Towards data-driven tele-medicine intelligence: community-based mental healthcare paradigm shift for smart aging amid COVID-19 pandemic.

Purpose: Telemedicine are experiencing an unprecedented boom globally since the beginning of the COVID-19 pandemic. As the most vulnerable groups amid COVID-19, the digital delivery of healthcare poses great challenges to the elderly population, caregiver, health service providers, and health policy makers. To bridge the service delivery gaps between the telemedicine demand side and supply side, explore evidence-based approach for integrated care, address challenges for aging policy, and build foundation for the development of data-driven and community-based telemedicine, our R&D team applied translational research to design and develop telemedicine "SMART" for enhancing elderly mental health wellbeing amid COVID-19. Our aim is to investigate the preparedness mechanisms of mental health disease including response, intervention, and connection these three healthcare delivery pipelines with the collection, consolidation, and synergy of heath parameters and social determinants, using data analytics approach to achieve Evidence-Based Medicine (EBM). Methods: A mix of quantitative and qualitative research design for scientifically rigorous consultation and analysis was conducted from Jan 2020 to June 2021 in Hong Kong. An exploratory and descriptive qualitative design was used in this study. The data were collected through focus group discussions conducted from elderly and their caregivers living in 10 main districts of Hong Kong. Our research pilot tested "SMART" targeting for elderly with mental health improvement needs. Baseline questionnaire with 110 tele-medicine product users includes questions on demographic information, self-rated mental health digital adoption. The follow-up five focus group discussions with 57 users (elderly and their caregivers) further explore the social determinants of telemedicine transformation and help propose the integrated telemedicine paradigm shift framework establishment, development, and enhancement. Results: Grounded on the baseline needs assessment and feedbacks collected, it is evident that multi-dimensional health information from the four various streams (community, clinic, home, remote) and customized digital health solutions are playing a key role in addressing elderly mental health digital service needs and bridging digital divide. The designed tele-medicine product lines up health service provider (supplier side) and elderly specific needs (demand side) with our three-level design, enables elderly and their families to follow and control their own health management and connect with the service provider, community of practice (CoP), and health policy makers. Conclusion: It's beneficial to involve elderly and gerontechnology stakeholders as part of Community-Based Participatory Research (CBPR) before and throughout the developing and delivery phases an integrated and age-friendly digital intervention. The challenges in applying and disseminating telemedicine reflected by the elderly and caregivers can be used as important input for further development and indicators for the sustainable and integrated elderly primary care framework. Supplementary Information: The online version contains supplementary material available at 10.1007/s13755-022-00198-4.

Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma.

PURPOSE: Effective treatment options are limited for patients with advanced (metastatic or unresectable) melanoma who progress after immune checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes has demonstrated efficacy in advanced melanoma. Lifileucel is an autologous, centrally manufactured tumor-infiltrating lymphocyte product. METHODS: We conducted a phase II open-label, single-arm, multicenter study in patients with advanced melanoma who had been previously treated with checkpoint inhibitor(s) and BRAF ± MEK targeted agents. Lifileucel was produced from harvested tumor specimens in central Good Manufacturing Practice facilities using a streamlined 22-day process. Patients received a nonmyeloablative lymphodepletion regimen, a single infusion of lifileucel, and up to six doses of high-dose interleukin-2. The primary end point was investigator-assessed objective response rate (ORR) per RECIST, version 1.1. RESULTS: Sixty-six patients received a mean of 3.3 prior therapies (anti-programmed death 1 [PD-1] or programmed death ligand 1 [PD-L1]: 100%; anticytotoxic T-lymphocyte-associated protein-4: 80%; BRAF ± MEK inhibitor: 23%). The ORR was 36% (95% CI, 25 to 49), with two complete responses and 22 partial responses. Disease control rate was 80% (95% CI, 69 to 89). Median duration of response was not reached after 18.7-month median study follow-up (range, 0.2-34.1 months). In the primary refractory to anti-PD-1 or PD-L1 therapy subset, the ORR and disease control rate were 41% (95% CI, 26 to 57) and 81% (95% CI, 66 to 91), respectively. Safety profile was consistent with known adverse events associated with nonmyeloablative lymphodepletion and interleukin-2. CONCLUSION: Lifileucel demonstrated durable responses and addresses a major unmet need in patients with metastatic melanoma with limited treatment options after approved therapy, including the primary refractory to anti-PD-1 or PD-L1 therapy subset.

Hypoxic preconditioning potentiates the trophic effects of mesenchymal stem cells on co-cultured human primary hepatocytes.

INTRODUCTION: Mesenchymal stem/stromal cells (MSCs) improve the metabolic function of co-cultured hepatocytes. The present study aimed to further enhance the trophic effects of co-culture with hepatocytes using hypoxic preconditioning (HPc) of the MSCs and also to investigate the underlying molecular mechanisms involved. METHODS: Human adipose tissue-derived MSCs were subjected to hypoxia (2 % O2; HPc) or normoxia (20 % O2) for 24 h and then co-cultured with isolated human hepatocytes. Assays of metabolic function and apoptosis were performed to investigate the hepatotrophic and anti-apoptotic effects of co-culture. Indirect co-cultures and co-culture with MSC-conditioned medium investigated the role of paracrine factors in the hepatotrophic effects of co-culture. Reactive oxygen species (ROS) activity was antagonised with N-acetylcysteine to investigate whether HPc potentiated the effects of MSCs by intracellular ROS-dependent mechanisms. Tumour necrosis factor (TNF)-α, transforming growth factor (TGF)-ß1, and extracellular collagen production was determined and CASP9 and BAX/BCL-2 signalling pathways analysed to investigate the role of soluble factors, extracellular matrix deposition, and apoptosis-associated gene signalling in the effects of co-culture. RESULTS: HPc potentiated the hepatotrophic and anti-apoptotic effects of co-culture by ROS-dependent mechanisms. There was increased MSC TGF-ß1 production, and enhanced MSC deposition of extracellular collagen, with reduced synthesis of TNF-α, as well as a downregulation of the expression of pro-apoptotic CASP9, BAX, BID and BLK genes and upregulated expression of anti-apoptotic BCL-2 in hepatocytes. CONCLUSIONS: HPc potentiated the trophic and anti-apoptotic effects of MSCs on hepatocytes via mechanisms including intracellular ROS, autocrine TGF-ß, extracellular collagen and caspase and BAX/BCL-2 signalling pathways.

Small intestinal submucosa seeded with intestinal smooth muscle cells in a rodent jejunal interposition model.

BACKGROUND: Small intestinal submucosa (SIS) is a porcine-derived, acellular, collagen-based matrix that has been tested without seeded smooth muscle cells (SMCs) for intestinal tissue engineering. We examined the expression patterns of contractile proteins of SIS with SMCs implanted in an in vivo rodent model. MATERIALS AND METHODS: Intestinal SMCs were isolated from Lewis rat pups. Four-ply tubular SMCs-seeded SIS or blank SIS scaffolds were implanted in an adult rat jejunal interposition model. Recipients were sacrificed at 2, 4, and 8 wk following the implantation. The retrieved specimens were examined using antibodies against contractile proteins of SMCs. RESULTS: Cultured intestinal SMCs expressed α-smooth muscle actin (α-SMA), calponin, and less smooth muscle myosin heavy chain (SM-MHC) in vitro. Cell-seeded SIS scaffolds contracted significantly over 8 wk of implantation but were comparable to SIS scaffolds without cell seeding. Implanted cell-seeded SIS scaffolds at 2 wk expressed extensive α-SMA, some calponin, and minimal SM-MHC. At 4 wk, α-SMA-expressing cells decreased significantly, whereas calponin or SM-MHC expressing cells were rarely detected. A small number of α-SMA-expressing cells were present at 8 wk, whereas more calponin or SM-MHC expressing cells emerged in proximity with the anastomotic interface. CONCLUSIONS: Cell-seeded SIS contracted significantly after implantation, but the expressions of contractile proteins were present at the site of SIS interposition. No organized smooth muscle was formed at the site of implantation. A better scaffold design is needed to produce structured smooth muscle.

Benzalkonium chloride-treated anorectums mimicked endothelin-3-deficient aganglionic anorectums on manometry.

BACKGROUND/PURPOSE: The anorectal spasticity in Hirschsprung disease may be caused by the absence of enteric ganglia and/or the presence of hypertrophic nerves. Anorectal manometry of chemically denervated rectums was compared with that of congenital aganglionic rectums that also possessed hypertrophic nerves. METHODS: Aganglionic and ganglionic littermates were produced from breeding heterozygous lethal-spotted mice. Benzalkonium chloride was endorectally injected into ganglionic rectums to ablate the neural elements. Anorectal manometry was performed before the injection and on day 14 postinjection. The anorectal resting pressure was calculated based on the manometric tracing. Rectums were retrieved on day 14 for histologic evaluations. RESULTS: Benzalkonium chloride injection successfully ablated the rectal ganglia. Although ganglionic littermates exhibited regular slow waves on anorectal manometry, aganglionic lethal-spotted mice showed irregular waves. Similar to lethal spotted mice, benzalkonium chloride-treated mice exhibited significantly higher anorectal resting pressure than that of ganglionic mice. The slow waves were absent in benzalkonium chloride-treated mice. CONCLUSION: Benzalkonium chloride treatment produced aganglionic rectums that had higher resting pressure similar to the congenital aganglionic rectums. This suggests that hypertrophic nerves in congenital aganglionosis are not necessary to produce the anorectal spasticity.

Transplantation of adrenal cortical progenitor cells enriched by Nile red.

BACKGROUND: The adrenal cortex may contain progenitor cells useful for tissue regeneration. Currently there are no established methods to isolate these cells. MATERIAL AND METHODS: Murine adrenal cells were sorted into a Nile-red-bright (NR(bright)) and a Nile-red-dim (NR(dim)) population of cells according to their degree of cholesterol content revealed by Nile red fluorescence. The cells were transplanted under the renal capsule to determine their ability for regeneration. RESULTS: The NR(bright) cells contained an abundance of lipid droplets, whereas the NR(dim) cells contained little. The NR(bright) cells expressed Sf1 and the more differentiated adrenal cortical genes, including Cyp11a1, Cyp11b1, and Cyp11b2, whereas the NR(dim) cells expressed Sf1 but not the more differentiated adrenal cortical genes. After 56 d of implantation in unilateral adrenalectomized mice, the NR(dim) cells expressed Sf1 and the more differentiated adrenal cortical genes, whereas the NR(bright) cells ceased to express Sf1 as well as the more differentiated adrenal cortical genes. NR(dim) cells also proliferated in the presence of basic fibroblast growth factor. CONCLUSIONS: The population of NR(dim) cells contained adrenal cortical progenitor cells that can proliferate and give rise to differentiated daughter cells. These cells may be useful for adrenal cortical regeneration.