostic and therapeutic interventions.

BACKGROUND: Implantation of radiopaque markers during aortic root surgery might possibly facilitate upcoming coronary angiography or transcatheter aortic valve implantation. Aim of this study was to report the impact of surgically placed radiopaque markers on procedural characteristics and on angiographic outcomes. METHODS: We retrospectively analyzed baseline characteristics, preoperative and postoperative data as well as procedural findings. In addition, a subgroup analysis of all patients who underwent coronary angiography after aortic root surgery was performed to report radiation time and contrast media used. RESULTS: A total of 469 patients underwent aortic root surgery between January 2008 and April 2020. Patients were divided into two groups: group w/ markers (n = 182) and group w/o markers (n = 287). A propensity score matching was performed resulting in a total of 28 patients w/ markers and 28 patients w/o markers. Aortic cross-clamp time did not differ statistically significantly between the group w/o markers and the group w/ markers (124.0 [96.0-150.0] versus 123.0 [110.0-149.0] min, p = 0.09). There was no increased probability for requirement of postoperative angiography in the group w/o markers compared to the group w/ markers (11.8% versus 15.4%, p = 0.27). There was no statistically significant difference in the radiation time 5.5 [3-6.5] versus 5 [2.5-7.5] min, p = 0.62) nor in the amount of contrast media used (85 [77.5-100] versus 80 [60-90] ml, p = 0.07). CONCLUSIONS: Surgically placed radiopaque markers during aortic root surgery do not increase operative risk and have the potential for facilitating secondary diagnostic and therapeutic interventions.

Outcome of Stanford type B dissection in patients with Marfan syndrome.

OBJECTIVES: The aim of this study was to determine the outcome of Stanford type B aortic dissection in patients with Marfan syndrome (MFS) and to evaluate aortic diameters at time of dissection as well as the impact of previous aortic root replacement. METHODS: Analysis of all patients with MFS fulfilling Ghent criteria seen at this institution since 1995 until 2022. RESULTS: Thirty-six (19%) out of 188 patients with MFS suffered from Stanford type B aortic dissection during the study period. The Mean aortic diameter at the time of dissection was 39.0 mm [95% confidence interval (CI): 35.6-42.3]. The mean pre-dissection diameter (available in 25% of patients) was 32.1 mm (95% CI: 28.0-36.3) and the mean expansion was 19% (95% CI: 11.9-26.2). There was no correlation between age and diameter at the time of dissection (<20, 21-30, 31-40, 41-50, 51-60, <61 years; P = 0.78). Freedom from intervention after dissection was 53%, 44% and 33% at 1, 5 and 10 years. Aortic growth rate in those patients that had to undergo intervention within the 1st year after dissection was 10.2 mm/year (95% CI: 4.4-15.9) compared to 5.8 mm/year (95% CI: 3.3-8.3, P = 0.109) in those thereafter. The mean time between dissection and intervention was 1.8 years (95% CI: 0.6-3.0). While type B dissection seems more frequent after previous elective aortic repair (58% vs 42%), there was no difference between valve-sparing root replacement (VSRR) compared to Bentall procedures [Hazard ratio (HR) for VSRR 0.78, 95% CI: 0.31-2.0, P-value = 0.61]. The mean age of the entire population at the end of follow-up was 42 years (95% CI: 39.2-44.7). The mean follow-up time was 9 years (95% CI: 7.8-10.4). CONCLUSIONS: Stanford type B dissection in patients with MFS occurs far below accepted thresholds for intervention. Risk for type B dissection is present throughout lifetime and two-thirds of patients need an intervention after dissection. There is no difference in freedom from type B dissection between a Bentall procedure and a VSRR.

Ketamine, propofol and low dose remifentanil versus propofol and remifentanil for ERCP outside the operating room: is ketamine not only a "rescue drug"?

BACKGROUND: Endoscopic retrograde cholangiopancreatography ERCP is a painful and long procedure requiring transient deep analgesia and conscious sedation. An ideal anaesthetic that guarantees a rapid and smooth induction, good quality of maintenance, lack of adverse effects and rapid recovery is still lacking. This study aimed to compare safety and efficacy of a continuous infusion of low dose remifentanil plus ketamine combined with propofol in comparison to the standard regimen dose of remifentanil plus propofol continuous infusion during ERCP. MATERIAL/METHODS: 322 ASAI-III patients, 18-85 years old and scheduled for planned ERCP were randomized. Exclusion criteria were a predictable difficult airway, drug allergy, and ASA IV-V patients. We evaluated Propofol 1 mg/kg/h plus Remifentanil 0.25 µg/kg/min (GR) vs. Propofol 1 mg/kg/h plus Ketamine 5 µg/kg/min and Remifentanil 0.1 µg/kg/min (GK). Main outcome measures were respiratory depression, nausea/vomiting, quality of intraoperative conditions, and discharge time. P≤0.05 was statistically significant (95% CI). RESULTS: Respiratory depression was observed in 25 patients in the GR group compared to 9 patients in the GK group (p=0.0035). ERCP was interrupted in 9 cases of GR vs. no cases in GK; patients ventilated without any complication. Mean discharge time was 20±5 min in GK and 35±6 min in GR (p=0.0078) and transfer to the ward delayed because of nausea and vomiting in 30 patients in GR vs. 5 patients in GK (p=0.0024). Quality of intraoperative conditions was rated highly satisfactory in 92% of GK vs. 67% of GR (p=0.028). CONCLUSIONS: The drug combination used in GK confers clinical advantages because it avoids deep sedation, maintains adequate analgesia with conscious sedation, and achieves lower incidence of postprocedural nausea and vomiting with shorter discharge times.

Early Experience With a Novel Suture Device for Sternal Closure in Pediatric Cardiac Surgery.

BACKGROUND: Sternal closure by absorbable suture material is an established method for chest closure in pediatric cardiac surgical procedures. However, the formation of granuloma around knotted suture material is frequently observed and has potential for prolonged wound healing and infection, particularly in newborns and infants. This retrospective study analyzed the suitability and reliability of a novel absorbable, self-locking, multianchor knotless suture with antibacterial technology for sternal closure in pediatric cardiac surgical procedures. METHODS: The applied material (STRATAFIX Symmetric PDS Plus, Ethicon) presents a polydioxanon (PD) suture with a self-locking, multianchor design that enables a sternal closure in a continuous knotless suture technique. All children undergoing knotless closure after standard median sternotomy were examined for the occurrence of sternal wound infection or sternal instability by applying the screening criteria of the Centers for Disease Control and Prevention at hospital discharge and at 30 and 60 days. RESULTS: The new knotless sternal closure was used in 130 patients. Patients were a mean age of 19.0 ± 31.9 months (range, 0-142 months), and mean bodyweight was 7.8 ± 6.6 kg (range, 2.4-35 kg). Delayed sternal closure occurred in 23 patients, with a mean closure time after 2.9 ± 2.6 days. One superficial incisional sternal site infection occurred, but no cases of deep sternal site infection or sternal instability were observed. CONCLUSIONS: The application of the absorbable, knotless suture technique provides excellent results regarding the rate of sternal wound infection and improved healing after median sternotomy in pediatric patients.

Comprehensive review with pooled analysis on external and internal jugular vein aneurysm.

OBJECTIVE: The aim of the present comprehensive review was to present an overview of the clinical presentation and treatment options for external (EJVAs) and internal jugular vein aneurysms (IJVAs) to help clinicians in evidence-based decision making. METHODS: A systematic literature search was conducted in accordance with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) statement and included MEDLINE, Embase, Cochrane Library, Scopus, WHO (World Health Organization) trial register, ClinicalTrials.gov, and the LIVIVO search portal. The inclusion criteria were studies of patients who had presented with IJVAs or EJVAs. The exclusion criteria were animal and cadaver studies and reports on interventions using the healthy jugular vein for access only (ie, catheterization). Analysis of the pooled data from all eligible case reports was performed. RESULTS: From 1840 identified reports, 196 studies were eligible. A total of 256 patients with JVAs were reported, with 183 IJVAs and 73 EJVAs. IJVAs were reported to occur in 66% on the right side compared with the left side (P = .011). The patients with IJVAs were mostly children (median age, 12 years; interquartile range, 5.8-45.2 years). The patients with EJVAs were young adults (median age, 30 years; interquartile range, 11.0-46.5 years). EJVAs were more frequently reported in women and IJVAs in men (P = .008). Most of the patients were asymptomatic. Pulmonary embolization in association with thrombosed EJVAs was only reported for one patient. A report of the outcomes after surgery and conservative management was missing for ∼50% of the patients. No relevant complications were reported after ligation of the EJVA without reconstruction. Intracranial hypertension after ligation of the right-sided IJVA was reported in three children; in one of them, a pontine infarction was observed. CONCLUSIONS: JVAs are a disease of the younger population but can occur at any age. It seems to be safe to observe patients with nonthrombosed JVAs. However, in the presence of thrombus or pulmonary embolization, surgical treatment should be considered. A reconstruction technique of the IJVA with venous patency preservation should be preferred.

The impact of sex and gender on aortic events in patients with Marfan syndrome.

OBJECTIVES: The aim of this study was to explore sex and gender differences regarding aortic events in Marfan patients. METHODS: We analysed all data from our connective tissue disorder database. Only patients with Marfan syndrome were included. For analysis, patients were divided by sex. Female patients were further divided into 2 subgroups: with versus without children. Aortic events were defined as Stanford type A aortic dissection (TAAD) or type B aortic dissection (TBAD) or any aortic intervention. RESULTS: A population of 183 Marfan patients was analysed for the purpose of this study. One hundred four (57%) were male and 79 (43%) were female patients. Thirty-seven (47%) of the 79 female patients had at least 1 child. Male patients had a significantly higher probability of experiencing an aortic event (P = 0.015) compared to female patients. However, there was no increased probability for recurrent events in male patients compared to female patients (P = 0.063). Follow-up revealed no sex and gender differences in the occurrence of Stanford TAAD or TBAD between male and female patients (P = 0.324/P = 0.534). While 11% of women with children suffered from peripartum aortic events, 24% experienced Stanford TAAD unrelated to pregnancy. CONCLUSIONS: Male patients have a higher risk of aortic events than female patients. The majority of women were not aware of their Marfan syndrome diagnosis before conceiving. One out of 10 women suffered from peripartum Stanford TAAD or TBAD. Twice as many female patients with children suffered from aortic dissection unrelated to childbirth. There were no sex and gender differences affecting mortality in Marfan patients.

[Gastric Bypass: Weight Loss with Complications]. / Magenbypass: Abnehmen mit Komplikationen.

Gastric Bypass: Weight Loss with Complications Abstract. Roux-en-Y gastric bypass (RYGBP) is the most often performed bariatric operation worldwide with internal hernia as one of the main long-term complications. To our knowledge, we report the first case of post-ischemic small-bowel strictures observed after a successful operation of an internal hernia after RYGBP. During emergency surgery a Petersen and a Brolin hernia were diagnosed and repaired. The initially ischemic small intestine was recovered. However, a week later the patient presented herself again due to ischemia-induced small-bowel strictures. These were treated successfully by endoscopic balloon dilatation.

Impact of new technologies and experience on procedural aspects of surgical aortic valve replacement - a process analysis.

BACKGROUND: Surgical aortic valve replacement (SAVR) is the treatment of choice in severe symptomatic aortic valve disease. New techniques and prostheses have been recently developed to facilitate the procedure and reduce aortic cross-clamp time (AOx). The aim of this study was to analyse the different procedural steps in order to identify the most time-consuming part during aortic clamping time and to compare impact of experience on procedural aspects. METHODS: AOx during SAVR was divided into five consecutive steps. Duration of each step was measured. The first procedural step started with clamping of the aorta and ended with the beginning of the second step starting with the resection of the native aortic valve. The third step started with placement of the first valve anchoring suture, the fourth step started with tying of the first suture and the fifth and final step started after the cut of the last suture and ended with removal of the aortic clamp. Surgeons were divided into two groups based on their experience, which in our analysis was defined as a total SAVR experience of more than 100 procedures. RESULTS: From March 2013 to August 2015 57 nonconsecutive patients (33% female; age, median 71.0 years, interquartile range 65.0-76.0) undergoing isolated SAVR for severe aortic valve stenosis in our institution were included in this process analysis. Two different prostheses were implanted. Forty-eight (84%) patients received a tissue valve (Perimount Magna Ease, Edwards Lifesciences, Irvine, USA) and 9 (16%) patients received a mechanical prosthesis (Medtronic AP 360, St-Paul, MN, USA). The mean estimated risk of mortality was 1.1% (0.7-1.6) according to the logistic EUROScore II. Overall duration of AOx was 50.5 ± 13.8 min, with 32.3% (16.4 ± 5.9 min) accounting for placing the sutures into the native annulus and the prosthetic sewing ring and 18.5% (9.2 ± 3.0min) accounting for tying and cutting the sutures. Surgeons with more experience performed 35 operations (61.4%) and needed an average of 44.1 ± 11.5 min versus 60.6 ± 11.0 min (p <0.001) for less experienced surgeons. Surgeons with more experience needed 14.0 ± 5.0 min for the suturing step and 8.4 ± 2.8 min for tying the sutures compared with 20.2 ± 5.2 min and 10.5 ± 3.0 min, respectively, for the less experienced surgeons with (p <0.001 and p = 0.010). CONCLUSION: Placing and tying sutures in the prostheses accounts for over half (50.8%) of AOx during isolated SAVR. Experienced surgeons have significantly reduced AOx. This shortening is equally distributed between all five procedural steps.

Wolfram syndrome. How much could knowledge challenge the fate? A case report.

BACKGROUND: Wolfram syndrome (WS) is a rare, autosomic recessive genetic disorder. The mortality rate of WS is about 65% before 35 years of age. It presents diagnostic challenges in the clinical practice due to its incomplete characterization. This report represents the first case of undiagnosed Wolfram syndrome in a patient over 53 years old. CASE REPORT: A 53-year-old white woman developed a respiratory complication necessitating extended ICU care and respiratory rehabilitation. This respiratory complication proved to be a consequence of undiagnosed WS. CONCLUSIONS: The report discusses the clinical elements that suggested the diagnosis, the problems related to the ICU management of this patient, in particular the weaning difficulties, and the need for rehabilitation. Finally, the report considers the ethical aspect of timely diagnosis on the course and outcome of WS.