Endovascular salvage of failing arterio-venous fistulas utilising sirolimus eluting balloons: Six months results from the ISABELLA trial

Background: Aim of this pilot clinical study was to evaluate the safety and efficacy of the Selution Sustained Limus Release (SLR)™ sirolimus-eluting balloon (SEB) for improving failing arterio-venous fistulas (AVF) patency in Asian haemodialysis patients. Methods: Prospective single-centre, multi-investigator, non-consecutive, non-blinded single arm trial. Forty end-stage renal failure Asian patients with a dysfunctional AVF underwent SEB angioplasty between May and November 2020. All stenotic lesions were prepared with high pressure non-compliant balloon angioplasty prior to SEB angioplasty. Endpoints of interest included target lesion primary patency and circuit access patency and safety through 30 days. All patients received dual antiplatelet therapy for 1 month and were followed up with Duplex ultrasound at 6 months. Results: There was one subject dropout so final n = 39 patients (mean age 65.0 ± 11.9; males = 26 (66.7%)) and n = 43 target lesions treated. Main indication for intervention was dropping access flow (24/39; 61.5%) and most common target lesion was in the juxta-anastomosis (24/43; 54.5%). There was 100% technical and procedural success. There were no adverse events related to the SEB. Target lesion primary patency rates at 3 and 6 months were 39/41 (95.1%) and 28/39 (71.8%) respectively. Access circuit patency rates at 3 and 6 months were 35/37 (94.6%) and 22/35 (62.9%) respectively. There were 3 (7.7%) deaths all attributable to patients’ underlying co-morbidities. Conclusions: Fistuloplasty using the novel Selution SLR™ SEB for dysfunctional AVF circuits seems a safe and effective modality in Asian haemodialysis patients at 6 months but larger randomised controlled studies are required now to determine its true efficacy against plain balloon angioplasty.

Remotely Supervised Cranial Electrical Stimulation and Clinical Pain for Older Adults With Knee Osteoarthritis

Knee osteoarthritis (KOA) is one of the most prominent causes of chronic pain, functional impairment, and disability in older adults. The current standards of care for KOA are aimed toward reducing pain and are largely comprised of analgesic medications, but existing pharmacologic approaches often produce significant adverse effects. Moreover, recent evidence suggests that KOA pain is characterized by alterations in pain-related brain mechanisms. Cranial electrical stimulation (CES), which delivers a low-amplitude alternating electric current to the brain, can facilitate the reversal of maladaptive brain function. Portable CES devices can be used at home with real-time monitoring through a secure videoconferencing platform to facilitate high adherence. Thus, the purpose of this pilot clinical study was to examine the preliminary efficacy of remotely supervised CES on clinical pain severity in older adults with KOA. Thirty participants with KOA were randomly assigned to receive 10 daily sessions of remotely supervised CES with 0.1 mA at a frequency of 0.5 Hz for 60 minutes (n=15) or sham CES (n=15). We measured clinical pain severity using the numeric rating scale (NRS; range, 0 – 100). Participants (67% female) had a mean age of 59 years. Active CES significantly reduced scores on the NRS (Cohen’s d = 1.43, P < 0.01). Participants tolerated CES well without any adverse events. Our findings demonstrate the promising clinical efficacy of remotely supervised CES for older adults with KOA. Future studies with larger-scale randomized controlled trials with follow-up assessments are needed to validate and extend our findings.

Preclinical Evaluation and Pilot Clinical Study of Al18F-DX600-BCH for non-invasive PET Mapping of Angiotensin Converting Enzyme 2 in Mammal

Angiotensin-converting enzyme 2 (ACE2), a transmembrane protein, is the main entry point for certain coronaviruses including the new coronavirus SARS-CoV-2 to enter cells. Synthesizing the PET imaging probe Al18F-DX600-BCH which is high-affinity ACE2 is aim to detect the expression of ACE2 in body and monitor the therapeutic effect. The Al18F-DX600-BCH was obtained manually with a 20.4% ± 5.2% radiochemical yield without attenuation correction and an over 99% purified radiochemical purity, being stable in vitro within 4 hours and cleared rapidly in blood (the half-lives of the distribution phase and clearance phase were 2.12 min and 25.31 min, respectively). Results of both biodistribution and PET imaging showed that Al18F-DX600-BCH was highly accumulated in the kidney (SUVkidney/normal > 50), and specific uptake in testis (SUVtestis/normal > 10) was observed in rat images. The kidney (++), gastrointestinal (++) and bronchial (+++) cells were evidenced of ACE2 positive by IHC staining of rats. A total of 10 volunteers were enrolled and received PET/CT 1 hour and 2 hours after injection or dynamic PET/CT during 0-330 seconds (NCT04542863), from which strong radioactivity accumulation was mostly observed in the genitourinary system (SUVrenal cortex = 32.00, SUVtestis = 4.56), and moderate accumulation in conjunctiva and nasal mucosa for several cases. This work firstly reported the probe Al18F-DX600-BCH targeting ACE2, conducting preliminary preclinical experiments and a total of 10 clinical transformations, which demonstrated the potential and possibility of non-invasive mapping of ACE2. Trial registration: ClinicalTrials.gov NCT04542863. Registered 9 September 2020.

Effect of Resveratrol on Serum Levels of Type II Collagen and Aggrecan in Patients with Knee Osteoarthritis: A Pilot Clinical Study

Treatment of knee osteoarthritis (OA) remains a challenging concern. Preclinical studies provided accumulating evidence on resveratrol efficacy in ameliorating degenerative articular damage. The present study was conducted to evaluate the effects of resveratrol as monotherapy on the serum level of type II collagen (Coll 2-1) and aggrecan in patients with knee osteoarthritis. The study was an open-labeled noncontrolled clinical trial. Resveratrol 500 mg/day in a single oral dose was given to the patients with knee osteoarthritis for 90 days. The serum levels of Coll-2-1, aggrecan, and biomarkers of inflammation were measured pre- and posttreatment. Hematological profiles and both hepatic and renal function markers were investigated at the baseline and at the end of the treatment for evaluating the tolerability and safety of resveratrol. Visual Analog Scale (VAS) for pain and Knee injury and Osteoarthritis Outcome Score (KOOS) for disease activity were clinically assessed monthly. Administration of 500 mg resveratrol for three months led to a nonsignificant decrease in the serum level of Coll 2-1 while a significant increase in aggrecan serum level. Resveratrol significantly improves pain score measured by VAS and KOOS after 30 days. Improvements in patients’ activity and functional status were also evident at day 30 and kept on for three months which was reflected by KOOS subscale scores and with a significant improvement in all KOOS areas. In conclusion, oral administration of resveratrol as a monotherapy provides a remarkable improvement in the clinical status of the patients but has no significant effect on serum levels of Coll 2-1.

CLOTHES DEVELOPMENT BASED ON METHODS OF HANDLING OF PREMATURE BABIES IN THE INTENSIVE CARE UNIT

The health of children born prematurely remains a significant challenge, but clothing products designed considering medical requirements and handling methods used in the intensive care unit, may contribute to the reduction of neonatal mortality. Assistants in the therapy unit implement practices based on the needs of vulnerable infants, from the very first second of life. This pilot clinical study was conducted in a specialised on neonatal intensive care unit, at the IMSP Municipal Clinical Hospital Gheorghe Paladi from Chisinau. Informed consent of parents and/or careers was required. All users (nurses and doctors) were informed about the product and instructed regarding dressing and undressing process. This controlled study was conducted under the supervision of doctors and nurses. As the study was exploratory in nature, aspects of grounded theory have been used for qualitative data collection. The sample studied consists of preterm infants less than 30 weeks GA, admitted by UTIN in 2018. The population eligible for qualitative data collection was made up of neonatology nurses from the clinic. To obtain a heterogeneous sample, aspects such as age, work experience, environment, and education were considered. The method of observation and subsequent testing used of the newly designed products and every manipulation under medical conditions was intensely studied. Local reactions, if any, due to the texture and quality of the textile material that come into contact with the baby's skin, were also carefully monitored. The process of dressing and stripping off the products, carrying out medical manipulations (in case of neonatal emergencies), were also carefully observed for developing ease of use clothes.

Evidence of acrolein in synovial fluid of dogs with osteoarthritis as a potential inflammatory biomarker

Background Acrolein is a known pro-inflammatory toxic aldehyde, propagating cellular damage and tissue inflammation in humans and animal models of various diseases. Osteoarthritis (OA) has a significant inflammatory component; however, presence of acrolein in synovial fluid of joints with OA has not been previously reported. The first aim of this study was to evaluate evidence of acrolein in the synovial fluid of dogs with OA as well as in Control joints. The second aim was to determine if evidence of acrolein can be detected in synovial fluid samples that have been in a frozen state for long periods of time. Methods In this pilot clinical study, synovial fluid samples were prospectively collected (i.e., New samples) from a single joint of both clinically healthy (New Control, n = 5) and dogs with OA (New OA, n = 16) and frozen until the time of analysis. Additionally, frozen synovial fluid samples from a biobank (i.e., Old samples) were used to evaluate ability to detect evidence of acrolein in long-term stored samples (median of 4.89 years) in Old Control (n = 5) and Old OA (n = 5) samples. Measurements of acrolein in all synovial fluid samples was based on detection of its major protein adduct, N ε - (3-formyl-3, 4-dehydropiperidino)lysine (FDP-lysine), using the western blot method. Synovial fluid matrix metalloproteinase 2 (MMP2) was measured in all samples using the western blot method as a positive control of OA inflammation. Results Acrolein-lysine adduct was detected in both Control (n = 10) and OA (n = 21) groups in both Old and New samples. Acrolein-lysine adduct and MMP2 were detectable at a lower level in the Old compared to New synovial fluid samples; however, the differences were not statistically significant (p > 0.1). The measured MMP2 levels were significantly higher in the OA compared to Control group samples (p = 0.033), but not for acrolein-lysine adduct (p = 0.30). Conclusions This study confirmed evidence of acrolein in canine synovial fluid of both OA and Control groups. Freezing of synovial fluid for up to 5 years does not appear to significantly affect the ability to detect acrolein-lysine adduct and MMP2 in these samples.

A Pilot Study to Assess the Salivary Gland Regenerative Potential of Bone Marrow Mesenchymal Stromal Cells from Treated Head and Neck Cancer Patients

Background: Salivary dysfunction is a significant side effect of radiation therapy for head and neck cancer (HNC). Preliminary data suggests that mesenchymal stromal cells (MSCs) can improve salivary function. Whether MSCs from HNC patients who have completed chemoradiation are functionally similar to those from healthy patients is unknown. We performed a pilot clinical study to determine whether bone marrow-derived MSCs (BM-MSCs) from HNC patients could be used for the treatment of RT-induced salivary dysfunction.Methods: An IRB-approved pilot clinical study was untaken on HNC patients with xerostomia who had completed treatment two or more years prior. Patients underwent iliac crest bone marrow aspirate and BM-MSCs were isolated and cultured. Culture expanded BM-MSCs were stimulated with IFNγ and cryopreserved prior to reanimation and profiling for functional markers by flow cytometry and ELISA. BM-MSCs were additionally injected into mice with radiation-induced xerostomia and the changes in salivary gland histology were examined. Results: A total of six subjects were enrolled. BM-MSCs from all subjects were culture expanded to >20 million cells in a median of 15.5 days (range 8-20 days). Flow cytometry confirmed that cultured cells from HNC patients were BM-MSCs. Functional flow cytometry demonstrated that these IFNγ-stimulated BM-MSCs acquired an immunosuppressive phenotype. IFNγ-stimulated BM-MSCs from HNC patients were found to express GDNF, WNT1, and R-spondin 1 as well as pro-angiogenesis and immunomodulatory cytokines. In mice, IFNγ-stimulated BM-MSCs decreased the loss of acinar cells decreased the formation of fibrosis. Conclusions: BM-MSCs from previously treated HNC patients can be expanded for auto-transplantation and are functionally active. Furthermore, IFNγ-stimulated BM-MSCs express proteins implicated in salivary gland regeneration. This study provides preliminary data supporting the feasibility of using autologous BM-MSCs from HNC patients to treat RT-induced salivary dysfunction.Trial Registration: NCT04007081, Registered July 5, 2019, https://clinicaltrials.gov/ct2/show/NCT04007081