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Obesity remains one of the largest health problems in the world, arising from the excess storage of triglycerides (TAGs). However, the full complement of genes that are important for regulating TAG storage is not known. The Glut1 gene encodes a Drosophila glucose transporter that has been identified as a potential obesity gene through genetic screening. Yet, the tissue-specific metabolic functions of Glut1 are not fully understood. Here, we characterized the role of Glut1 in the fly brain by decreasing neuronal Glut1 levels with RNAi and measuring glycogen and TAGs. Glut1RNAi flies had decreased TAG and glycogen levels, suggesting a nonautonomous role of Glut1 in the fly brain to regulate nutrient storage. A group of hormones that regulate metabolism and are expressed in the fly brain are Drosophila insulin-like peptides (Ilps) 2, 3, and 5. Interestingly, we observed blunted Ilp3 and Ilp5 expression in neuronal Glut1RNAi flies, suggesting Glut1 functions in insulin-producing neurons (IPCs) to regulate whole-organism TAG and glycogen storage. Consistent with this hypothesis, we also saw fewer TAGs and glycogens and decreased expression of Ilp3 and Ilp5 in flies with IPC-specific Glut1RNAi. Together, these data suggest Glut1 functions as a nutrient sensor in IPCs, controlling TAG and glycogen storage and regulating systemic energy homeostasis. [ABSTRACT FROM AUTHOR]

Rationale: Malignant pleural effusions (MPEs) are associated with significant health service use and healthcare costs, but the current evidence is limited. Objectives: To compare 12-month post-procedure: 1) health service utilization; and 2) healthcare costs after indwelling pleural catheter (IPC) insertion with at-home drainage performed by home care nursing services, versus in-hospital chemical pleurodesis. Methods: We performed a retrospective population-based study on a cohort of adults with MPEs who underwent IPC insertion or chemical pleurodesis between January 1, 2015 and December 31, 2019 using provincial health administrative data (Ontario, Canada). Patients were followed from the procedure date until death or until 12 months after the procedure. Inverse probability of treatment weighting was performed to adjust for imbalances in baseline characteristics. Differences in length of stay, readmissions, emergency department visits, home care visits, and healthcare costs were estimated using weighted regression analysis. Results: Of 5,752 included individuals, 4,432 (77%) underwent IPC insertion and 1,320 (23%) had pleurodesis. In the weighted sample, individuals who received an IPC had fewer inpatient days (12.4 d vs. 16 d; standardized mean difference, 0.229) but a higher proportion of subsequent admissions for empyema (2.7% vs. 1.1%; P = 0.0002) than those undergoing pleurodesis. Individuals with IPCs received more hours of nursing home care (41 h vs. 21.1 h; standardized mean difference, 0.671) but overall had lower average healthcare costs ($40,179 vs. $46,640 per patient; standardized mean difference, 0.177) than those receiving pleurodesis. Conclusions: IPCs with home nursing drainage are associated with reduced health resource use compared with pleurodesis in adults with MPEs, even after controlling for important baseline and clinical characteristics. Given that both procedures have similar health outcomes, our findings support the ongoing promotion of IPCs to increase outpatient management of patients with MPEs. [ABSTRACT FROM AUTHOR]

Background: Islet cell transplantation is an emerging therapy in the treatment of diabetes mellitus. Differentiation of islet cells from mesenchymal stem cells (MSCs) is a potential solution to the challenge of insufficient donor sources. This study investigated whether human umbilical cord‐derived MSCs could effectively differentiate into insulin‐producing cells (IPCs) and evaluated the therapeutic efficacy of IPCs in treating diabetes. Methods: IPCs were induced from MSCs by a two‐step protocol. IPC expression products were evaluated by western blot and real‐time PCR. IPC insulin secretion was evaluated by ELISA. The viability of IPCs was measured by FDA/PI and dithizone staining. The non‐human primate tree shrew was used as a diabetes model. After a single STZ induction into a diabetes model, a single intraportal transplantation of IPCs, MSCs, or normal saline was performed (n = 6 per group). Blood glucose was monitored for 3 weeks, then the animals were euthanized and the distribution of IPCs in the liver was examined pathologically. Results: After about 3 weeks of in vitro induction, IPCs formed microspheres of 100–200 μm, with >95% viable cells that were dithizone stain positive. IPCs expressed islet‐related genes and proteins and secreted high levels of insulin whether stimulated by low or high levels of glucose. After transplantation of IPCs into diabetic tree shrews, blood glucose levels decreased rapidly to near normal and were significantly lower than the MSC or saline groups for 3 weeks thereafter. Conclusion: We present the novel discovery that IPCs derived from human umbilical cord MSCs exert a therapeutic effect in a non‐human primate model of diabetes. This study provides a preliminary experimental basis for the use of autologous MSC‐derived IPCs in the treatment of human diabetes. [ABSTRACT FROM AUTHOR]

The global population of individuals afflicted with diabetes mellitus has been increasing year by year, and this disease poses a serious threat to human health as well as the economies worldwide. Pancreatic or islet transplantations provide one of the most effective and long-term therapies available to treat diabetes, but the scarcity and quality of pancreatic islets limit their use in treatments. Here, we report the development of a one-step, monolayer culture, and chemical-based protocol that efficiently mediates the differentiation of human adipose-derived stem cells (hADSCs) into insulin-producing cells (IPCs). Our data indicate that hADSCs in monolayer culture that are allowed to differentiate into IPCs are superior to those in suspension cultures with respect to insulin secretion capacity (213-fold increase), cell viability (93.5 ± 3.27% vs. 41.67 ± 13.17%), and response to glucose stimulation. Moreover, the expression of genes associated with pancreatic lineage specification, such as PDX1, ISL1, and INS (encoding insulin), were expressed at significantly higher levels during our differentiation protocol (6-fold for PDX1 and ISL1, 11.5-fold for INS). Importantly, in vivo studies demonstrated that transplantation with IPCs significantly mitigated hyperglycemia in streptozotocin-induced diabetic rats. Our results indicate that this one-step, rapid protocol increases the efficiency of IPC generation and that the chemical-based approach for IPC induction may reduce safety concerns associated with the use of IPCs for clinical applications, thereby providing a safe and effective cell-based treatment for diabetes. [ABSTRACT FROM AUTHOR]

In patients with type 1 diabetes (T1D), compromised pancreatic β-cell functions are compensated through daily insulin injections or the transplantation of pancreatic tissue or islet cells. However, both approaches are associated with specific challenges. The transplantation of mesenchymal stem cells (MSCs) represents a potential alternative, as MSCs have tissue-forming capacity and can be isolated from various tissues. The human umbilical cord (hUC) is a good source of freely available MSCs, which can be collected through pain-free, non-invasive methods subject to minimal ethical concerns. We sought to develop a method for the in vitro generation of insulin-producing cells (IPCs) using MSCs. We examined the potential therapeutic uses and efficacy of IPCs generated from hUC-derived MSCs (hUC-IPCs) and human adipose tissue (hAD)-derived MSCs (hAD-IPCs) through in vitro experiments and streptozotocin (STZ)-induced C57BL/6 T1D mouse models. We discovered that compared to hAD-IPCs, hUC-IPCs exhibited a superior insulin secretion capacity. Therefore, hUC-IPCs were selected as candidates for T1D cell therapy in mice. Fasting glucose and intraperitoneal glucose tolerance test levels were lower in hUC-IPC-transplanted mice than in T1D control mice and hAD-IPC-transplanted mice. Our findings support the potential use of MSCs for the treatment of T1D. [ABSTRACT FROM AUTHOR]

Background: Little is known about patient outcomes following treatment of malignant pleural effusions (MPE) in the real-world setting. Research question: We aimed to compare post-procedure all-cause mortality between individuals who received indwelling pleural catheter (IPC) insertion versus chemical pleurodesis for managing MPEs. Study design and methods: We performed a retrospective population-based study using provincial health administrative data (Ontario, Canada) of adults with a MPE who underwent IPC insertion or chemical pleurodesis between 2015 and 2019. Individuals were followed until death or March 31, 2021. Difference in post-procedure mortality was calculated using inverse probability of treatment weighting (IPTW)-adjusted Cox proportional hazard regression analysis to balance potential confounders at baseline. Results: We identified 4,790 (77.3%) individuals who received an IPC and 1,407 (22.7%) who had chemical pleurodesis for MPE. IPC insertions are increasing and chemical pleurodesis procedures are decreasing. The majority of IPCs were inserted in outpatients (61%), by pulmonologists (64.2%) and at sites with higher annual IPC volume, while chemical pleurodesis procedures were generally done by thoracic surgeons (74%) and at sites with higher annual pleurodesis volumes. In unadjusted comparison median time from initial cancer diagnosis to intervention was significantly longer in the IPC group (244 days, interquartile range [IQR]:33–903) compared to pleurodesis group (81 days, IQR:10–737; p < 0.0001). Unadjusted median time from index procedure to death was significantly longer in the pleurodesis group (165[IQR:48–457] days vs. 81[IQR:29–256] days, p < 0.0001), however the difference between groups became insignificant after the IPTW was applied (HR 1.27, 95%CI 0.95–1.69). 35% of IPCs were removed prior to death or end of follow-up. Interpretation: After adjusting for differences in baseline characteristics there was no difference in post-procedure mortality between IPC and chemical pleurodesis groups. In the real world, there are significant differences in the characteristics of patients who receive these two procedures and notable regional practice variation between procedure use. Future research should evaluate these variations in care and their effect on patient outcomes. [ABSTRACT FROM AUTHOR]

Background/aim: Type 1 diabetes mellitus (T1DM) is caused by the autoimmune-mediated destruction of insulin-producing cells (IPCs) and still has no effective cure. Better understanding of the molecular mechanisms involved in the differentiation of embryonic stem cells (ESCs) into IPCs may help us improve the therapeutic strategies for treating T1DM. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (Pfkfb1-4) are key regulators of glucose metabolism. Although Pfkfb3 has been shown to be required for the growth of early differentiated mouse ESCs (mESCs), more studies are needed to further assess the roles of Pfkfb isoenzymes in embryonic development and differentiation, particularly into specific cell types. In this study, we aimed to elucidate the changes in the expression of Pfkfb isoenzymes on the differentiation of mESCs into IPCs. Materials and methods: A 3-step protocol was used to differentiate R1 and J1 mESCs into IPCs. The changes in the gene expression of MafA, MafB, Ins2, and Nkx6.1 (IPC specific markers) and Pfkfb1-4 were analyzed using real-time quantitative polymerase chain reaction (qPCR). Insulin expression and secretion were determined by immunofluorescence (IF) staining and the enzyme linked immunosorbent assay (ELISA), respectively. Results: Upon differentiation, the IPC specific markers in differentiated cells were upregulated. Continued differentiation was confirmed by the development of insulin-positive islet-like clusters that secreted insulin in response to glucose uptake. Expressions of the Pfkfb2 and Pfkfb3 isoenzymes were markedly increased in various stages of differentiation. Conclusion: These findings suggest that Pfkfb2 and Pfkfb3 may impact the differentiation of mESCs into IPCs and the regulation of the insulin response to glucose levels. This study also lays a foundation for researchers to further probe the roles of Pfkfb isoenzymes on the differentiation of mESCs into IPCs and may open new avenues for regenerative medicine. [ABSTRACT FROM AUTHOR]

The adoptive transfer of insulin-producing cells (IPCs) is one of the promising treatments for insulin-dependent diabetes mellitus. While the use of allogeneic cell resources is inevitable in the case of a series of patients, alloimmune responses are a major barrier ahead of the successful implementation of allogeneic therapeutic cells. This study is aimed at evaluating the potential of CTLA4-Ig, as an approved immunomodulatory biologic, in protecting the IPCs against allogeneic immune responses. The C57BL/6 and BALB/c mice were used to establish a murine model of allogeneic cell transplantation. The mouse bone-marrow-derived mesenchymal stem cells were in vitro differentiated into IPCs, and the in vitro as well as the in vivo immune responses against IPCs were evaluated in the presence and absence of CTLA4-Ig. The allogeneic IPCs induced the in vitro activation of CD4+ T-cells, IFN-γ release, and the proliferation of lymphocytes, which all were controlled by CTLA4-Ig. Upon in vivo transfer of IPC into an allogeneic host, the splenic CD4+ and CD8+ T-cells exhibited a significant activation, and there was a significant donor-specific antibody response. Either of the mentioned cellular and humoral responses were modulated by a CTLA4-Ig regimen. This regimen also reduced the infiltration of CD3+ T-cells into the IPC injection site along with the improved overall survival of diabetic mice. CTLA4-Ig could be a complementary therapy for improving the efficacy of allogeneic IPC therapy through modulating the cellular and humoral responses that can lead to prolonged durability of IPCs within an allogeneic host. [ABSTRACT FROM AUTHOR]

Background: Interpersonal Communication Skills (IPCS) are one of the core clinical skills that should be developed by the Public Health Midwives (PHMs), who are grass-root level public healthcare providers in primary healthcare settings in Sri Lanka. This study aimed to develop and validate the Interpersonal Communication Assessment Tool (IPCAT), an observational rating scale, to assess the IPCS of PHMs. Methods: Item generation, item reduction, instrument drafting, and development of the tool's rating guide were made by an expert panel. A cross-sectional study was conducted in five randomly selected Medical Officer of Health (MOH) areas, the smallest public health administrative division in the district of Colombo, Sri Lanka, to identify the factor structure, which is the correlational relationship between a number of variables in the tool. A sample of 164 PHMs was recruited. The data on IPCS were collected by video-recording the provider-client interaction using simulated clients. All recorded videos were rated by a rater using the drafted IPCAT, which included a Likert scale of 1(poor) to 5 (excellent). Exploratory factor analysis was conducted using the Principal Axis Factoring extraction method and the Varimax rotation technique to explore the factors. Three independent raters were used to rate ten randomly selected videos to assess the tool's internal consistency and inter-rater reliability. Results: The IPCAT obtained a five-factor model with 22 items, and all five factors explained 65% of the total variance. The resulting factors were "Engaging" (six items on making rapport), "Delivering" (four items on paying respect), "Questioning" (four items on asking questions), "Responding" (four items on empathy), and "Ending" (four items to assess the skills of ending a conversation productively). The internal consistency, Cronbach's Alpha value, for all five factors was above 0.8, and the inter-rater reliability (ICC) was excellent (0.95). Conclusions: The Interpersonal Communication Assessment Tool is a valid and reliable tool for assessing the interpersonal communication skills of Public Health Midwives. Trial registration: Clinical Trial Registry, Sri Lanka. Ref No, SLCTR/2020/006(February 4th,2020) [ABSTRACT FROM AUTHOR]