Loss of chondroitin 6-sulfate and hyaluronan from failed porcine bioprosthetic valves

Explanted porcine bioprosthetic valves have a thinned spongiosa, partially because of an overall loss of glycosaminoglycans (GAGs). We measured the concentrations of specific GAG classes in explanted bioprosthetic valves (n = 14, implanted 12.0 +/- 4.7 years) compared with glutaraldehyde-fixed porcine controls. After extraction with NaOH, GAGs were analyzed using either a hexuronic acid assay or fluorophore-assisted carbohydrate electrophoresis to quantify the individual GAG classes. The total GAG concentration in explants was 198 +/- 95 pmol/mg wet weight-93% less than freshly fixed controls. Explants also contained altered proportions of the different GAG classes relative to controls. The proportions of hyaluronan and chondroitin/dermatan-6-sulfate were reduced from 39 to 7% and 34 to 18% of total GAGs, respectively. The predominant explant GAG class was chondroitin/dermatan-4-sulfate (proportion elevated from 14 to 70%). This GAG is commonly found in the collagen-associated proteoglycan decorin, which is likely well crosslinked by glutaraldehyde. Chondroitin-6-sulfate is commonly found in the water- and hyaluronan-binding proteoglycan versican, which is likely poorly crosslinked. The loss of versican and its associated water-binding capacity is consistent with the thinned spongiosa. The resultant compromise of hydration, compressive resistance, and viscoelasticity may be responsible for the deterioration of the bioprosthesis in vivo.     

Supplementation with Octacosanol Affects the Level of PCSK9 and Restore Its Physiologic Relation with LDL-C in Patients on Chronic Statin Therapy

Dietary supplementation with sugar cane derivates may modulate low-density lipoprotein cholesterol (LDL-C) and proprotein convertase subtilisin/kexin type 9 (PCSK9) levels. The purpose of this study was to determine if dietary supplement (DS), containing Octacosanol (20 mg) and vitamin K2 (45 µg), could restore the disrupted physiologic relation between LDL-C and serum PCSK9. Double-blind, randomized, placebo-controlled, single-center study including 87 patients on chronic atorvastatin therapy was conducted. Eighty-seven patients were randomized to receive DS (n = 42) or placebo (n = 45), and followed for 13 weeks. Serum PCSK9 levels, lipid parameters and their relationship were the main efficacy endpoints. The absolute levels of PCSK9 and LDL-C were not significantly different from baseline to 13 weeks. However, physiologic correlation between % change of PCSK9 and % change of LDL-C levels was normalized only in the group of patients treated with DS (r = 0.409, p = 0.012). This study shows that DS can restore statin disrupted physiologic positive correlation between PCSK9 and LDL-C. Elevated PCSK9 level is an independent risk factor so controlling its rise by statins may be important in prevention of cardiovascular events.     

Primary versus revision implant for inflatable penile prosthesis: A propensity score-matched comparison

Inflatable penile prosthesis (IPP) provides excellent outcomes after virgin implants. However, few data on IPP after revision surgery are available. This study aimed at comparing the outcomes of IPP in patients undergoing primary or revision implant surgery. Patients who underwent revision implant surgery (Group 1) between 2013 and 2020 were identified. Overall, 20 patients (Group 1) could be matched with a contemporary matched pair cohort of surgery-naive patients (Group 2) in a 1:1 ratio. Patients in Group 2 had a significantly shorter operative time [median (IQR): 84 (65–97) vs. 65 (51–75) min; p = .01] and lower rate of overall complications (25% vs. 10%; p = .01). Of note, mean (SD) scores for the Quality of Life and Sexuality with Penile Prosthesis (QoLSPP) questionnaire demonstrated high satisfaction and IPP efficacy in both Groups 1 and 2: functional domain [3.9 (1.0) vs. 4.0 (1.2); p = .4], personal [3.9 (1.1) vs. 4.0 (1.1); p = .3], relational [3.8 (1.3) vs. 3.9 (1.1); p = .5] and social [3.9 (1.1) vs. 4.0 (1.2); p = .2]. These results suggest that in experienced hands, IPP offers high satisfaction to both patients and partners even in the setting of revision implant. However, it is mandatory to inform those patients about the increased risk of perioperative complications.     

Predictive factors of recurrence in adenocarcinoma of the esophagogastric junction in the multimodal era

IntroductionAdenocarcinoma of the esophagogastric junction (AEGJ) represents a poor prognostic tumor. We evaluated the recurrence pattern and risk factors associated with recurrence in patients undergoing surgical resection by AEJG.MethodsRecurrences were categorized as locoregional, peritoneal, or distant. These three recurrence groups and a non-recurrence group were compared, and overall survival (OS) and disease-free survival (DFS) for each one was obtained.ResultsWe analyzed 188 patients with curative surgical treatment. Recurrence was observed in 72 (38.3%) patients. Locoregional recurrence was observed in 17 (23.6%); 20 (27.8%) peritoneal recurrence and 35 (48.6%) distant metastasis. DFS was 9, 5, and 8 months, and OS was 21.8, 13.2, and 20.8, respectively. Tumors larger than 5 cm are risk factors for peritoneal recurrence (OR:2.88, p = 0.012). Positive lymph nodes were related to distant metastasis (OR:9.15, p = 0.040), and lymphatic invasion for locoregional recurrence (OR:3.81, p = 0.028).ConclusionAEGJ is associated with high rates of early recurrence.     

Re-evaluating Blood Markers as Predictors of Outcome in Multivisceral and Intestinal Transplantation

BackgroundMultivisceral transplant (MVTx) and isolated intestinal transplant (ITx) are complex surgical procedures. The subsequent proinflammatory state in the immediate postoperative period makes interpretation of blood markers difficult.MethodWe aimed to establish the course of various blood markers after MVTx/ITx, and to evaluate their use as diagnostic markers of complications. This was a single center prospective cohort. We analyzed blood markers collected preoperatively, on alternate days for the first postoperative week, and then weekly for 4 weeks. This study was in compliance with The Declaration of Helsinki.ResultsOver a 16-month period (July 2017-October 2018), 20 subjects aged 2 to 67 years with a median age of 24.5 years received MVTx/ITx. Twelve recipients (60%) had an infection. Neutrophil lymphocyte count ratio (NLCR) was higher than established upper limits of normal, regardless of infection status. NLCR and white blood cell count were useful to identify infected MVTx/ITx recipients, with P values <.05 for 2 and 1 of 7 time points post transplant, respectively. Higher preoperative eosinophil% predicted future acute cellular rejection (P value .023).ConclusionsThis is the first study to extensively track the course of blood markers post MVTx/ITx and identified NLCR and white blood cell count as potential diagnostic blood markers of infection.     

Safety and efficacy of the cystic fibrosis transmembrane conductance regulator potentiator icenticaftor (QBW251)

BackgroundThis is the first-in-human study of icenticaftor, an oral potentiator of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) channel. Restoration of CFTR activity has shown significant clinical benefits, but more studies are needed to address all CFTR mutations.MethodsSafety, pharmacodynamics/pharmacokinetics of icenticaftor were evaluated in a randomized, double-blind, placebo-controlled study in healthy volunteers. Efficacy was assessed in adult CF patients with ≥1 pre-specified CFTR Class III or IV mutation (150 and 450 mg bid), or homozygous for F508del mutation (450 mg bid). Primary efficacy endpoint was change from baseline in lung clearance index (LCI_2.5). Secondary endpoints included %predicted FEV₁ and sweat chloride level.ResultsClass IV mutations were present in 22 patients, Class III in 2 (both S549N), and 25 were homozygous for F508del. Icenticaftor was well-tolerated in healthy and CF subjects with no unexpected events or discontinuations in the CF groups. The most frequent study-drug related adverse events in CF patients were nausea (12.2%), headache (10.2%), and fatigue (6.1%). Icenticaftor 450 mg bid for 14 days showed significant improvements in all endpoints versus placebo in patients with Class III and IV mutations; mean %predicted FEV₁ increased by 6.46%, LCI_2.5 decreased by 1.13 points and sweat chloride decreased by 8.36 mmol/L. No significant efficacy was observed in patients homozygous for a single F508del.ConclusionsIcenticaftor was safe and well-tolerated in healthy volunteers and CF patients, and demonstrated clinically meaningful changes in lung function and sweat chloride level in CF patients with Class III and IV CFTR mutations.ClinicalTrials.gov: NCT02190604     

How Stigma Toward Anal Sexuality Promotes Concealment and Impedes Health-Seeking Behavior in the U.S. Among Cisgender Men Who Have Sex with Men

Archives of Sexual Behavior - Gay, bisexual, and other men who have sex with men (MSM) experience alarming HIV disparities alongside sub-optimal engagement in HIV interventions. Among MSM, stigma...