BackgroundSubjective tinnitus is a phantom sensation experienced in the absence of any source of sound. Its mechanism remains unclear, and no approved drugs are available. Vagus nerve stimulation (VNS) is an exciting new method to treat tinnitus, but direct electrical stimulation of the cervical vagus has disadvantages. This randomized controlled clinical trial aims to overcome these limitations by stimulating the auricular branch of vagus nerve (ABVN) on the outer ear. Since the ABVN is the only peripheral branch of the vagus nerve distributed on the ear’s surface, it should be possible to achieve analogous efficacy to VNS by activating the central vagal pathways. However, researches have indicated that the curative effect lies in a combination of auditory and vagal nerve stimulation. Moreover, from traditional Chinese theory, auricular acupoints used to treat tinnitus are mainly in the regions supplied by the ABVN. Whether stimulation at the auricular acupoints is due to unintentional stimulation of vagal afferent fibers also needs evidence.Methods/designA total of 120 subjects with subjective tinnitus are randomized equally into four groups: (1) electrical stimulation at auricular acupoints (CO10, CO11, CO12, and TF4) innervated by the ABVN; (2) electrical stimulation at auricular acupoints (CO10, CO11, CO12, and TF4) innervated by ABVN pairing tones; (3) electrical stimulation at auricular acupoints innervated by non-ABVN pairing tones; (4) electrical acupuncture. Patients will be treated for 30 minutes every other day for 8 weeks. The primary outcome measure is the Tinnitus Handicap Inventory. The secondary outcome measure combines a visual analogue scale to measure tinnitus disturbance and loudness with the Hospital Anxiety and Depression Scale. Assessment is planned at baseline (before treatment) and in the 4th and 8th week, with further follow-up visits after termination of the treatment at the 12th week. Any adverse events will be promptly documented.DiscussionCompletion of this trial will help to confirm whether ABVN or the combination of ABVN and sound stimulus plays a more important role in treating tinnitus. Moreover, the result of this clinical trial will enhance our understanding of specific auricular acupoints.Trial registrationChinese Clinical Trials Register ChiCTR-TRC-14004940.

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NCT02229461.

Background CYNK-001 is a cryopreserved, allogeneic, off-the-shelf natural killer (NK) cell investigational product derived from placental CD34+ cells. CYNK-001 exhibits cytotoxicity against various cancer cell types as well as virally infected cells and secretes immunomodulatory cytokines upon target activation. This is the first study to evaluate the safety and potential efficacy of CYNK-001 to treat patients (pts) with SARS-CoV-2, previously investigated in only solid tumor and hematologic malignancies. Methods Placental CD34+ cells were cultured in the presence of cytokines for 35 days to generate CYNK-001 under the cGMP conditions. Pts with a positive RT-PCR test for SARS-CoV-2 from the nasopharynx and having moderate to severe illness, not requiring intensive care support or mechanical ventilation, were eligible. All enrolled pts received best supportive care. In the Phase 1 trial focused on safety of administration, a total of 14 pts will receive up to 3 CYNK-001 infusions on Days 1 (1.5e8 cells), 4 (6e8 cells), 7 (6e8 cells). Efficacy was measured by SARS-CoV-2 clearance as measured by RT-PCR testing and clinical measures of improvement, including pulmonary status, and inflammatory marker changes. Results Four of 6 pts treated to date were evaluable at the time of submission. All had multiple medical co-morbidities. Peripheral oxygen saturation (Sp02) ranged between 88-92% on up to 8L of supplemental oxygen and all had evidence of multilobar pneumonia on chest radiography. Two pts had received no prior therapy for COVID-19. The other 2 pts received remdesivir and dexamethasone, with the 4th pt also receiving convalescent plasma. In all 4 pts, all infusions were well tolerated. In 3 of 4 pts, oxygenation improved after the first infusion of CYNK-001 and radiographic improvement was noted. The 4th pt developed progressive hypoxemia prior to the administration of the first dose of CYNK-001, requiring more than 30L of supplemental oxygen delivered by facemask to support a Sp02>90%. All 3 doses of CYNK-001 were administered, but oxygen requirements increased. Twelve days after first CYNK-001 dose, the pt declined mechanical ventilation and died of respiratory failure. Attribution to CYNK-001 could not be ruled out. The remaining 3 pts were discharged with an average follow-up of 16 (9-32) days after first infusion. Conclusion In the first study to measure the safety and potential efficacy of CYNK-001 infusions to treat pts with COVID-19 disease, infusions were generally well tolerated with one Grade 5 event of hypoxic respiratory failure. Early efficacy has been seen in 3 of 4 pts with improvement of oxygenation, inflammatory markers, and radiographic findings. Once Phase 1 is completed, the Phase 2 portion of the study will test this approach in a randomized fashion compared to best available therapy to confirm efficacy of this approach. Citation Format: Corey Casper, Leonid Groysman, Vinay Malhotra, Eric Whitman, Stacy Herb, Erica Rave, Alan Lew, Cristina Goman, Zachary Sagawa, Monica Thakar, Victoria Lacasse, Cherie Daly, Shuyang He, Lin Kang, Sharmila Koppisetti, Tanel Mahlakõiv, Sunday Osokoya, William van der Touw, Junhong Zhu, Greg Berk, Xiaokui Zhang, Andrew Pecora, Robert Hariri. Early report of a phase I/II study of human placental hematopoietic stem cell derived natural killer cells (CYNK-001) for the treatment of adults with COVID-19 (NCT04365101) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT201.

Neuropathy is a major cause of morbidity and mortality in individuals with diabetes, with no effective therapy to alter the inevitable progression of nerve damage. We hypothesized that mesenchymal stroma cell-like populations, that are characterized as immune modulators also have the potential of inducing angiogenesis and neurite outgrowth, might be useful in treating diabetic peripheral neuropathy (DPN). The aims of this study were to investigate the efficacy and safety of mesenchymal stem cell-like product (PDA-002) in treating DPN. A phase-2 randomized placebocontrolled trial was conducted in 26 patients with DPN. Treatment consisted of three rounds of intramuscular injections in one lower limb using one of the three randomized treatment arms PDA-002 (low-dose 3 Â 10 6 cells), PDA-002 (high-dose 30 Â 10 6 cells), or placebo. Three treatments per patient occurred on days 1, 29, and 57. Study endpoints included efficacy and safety of PDA-002 in treating DPN in both lower extremities following unilateral local injection. Outcome measures included intra-epidermal nerve fiber density (IENFD) up to 1 year from the day of treatment with 6-month as the primary outcome measurement. In this phase 2 study of DPN, PDA-002 was well tolerated in both doses. No significant changes were noted in IENFD in both the treated and untreated leg in the NIS-LL, NTSS-6, or UENS. Mesenchymal stem cells represent a novel mechanism for treating diabetic neuropathy and are well tolerated. Preliminary results highlight the need of further investigation of PDA-001 as a disease modifying agent for treatment of DPN. K E Y W O R D S diabetes, diabetic peripheral neuropathy, neuropathy, stem cells 1 | INTRODUCTION Diabetes mellitus (DM) is a multi-organ system disease affecting the nerves, kidneys, eyes, and blood vessels. The estimated incidence of diabetes in the United States (US) exceeds 1.9 million new cases annually, with an overall prevalence of over 25 million people or 8.3% of the nation's population and approximately 50% of those with diabetes will have neurological complications. 1 Type 2 diabetes is by far the most common, accounting for 90% of all individuals with diabetes. 1The most common manifestation of diabetic peripheral neuropathy (DPN) is a distal symmetric polyneuropathy which initially affects the distal lower extremities and gradually ascends and can ultimately progress to sensory loss in the classical "stocking-glove" distribution. 2Abbreviations: CFB, change from baseline; DPN, diabetic peripheral neuropathy; IENFD, intra-epidermal nerve fiber density; NFD, nerve fiber density; NIS-LL, neurological impairment score of the lower limb; NTSS-6, 6-item neuropathy total symptom score; PDAC, placenta-derived adherent cells; UENS, Utah early neuropathy scale.