Development of a robotic cluster for automated and scalable cell therapy manufacturing.

BACKGROUND AIMS: The production of commercial autologous cell therapies such as chimeric antigen receptor T cells requires complex manual manufacturing processes. Skilled labor costs and challenges in manufacturing scale-out have contributed to high prices for these products. METHODS: We present a robotic system that uses industry-standard cell therapy manufacturing equipment to automate the steps involved in cell therapy manufacturing. The robotic cluster consists of a robotic arm and customized modules, allowing the robot to manipulate a variety of standard cell therapy instruments and materials such as incubators, bioreactors, and reagent bags. This system enables existing manual manufacturing processes to be rapidly adapted to robotic manufacturing, without having to adopt a completely new technology platform. Proof-of-concept for the robotic cluster's expansion module was demonstrated by expanding human CD8+ T cells. RESULTS: The robotic cultures showed comparable cell yields, viability, and identity to those manually performed. In addition, the robotic system was able to maintain culture sterility. CONCLUSIONS: Such modular robotic solutions may support scale-up and scale-out of cell therapies that are developed using classical manual methods in academic laboratories and biotechnology companies. This approach offers a pathway for overcoming manufacturing challenges associated with manual processes, ultimately contributing to the broader accessibility and affordability for personalized immunotherapies.

Vasospasm and subsequent stroke from paraneoplastic syndrome in a pediatric patient with an intracranial mature teratoma: a case report.

Teratomas account for 18-20% of all intracranial germ cell tumors and mostly occur in the pineal region with only a few cases of pediatric sellar and suprasellar teratomas described in the literature. Here, we present a case of a child with an intracranial mature teratoma with pancreatic features causing vasospasm and subsequent stroke, found to be positive for CDKN2A-an independent variant associated with malignancy and small vessel disease leading to stroke.

Current Strategies for Treatment of Mandibular Fractures With Plate Osteosynthesis: A European Prospective Study.

PURPOSE: The training and preferences of surgeons influence the type of surgical treatment for mandibular fractures. This multicentre prospective study analyzed the current treatment strategies and outcomes for mandibular fractures with open reduction and internal fixation (ORIF). MATERIAL AND METHODS: This prospective study included patients aged ≥16 years who underwent ORIF for mandibular fractures in 12 European maxillofacial centers. Age, sex, pretrauma dental status, fracture cause, site and type, associated facial fractures, surgical approach, plate number and thickness (≤1.4 or ≥1.5 mm), duration of postoperative maxillomandibular fixation, occlusal and infective complications at 6 weeks and 3 months, and revision surgeries were recorded. RESULTS: Between May 1, 2021 and April 30, 2022, 425 patients (194 single, 182 double, and 49 triple mandibular fractures) underwent ORIF for 1 or more fractures. Rigid osteosynthesis was performed for 74% of fractures and was significantly associated with displaced ( P =0.01) and comminuted ( P =0.03) fractures and with the number of nonsurgically treated fracture sites ( P =0.002). The angle was the only site associated with nonrigid osteosynthesis ( P <0.001). Malocclusions (5.6%) and infective complications (5.4%) were not associated with osteosynthesis type. CONCLUSION: Rigid osteosynthesis was the most frequently performed treatment at all fracture sites, except the mandibular angle, and was significantly associated with displaced and comminuted fractures and the number of nonsurgically treated fracture sites. No significant differences were observed regarding postoperative malocclusion or infections among osteosynthesis types.

A Critical View over the Newest Antidiabetic Molecules in Light of Efficacy-A Systematic Review and Meta-Analysis.

The increase in life expectancy without a decrease in the years lived without disability leads to the rise of the population aged over 65 years prone to polypharmacy. The novel antidiabetic drugs can improve this global therapeutic and health problem in patients with diabetes mellitus (DM). We aimed to establish the efficacy (A1c hemoglobin reduction) and safety of the newest antidiabetic drugs (considered so due to their novelty in medical practice use), specifically DPP-4i, SGLT-2i, GLP-1 Ra, and tirzepatide. The present meta-analysis followed the protocol registered at Prospero with the CRD42022330442 registration number. The reduction in HbA1c in the DPP4-i class for tenegliptin was 95% CI -0.54 [-1.1, 0.01], p = 0.06; in the SGLT2-iclass for ipragliflozin 95% CI -0.2 [-0.87, 0.47], p = 0.55; and for tofogliflozin 95% CI 3.13 [-12.02, 18.28], p = 0.69, while for tirzepatide it was 0.15, 95% CI [-0.50, 0.80] (p = 0.65). The guidelines for treatment in type 2 DM are provided from cardiovascular outcome trials that report mainly major adverse cardiovascular events and data about efficacy. The newest antidiabetic non-insulinic drugs are reported to be efficient in lowering HbA1c, but this effect depends between classes, molecules, or patients' age. The newest antidiabetic drugs are proven to be efficient molecules in terms of HbA1c decrease, weight reduction, and safety, but more studies are needed in order to characterize exactly their efficacy and safety profiles.

Manual versus rigid intraoperative maxillo-mandibular fixation in the surgical management of mandibular fractures: A European prospective analysis.

PURPOSE: Intraoperative stabilisation of bony fragments with maxillo-mandibular fixation (MMF) is an essential step in the surgical treatment of mandibular fractures that are treated with open reduction and internal fixation (ORIF). The MMF can be performed with or without wire-based methods, rigid or manual MMF, respectively. The aim of this study was to compare the use of manual versus rigid MMF, in terms of occlusal outcomes and infective complications. MATERIALS AND METHODS: This multi-centric prospective study involved 12 European maxillofacial centres and included adult patients (age ≥16 years) with mandibular fractures treated with ORIF. The following data were collected: age, gender, pre-trauma dental status (dentate or partially dentate), cause of injury, fracture site, associated facial fractures, surgical approach, modality of intraoperative MMF (manual or rigid), outcome (minor/major malocclusions and infective complications) and revision surgeries. The main outcome was malocclusion at 6 weeks after surgery. RESULTS: Between May 1, 2021 and April 30, 2022, 319 patients-257 males and 62 females (median age, 28 years)-with mandibular fractures (185 single, 116 double and 18 triple fractures) were hospitalised and treated with ORIF. Intraoperative MMF was performed manually on 112 (35%) patients and with rigid MMF on 207 (65%) patients. The study variables did not differ significantly between the two groups, except for age. Minor occlusion disturbances were observed in 4 (3.6%) patients in the manual MMF group and in 10 (4.8%) patients in the rigid MMF group (p > .05). In the rigid MMF group, only one case of major malocclusion required a revision surgery. Infective complications involved 3.6% and 5.8% of patients in the manual and rigid MMF group, respectively (p > .05). CONCLUSION: Intraoperative MMF was performed manually in nearly one third of the patients, with wide variability among the centres and no difference observed in terms of number, site and displacement of fractures. No significant difference was found in terms of postoperative malocclusion among patients treated with manual or rigid MMF. This suggests that both techniques were equally effective in providing intraoperative MMF.

Vaccination coverage among older adults: a population-based study in India.

Objective: To estimate the prevalence and explore the predictors of vaccine uptake among older adults in India. Methods: We used data from the national Longitudinal Ageing Study in India, a national household survey conducted during 2017-2018. Based on interviewees' self-reports, we calculated population-weighted estimates of the uptake of influenza, pneumococcal, typhoid and hepatitis B vaccines among 64 714 Indian adults aged 45 years or older. We performed multivariable binary logistic regression analysis to examine the sociodemographic and health-related predictors of uptake of the vaccinations. Findings: The coverage of each of the studied vaccinations was less than 2%. The estimated percentages of respondents reporting ever being vaccinated were 1.5% (95% confidence interval, CI: 1.4-1.6) for influenza, 0.6% (95% CI: 0.6-0.7) for pneumococcal disease, 1.9% (95% CI: 1.8-2.0) for typhoid and 1.9% (95% CI: 1.8-2.0) for hepatitis B. Vaccine uptake was higher among respondents with cardiovascular disease, diabetes or lung disease than those without any of these conditions. Uptake of influenza vaccine was higher among those with lung disease, while hepatitis B vaccine uptake was higher among those with cardiovascular disease or diabetes. Male sex, urban residence, wealthier household, more years of schooling, existing medical conditions and sedentary behaviours were significant predictors of vaccine uptake. Conclusion: Targeted policies and programmes are needed for improving the low vaccination coverage among older adults in India, especially among those with chronic diseases. Further research could examine vaccine access, vaccine hesitancy, and vaccine-related information and communication channels to older adults and their health-care providers.

The Relationship between COVID-19 and Hypothalamic-Pituitary-Adrenal Axis: A Large Spectrum from Glucocorticoid Insufficiency to Excess-The CAPISCO International Expert Panel.

Coronavirus disease 2019 (COVID-19) is a highly heterogeneous disease regarding severity, vulnerability to infection due to comorbidities, and treatment approaches. The hypothalamic-pituitary-adrenal (HPA) axis has been identified as one of the most critical endocrine targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that might significantly impact outcomes after infection. Herein we review the rationale for glucocorticoid use in the setting of COVID-19 and emphasize the need to have a low index of suspicion for glucocorticoid-induced adrenal insufficiency, adjusting for the glucocorticoid formulation used, dose, treatment duration, and underlying health problems. We also address several additional mechanisms that may cause HPA axis dysfunction, including critical illness-related corticosteroid insufficiency, the direct cytopathic impacts of SARS-CoV-2 infection on the adrenals, pituitary, and hypothalamus, immune-mediated inflammations, small vessel vasculitis, microthrombotic events, the resistance of cortisol receptors, and impaired post-receptor signaling, as well as the dissociation of ACTH and cortisol regulation. We also discuss the increased risk of infection and more severe illness in COVID-19 patients with pre-existing disorders of the HPA axis, from insufficiency to excess. These insights into the complex regulation of the HPA axis reveal how well the body performs in its adaptive survival mechanism during a severe infection, such as SARS-CoV-2, and how many parameters might disbalance the outcomes of this adaptation.

Accuracy of Original vs. Non-Original Abutments Using Various Connection Geometries for Single Unit Restorations: A Systematic Review.

PURPOSE: To ascertain whether the compatibility of non-original abutments (NOAs) with dental implants is influenced by the type of implant connection, i.e.- internal or external, and whether certain combinations of componentry may be as compatible as the original components. METHODS: A structured literature search was conducted using 3 electronic databases (MEDLINE® , The Cochrane Library, and Web of Science Core Collection) for studies reporting on the use of non-original abutments published between 1995 and 2020. This was supplemented with hand searching in relevant journals and references, as well as searching grey literature. Relevant studies were selected according to specific inclusion criteria. Data was collected for the following parameters: precision of fit, microleakage, micromorphological differences, micromotion, rotational misfit, screw loosening, maximum load capacity, fracture resistance, tensile strength, compressive strength and invivo implant and prosthesis outcomes. RESULTS: The electronic search and hand search yielded titles and abstracts of 5617 studies following de-duplication; based on the eligibility criteria, 40 studies were finally selected. Overall, original abutments showed better precision of fit, ability to resist microleakage, prevention of rotational misfit and micromotion, and fatigue strength compared with non-original abutments. Some non-original abutments on external connections were comparable with original abutments in terms of precision of fit and resistance to screw loosening and may be associated with less catastrophic failures than those on internal connections. CONCLUSION: Original abutments present more predictable outcomes than non-original abutments with regards to the parameters investigated. However, it seems that external connections can provide some level of compatibility in terms of precision of fit and may also exhibit less catastrophic failures than NOAs on internal connections. This may be due to the increased rotational freedom external connections provide. There is a lack of information regarding the influence of connection geometry on many aspects of compatibility and therefore the current clinical recommendation should be to use original abutments. More laboratory studies comparing non-original abutments on different implant connections are required. In addition, there is a need for long-term in vivo studies providing data on the clinical performance of non-original abutments.

Experimental and Emerging Free Fatty Acid Receptor Agonists for the Treatment of Type 2 Diabetes.

The current management of Type 2 Diabetes Mellitus (T2DM) includes incretin-based treatments able to enhance insulin secretion and peripheral insulin sensitivity as well as improve body mass, inflammation, plasma lipids, blood pressure, and cardiovascular outcomes. Dietary Free Fatty Acids (FFA) regulate metabolic and anti-inflammatory processes through their action on incretins. Selective synthetic ligands for FFA1-4 receptors have been developed as potential treatments for T2DM. To comprehensively review the available evidence for the potential role of FFA receptor agonists in the treatment of T2DM, we performed an electronic database search assessing the association between FFAs, T2DM, inflammation, and incretins. Evidence indicates that FFA1-4 agonism increases insulin sensitivity, induces body mass loss, reduces inflammation, and has beneficial metabolic effects. There is a strong inter-relationship between FFAs and incretins. FFA receptor agonism represents a potential target for the treatment of T2DM and may provide an avenue for the management of cardiometabolic risk in susceptible individuals. Further research promises to shed more light on this emerging topic.

An Update on the Current and Emerging Use of Thiazolidinediones for Type 2 Diabetes.

Guidelines have increasingly stressed the concept that adequate glycemic control is required to prevent or decrease the macro- and microvascular complications of type 2 diabetes mellitus (T2DM). PPAR-gamma agonists ("glitazones") are no longer prioritized due to their effects on heart failure. However, the association between these drugs and innovative therapies could be a valuable tool to attenuate the risk factors of the metabolic syndrome. Glitazones are used for the treatment of diabetes and associated comorbidities. There is substantial scientific evidence demonstrating the effect of glitazones at a cardiometabolic level, as well as on hematological and neurological pathologies that point to their usefulness. The use of glitazones has always been controversial both for the type of patients who must take these drugs and for the side effects associated with them. Unfortunately, the recent guidelines do not include them among the preferred drugs for the treatment of hyperglycemia and rosiglitazone is out of the market in many countries due to an adverse cardiovascular risk profile. Even though real-life studies have proven otherwise, and their pleiotropic effects have been highlighted, they have been unable to achieve primacy in the choice of antihyperglycemic drugs. It would be appropriate to demonstrate the usefulness of pioglitazone and its therapeutic benefit with further cardiovascular safety studies.

Metabolic Syndrome: From Molecular Mechanisms to Novel Therapies.

The metabolic syndrome (MetS) consists of a cluster of metabolic abnormalities including central obesity, insulin resistance, glucose intolerance, hypertension, and atherogenic dyslipidemia [...].

Cardiometabolic Alterations in the Interplay of COVID-19 and Diabetes: Current Knowledge and Future Avenues.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (coronavirus disease 2019 [COVID-19]) pandemic has raged for almost two years, with few signs of a sustained abatement or remission [...].

The Evolving Role of Fetuin-A in Nonalcoholic Fatty Liver Disease: An Overview from Liver to the Heart.

Nonalcoholic fatty liver disease (NAFLD) is strongly associated to the features of metabolic syndrome which can progress to cirrhosis, liver failure and hepatocellular carcinoma. However, the most common cause of mortality in people with NAFLD is not liver-related but stems from atherosclerotic cardiovascular disease (CVD). The prevalence of NAFLD is on the rise, mainly as a consequence of its close association with two major worldwide epidemics, obesity and type 2 diabetes (T2D). The exact pathogenesis of NAFLD and especially the mechanisms leading to disease progression and CVD have not been completely elucidated. Human fetuin-A (alpha-2-Heremans Schmid glycoprotein), a glycoprotein produced by the liver and abundantly secreted into the circulation appears to play a role in insulin resistance, metabolic syndrome and inflammation. This review discusses the links between NAFLD and CVD by specifically focusing on fetuin-A's function in the pathogenesis of NAFLD and atherosclerotic CVD.

Reconnoitering the Role of Long-Noncoding RNAs in Hypertrophic Cardiomyopathy: A Descriptive Review.

Hypertrophic cardiomyopathy (HCM) is the most common form of hereditary cardiomyopathy. It is characterized by an unexplained non-dilated hypertrophy of the left ventricle with a conserved or elevated ejection fraction. It is a genetically heterogeneous disease largely caused by variants of genes encoding for cardiac sarcomere proteins, including MYH7, MYBPC3, ACTC1, TPM1, MYL2, MYL3, TNNI3, and TNNT23. Preclinical evidence indicates that the enhanced calcium sensitivity of the myofilaments plays a key role in the pathophysiology of HCM. Notably, this is not always a direct consequence of sarcomeric variations but may also result from secondary mutation-driven alterations. Long non-coding RNAs (lncRNAs) are a large class of transcripts ≥200 nucleotides in length that do not encode proteins. Compared to coding mRNAs, most lncRNAs are not as well-annotated and their functions are greatly unexplored. Nevertheless, increasing evidence shows that lncRNAs are involved in a variety of biological processes and diseases including HCM. Accumulating evidence has indicated that lncRNAs are dysregulated in HCM, and closely related to sarcomere construction, calcium channeling and homeostasis of mitochondria. In this review, we have summarized the known regulatory and functional roles of lncRNAs in HCM.

Novel Therapeutical Approaches to Managing Atherosclerotic Risk.

Atherosclerosis is a multifactorial vascular disease that leads to inflammation and stiffening of the arteries and decreases their elasticity due to the accumulation of calcium, small dense Low Density Lipoproteins (sdLDL), inflammatory cells, and fibrotic material. A review of studies pertaining to cardiometabolic risk factors, lipids alterations, hypolipidemic agents, nutraceuticals, hypoglycaemic drugs, atherosclerosis, endothelial dysfunction, and inflammation was performed. There are several therapeutic strategies including Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) inhibitors, inclisiran, bempedoic acid, Glucagon-Like Peptide-1 Receptor agonists (GLP-1 RAs), and nutraceuticals that promise improvement in the atheromatous plaque from a molecular point of view, because have actions on the exposure of the LDL-Receptor (LDL-R), on endothelial dysfunction, activation of macrophages, on lipid oxidation, formations on foam cells, and deposition extracellular lipids. Atheroma plaque reduction both as a result of LDL-Cholesterol (LDL-C) intensive lowering and reducing inflammation and other residual risk factors is an integral part of the management of atherosclerotic disease, and the use of valid therapeutic alternatives appear to be appealing avenues to solving the problem.

Endocrinology in the Time of COVID-19: A Rapid Evolution of Knowledge and Care.

American singer-writer and visual artist Bob Dylan produced the song "The Times They Are a-Changin" in the 1960s, which became a rallying cry for the civil rights and anti-war movements in that decade [...].

Delirium: Medical Students' Knowledge and Effectiveness of Different Teaching Methods.

OBJECTIVE: Medical schools are often blamed for inadequately training doctors on delirium. This study assesses the knowledge of medical students regarding delirium and evaluates different teaching methods for comparing learning outcomes. METHODS: A video, a handout, and a video+handout were used as three different teaching methods. Students were randomly assigned to three groups and pre- and postintervention knowledge gains were compared. Interventions were held between 2015 and 2018 at the University of Heidelberg Medical School in Germany. Seventy-eight (video intervention 33; handout 26; video+handout 19) sixth-year medical students participated. Participants learned about delirium with the help of a video, a handout, and both a video+handout at the start of one-hour lectures dedicated to teaching about delirium. Pre- and postintervention questionnaires, comprising five multiple-choice questions and a self-estimated grade of knowledge about delirium, were used. Variables calculated were objective and subjective knowledge, recall, and accuracy of self-assessment. Microsoft Excel and analysis of covariance were used to analyze data. RESULTS: Knowledge gains for all interventions were large (d>0.8) irrespective of gender. Post hoc comparison showed video and video+handout methods were more effective with high recall for video (92.8%). Students rated their knowledge as satisfactory, although they scored 11.4 out of 20. Preintervention knowledge level was correctly estimated by 31% of students, and postintervention by 40.3% students. CONCLUSION: Teaching about delirium to medical students with a video resulted in better knowledge transfer and recall. Most medical students, particularly men, overestimated their knowledge about delirium.

GLP-1 receptor agonists and reduction of cardiometabolic risk: Potential underlying mechanisms.

Type 2 diabetes mellitus (T2DM) is a metabolic condition with an elevated impact on cardiovascular (CV) risk. The innovative therapeutic approaches for T2DM - incretin-based therapies (IBTs), including glucagon-like peptide 1 (GLP-1) receptor agonists, have become popular and more widely used in recent years. The available scientific data from clinical studies and clinical practice highlights their beyond glucose-lowering effects, which is achieved without any increase in hypoglycaemia. The former effects include reduction in body weight, lipids, blood pressure, inflammatory markers, oxidative stress, endothelial dysfunction, and subclinical atherosclerosis, thus reducing and potentially preventing CV events. In fact, the introduction of IBTs is one of the key moments in the history of diabetes research and treatment. Such therapeutic strategies allow customization of antidiabetic treatment to each patient's need and therefore obtain better metabolic control with reduced CV risk. The aim of the present paper is to provide a comprehensive overview of the effects of GLP-1RA on various cardiometabolic markers and overall CV risk, with particular attention on recent CV outcome studies and potential mechanisms. In particular, the effects of liraglutide on formation and progression of atherosclerotic plaque and mechanisms explaining its cardioprotective effects are highlighted.

Liraglutide improves metabolic parameters and carotid intima-media thickness in diabetic patients with the metabolic syndrome: an 18-month prospective study.

BACKGROUND: Liraglutide, a GLP-1 analogue, exerts several beneficial non-glycemic effects in patients with type-2 diabetes (T2DM), such as those on body weight, blood pressure, plasma lipids and inflammation markers. However, the effects of liraglutide on cardiovascular (CV) risk markers in subjects with the metabolic syndrome (MetS) are still largely unknown. We herein explored its effects on various cardio-metabolic risk markers of the MetS in subjects with T2DM. METHODS: We performed an 18-month prospective, real-world study. All subjects had T2DM and the MetS based on the AHA/NHLBI criteria. Subjects with a history of a major CV event were excluded. One hundred-twenty-one subjects (71 men and 50 women; mean age: 62 ± 9 years) with T2DM and the MetS, who were naïve to incretin-based therapies and treated with metformin only, were included. Liraglutide (1.2 mg/day) was added to metformin (1500-3000 mg/day) for the entire study. Fasting plasma samples for metabolic parameters were collected and carotid-intima media thickness (cIMT) was assessed by B-mode real-time ultrasound at baseline and every 6 months thereafter. RESULTS: There was a significant reduction in waist circumference, body mass index, fasting glycemia, HbA1c, total- and LDL-cholesterol, triglycerides, and cIMT during the 18-month follow-up. Correlation analysis showed a significant association between changes in cIMT and triglycerides (r = 0.362; p < 0.0001). The MetS prevalence significantly reduced during the study, and the 26% of subjects no longer fulfilled the criteria for the MetS after 18 months. CONCLUSIONS: Liraglutide improves cardio-metabolic risk factors in subjects with the MetS in a real-world study. Trial Registration ClinicalTrials.gov: NCT01715428.