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Background Mesenchymal stem cells (MSCs) are promising for cell-based therapies targeting a wide range of diseases. However, challenges in translating MSC-based therapies to clinical applications necessitate standardized protocols following Good Manufacturing Practices (GMP) guidelines. This study aimed at developing GMP-complained protocols for FPMSCs isolation and manipulation, necessary for translational research, by (1) optimize culture of MSCs derived from an infrapatellar fat pad (FPMSC) condition through animal-free media comparison and (2) establish feasibility of MSC isolation, manufacturing and storage under GMP-compliance (GMP-FPMSC). Methods FPMSCs from three different patients were isolated following established protocols and the efficacy of two animal component-free media formulations in the culturing media were evaluated. The impact of different media formulations on cell proliferation, purity, and potency of MSCs was evaluated through doubling time, colony forming unit assay, and percentage of MSCs, respectively. Furthermore, the isolation and expansion of GMP-FPMSCs from four additional donors were optimized and characterized at each stage according to GMP requirements. Viability and sterility were checked using Trypan Blue and Bact/Alert, respectively, while purity and identity were confirmed using Endotoxin, Mycoplasma assays, and Flow Cytometry. The study also included stability assessments post-thaw and viability assessment to determine the shelf-life of the final GMP-FPMSC product. Statistical analyses were conducted using one-way ANOVA with Tukey’s Multiple Comparisons. Results The study demonstrated that FPMSCs exhibited enhanced proliferation rates when cultured in MSC-Brew GMP Medium compared to standard MSC media. Cells cultured in this media showed lower doubling times across passages, indicating increased proliferation. Additionally, higher colony formation in FPMSCs cultured in MSC-Brew GMP Medium were observed, supporting enhanced potency. Data from our GMP validation, including cells from 4 different donors, showed post-thaw GMP-FPMSC maintained stem cell marker expression and all the specifications required for product release, including > 95% viability (> 70% is required) and sterility, even after extended storage (up to 180 days), demonstrating the reproducibility and potential of GMP-FPMSCs for clinical use as well as the robustness of the isolation and storage protocols. Conclusions The study underscores the feasibility of FPMSCs for clinical uses under GMP conditions and emphasizes the importance of optimized culture protocols to improve cell proliferation and potency in MSC-based therapies.

In this paper, we propose a fully standard-cell-based common-mode feedback (CMFB) loop with an explicit voltage reference to improve the CMRR of pseudo-differential standard-cell-based amplifiers and to stabilize the dc output voltage. This latter feature allows robust biasing of operational transconductance amplifiers (OTAs) based on a cascade of such stages. A detailed analysis of the CMFB is reported to both provide insight into circuit behavior and to derive useful design guidelines. The proposed CMFB is then exploited to build a fully standard-cell OTA suitable for automatic place and route. Simulation results referring to the standard-cell library of a commercial 130 nm CMOS process illustrated a differential gain of 28.3 dB with a gain-bandwidth product of 15.4 MHz when driving a 1.5 pF load capacitance. The OTA exhibits good robustness under PVT and mismatch variations and achieves state-of-the-art FOMs also thanks to the limited area footprint.

Previous studies on telemedicine interventions have shown that older diabetic patients experience difficulty in using computers, which is a barrier to remote communication between medical teams and older diabetic patients. However, older people in China tend to find it easy to use mobile phones and personal messaging apps that have a user-friendly interface. Therefore, we designed a mobile health (mHealth) system for older people with diabetes that is based on mobile phones, has a streamlined operation interface, and incorporates maximum automation. The goal of the research was to investigate the use of mobile phone-based telemedicine apps for management of older Chinese patients with type 2 diabetes mellitus (T2DM). Variables of interest included efficacy and safety. A total of 91 older (aged over 65 years) patients with T2DM who presented to our department were randomly assigned to one of two groups. Patients in the intervention group (n=44) were provided glucometers capable of data transmission and received advice pertaining to medication, diet, and exercise via the mHealth telemedicine system. Patients assigned to the control group (n=47) received routine outpatient care with no additional intervention. Patients in both groups were followed up at regular 3-month intervals. After 3 months, patients in the intervention group showed significant (P<.05) improvement in postprandial plasma glucose level. After 6 months, patients in the intervention group exhibited a decreasing trend in postprandial plasma glucose and glycated hemoglobin levels compared with the baseline and those in the control group (P<.05). Mobile phone-based telemedicine apps help improve glycemic control in older Chinese patients with T2DM. China Clinical Trial Registration Center ChiCTR 1800015214; http://www.chictr.org.cn/showprojen.aspx?proj=25949 (Archived by WebCite at http://www.webcitation.org/73wKj1GMq).

Standard-cell placement is the fundamental step in a typical VLSI/ASIC design flow. Its result, paired with the outcome of the routing procedure can be the decisive factor in rendering a design manufacturable. Global placement generates an optimized instance of the design targeting a set of metrics, while ignoring rules pertaining its feasibility. Legalization and detailed placement rectify this situation, attempting to attain minimum quality loss by often disregarding the connectivity between cells and making runtime the focal point of these steps. In this article, we present a set of variations on a connectivity-based legalization scheme that can either be applied as a legalizer or a detailed placer. The variations can be applied in the entirety of the chip area or in the confinement of a user-specified bin while they are guided by various optimization goals, e.g., total wire length, displacement and density. We analytically describe our variations and evaluate them through extensive simulations on commonly used benchmarks.

Adipose-derived stem cells (ADSCs) have raised big interest in therapeutic applications in regenerative medicine and appear to fulfill the criteria for a successful cell therapy. Their low immunogenicity and their ability to self-renew, to differentiate into different tissue-specific progenitors, to migrate into damaged sites, and to act through autocrine and paracrine pathways have been altogether testified as the main mechanisms whereby cell repair and regeneration occur. The absence of standardization protocols in cell management within laboratories or facilities added to the new technologies improved at patient’s bedside and the discrepancies in cell outcomes and engraftment increase the limitations on their widespread use by balancing their real benefit versus the patient safety and security. Also, comparisons across pooled patients are particularly difficult in the fact that multiple medical devices are used and there is absence of harmonized assessment assays despite meeting regulations agencies and efficient GMP protocols. Moreover, the emergence of the COVID-19 breakdown added to the complexity of implementing standardization. Cell- and tissue-based therapies are completely dependent on the biological manifestations and parameters associated to and induced by this virus where the scope is still unknown. The initial flow chart identified for stem cell therapies should be reformulated and updated to overcome patient infection and avoid significant variability, thus enabling more patient safety and therapeutic efficiency. The aim of this work is to highlight the major guidelines and differences in ADSC processing meeting the current good manufacturing practices (cGMP) and the cellular therapy-related policies. Specific insights on standardization of ADSCs proceeding at different check points are also presented as a setup for the cord blood and bone marrow.

Transistor aging, mostly due to bias temperature instability (BTI), is one of the major unreliability sources at nano‐scale technology nodes. BTI causes the circuit delay to increase and eventually leads to a decrease in the circuit lifetime. Typically, standard cells in the library are optimised according to the design time delay; however, because of the asymmetric effect of BTI, the rise and fall delays might become significantly imbalanced over the lifetime. In this study, the BTI effect is mitigated by balancing the rise and fall delays of the standard cells at the excepted lifetime. The authors find an optimal tradeoff between the increase in the library size and the lifetime improvement by non‐uniform extension of the library cells for various ranges of the input signal probabilities. The simulation results reveal that this technique can prolong the circuit lifetime by around 150% with a negligible area overhead. Moreover, the effect of different realistic workloads on the distribution of internal node signal probabilities is investigated. This is done to obtain the sensitivity of the proposed static (design time) approach to different workloads during system lifetime. The results show that the proposed approach is still efficient if the workload changes during the runtime.

Hepatocyte‐like cells (HLCs) derived from pluripotent stem cells (PSCs) or direct reprogramming are an unlimited source of human hepatocytes for biomedical applications. HLCs are used to model human diseases, develop precise drugs and establish groundbreaking regenerative cell‐based therapies. Primary human hepatocytes are the gold standard for studying human liver biology and pathology. However, their widespread use is limited by their rapid dedifferentiation in vitro, reliance on transplant‐rejected donor organs, poor scalability and significant batch‐to‐batch variations. Therefore, high‐quality ‘off‐the‐shelf’ HLCs are needed to overcome those limitations. Basic stepwise differentiation protocols have been developed to generate HLCs from PSCs. To evaluate the quality of the in vitro generated products, HLCs have been phenotyped using various methods. This review discusses various biological assays and methods available for the robust evaluation of HLC quality, emphasising the importance of using 24‐h cultured primary human hepatocytes (PHHs) as a reference standard for comparison.

Circulating endothelial cells (CEC) represent a restricted peripheral blood (PB) cell subpopulation with high potential diagnostic value in many endothelium-involving diseases. However, whereas the interest in CEC studies has grown, the standardization level of their detection has not. Here, we undertook the task to align CEC phenotypes and counts, by standardizing a novel flow cytometry approach, within a network of six laboratories. CEC were identified as alive/nucleated/CD45negative/CD34bright/CD146positive events and enumerated in 269 healthy PB samples. Standardization was demonstrated by the achievement of low inter-laboratory Coefficients of Variation (CV L ), calculated on the basis of Median Fluorescence Intensity values of the most stable antigens that allowed CEC identification and count (CV L of CD34bright on CEC ~ 30%; CV L of CD45 on Lymphocytes ~ 20%). By aggregating data acquired from all sites, CEC numbers in the healthy population were captured (median female  = 9.31 CEC/mL; median male  = 11.55 CEC/mL). CEC count biological variability and method specificity were finally assessed. Results, obtained on a large population of donors, demonstrate that the established procedure might be adopted as standardized method for CEC analysis in clinical and in research settings, providing a CEC physiological baseline range, useful as starting point for their clinical monitoring in endothelial dysfunctions.

Adult umbilical cord blood transplantation (CBT) has emerged as an important option for patients lacking matched related (MRD) and matched unrelated donors (MUD). We compared chronic GVHD (cGVHD) incidence, immunosuppression burden and late infections and hospitalizations in consecutive patients undergoing CBT ( n =51) versus peripheral blood MUD transplant ( n =57) at our center between June 2009 and April 2014. At 3 years post transplantation, the cumulative incidence (CI) of moderate to severe cGVHD was 44% following MUD versus 8% following CBT ( P =0.0006) and CI of any cGVHD was 68% following MUD versus 32% following CBT ( P =0.0017). Median time to being off immunosuppression among CB patients was 268 days versus not reached among MUD patients ( P <0.0001). Late infections and late hospitalized days were reduced in CB patients ( P =0.1 and <0.001, respectively). Three-year CI of transplant-related mortality (TRM) and relapse as well as 3-year overall survival (OS) were similar following CB and MUD transplantation. We demonstrate a significantly lower incidence of cGVHD, immunosuppression burden and late complication rate following UCB versus peripheral blood MUD transplant without decreased OS, increased relapse or early TRM. Combined with the rapid availability of UCB, these findings have led our center to move primarily to UCB over peripheral blood MUD when a MRD is not available.

Acceptance and commitment therapy (ACT) is a pragmatic approach to help individuals decrease avoidable pain. This study aims to evaluate the effects of ACT delivered via an automated mobile messaging robot on postoperative opioid use and patient-reported outcomes (PROs) in patients with orthopedic trauma who underwent operative intervention for their injuries. Adult patients presenting to a level 1 trauma center who underwent operative fixation of a traumatic upper or lower extremity fracture and who used mobile phone text messaging were eligible for the study. Patients were randomized in a 1:1 ratio to either the intervention group, who received twice-daily mobile phone messages communicating an ACT-based intervention for the first 2 weeks after surgery, or the control group, who received no messages. Baseline PROs were completed. Two weeks after the operative intervention, follow-up was performed in the form of an opioid medication pill count and postoperative administration of PROs. The mean number of opioid tablets used by patients was calculated and compared between groups. The mean PRO scores were also compared between the groups. A total of 82 subjects were enrolled in the study. Of the 82 participants, 76 (38 ACT and 38 controls) completed the study. No differences between groups in demographic factors were identified. The intervention group used an average of 26.1 (SD 21.4) opioid tablets, whereas the control group used 41.1 (SD 22.0) tablets, resulting in 36.5% ([41.1-26.1]/41.1) less tablets used by subjects receiving the mobile phone-based ACT intervention (P=.004). The intervention group subjects reported a lower postoperative Patient-Reported Outcome Measure Information System Pain Intensity score (mean 45.9, SD 7.2) than control group subjects (mean 49.7, SD 8.8; P=.04). In this study, the delivery of an ACT-based intervention via an automated mobile messaging robot in the acute postoperative period decreased opioid use in selected patients with orthopedic trauma. Participants receiving the ACT-based intervention also reported lower pain intensity after 2 weeks, although this may not represent a clinically important difference. ClinicalTrials.gov NCT03991546; https://clinicaltrials.gov/ct2/show/NCT03991546.