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Adequate and efficient availability of medicines is necessary to ensure patients receive optimal care. However, inefficient drug stock management can result in various problems, such as waste of resources, lack of necessary drugs, or even excessive stock. This study aims to improve the efficiency of the drug stock management process by using KMeans Clustering and Hierarchical Clustering methods on drug stock data. The data used includes information on initial stock, purchase, incoming distribution, service, outgoing distribution, outgoing adjustment, and final stock. Clustering analysis was performed to identify patterns in the drug stock data, which was then validated using Silhouette Score. The results showed that Hierarchical Clustering was able to achieve a Silhouette Score of 0.976, while KMeans achieved a Silhouette Score of 0.954

In this study, we address the evolving threat of Maleficent Neural Networks, also known as “Evil” Neural Networks, malicious neural networks embedded with malware. Due to the absence of effective detection mechanisms, these malicious models remain undetected, posing significant challenges to the security of users and systems in the rapidly expanding field of Artificial Intelligence and Machine Learning. This research provides a comprehensive examination of Maleficent Neural Networks, and their detection, mitigation, and security issues, based on recent foundational studies. A discussion of ethical and legal concerns surrounding the deliberate infusion of malware into neural networks is also included, emphasising the need for collaborative efforts among experts in the fields of AI, machine learning, and cyber security. The study shows that this new threat possesses several risks, and the number of works on the topic we identified confirms that more research is needed in this direction. Moreover, we propose promising future directions, including the creation of advanced adversarial defence mechanisms and the development of new methods to detect malware within neural networks.

Abstract Given the importance of coastal upwelling systems to ocean productivity, fisheries, and biogeochemical cycles, their response to climate change is of great interest. However, there is no consensus on future productivity changes in these systems, which may be controlled by multiple drivers including wind‐driven and geostrophic transport, stratification, and source water properties. Here we use an ensemble of regional ocean projections and recently developed upwelling indices for the California Current System to disentangle these sometimes‐competing influences. Some changes are consistent among models (e.g., decreased mixed layer depth), while for others there is a lack of agreement even on the direction of future change (e.g., nitrate concentration in upwelled waters). Despite models' diverging projections of productivity changes, they agree that those changes are predominantly driven by subsurface nitrate concentrations, not by upwelling strength. Our results highlight the need for more attention to processes governing subsurface nutrient changes, not just upwelling strength.

BackgroundThe COVID-19 pandemic has forced many health care providers to make changes in their treatment, with telemedicine being expanded on a large scale. An earlier study investigated the acceptance of telephone calls but did not record satisfaction with treatment or patients’ preferences. This warranted a follow-up study to investigate acceptance, satisfaction, and preferences regarding telemedicine, comprising of phone consultations, among health care recipients. ObjectiveThe primary aim was to assess the acceptance and satisfaction of telemedicine during the subsequent months of 2021-2022, after the initial wave of the COVID-19 pandemic in Switzerland. Furthermore, we aimed to assess patients’ preferences and whether these differed in patients who had already experienced telemedicine in the past, as well as correlations between acceptance and satisfaction, pain intensity, general condition, perception of telemedicine, and catastrophizing. Finally, we aimed to investigate whether more governmental restrictions were correlated with higher acceptance. MethodsAn anonymous cross-sectional web-based survey was conducted between January 27, 2021, and February 4, 2022, enrolling patients undergoing outpatient pain therapy in a tertiary university clinic. We conducted a descriptive analysis of acceptance and satisfaction with telemedicine and investigated patients’ preferences. Further, we conducted a descriptive and correlational analysis of the COVID-19 stringency index. Spearman correlation analysis and a chi-square test for categorical data were used with Cramer V statistic to assess effect sizes. ResultsOur survey was completed by 60 patients. Telemedicine acceptance and satisfaction were high, with an average score of 7.6 (SD 3.3; on an 11-point Numeric Rating Scale from 0=not at all to 10=completely), and 8.8 (SD 1.8), respectively. Respondents generally preferred on-site consultations to telemedicine (n=35, 58% vs n=24, 40%). A subgroup analysis revealed that respondents who already had received phone consultation, showed a higher preference for telemedicine (n/N=21/42, 50% vs n/N=3/18, 17%; χ22 [N=60]=7.5, P=.02, Cramer V=0.354), as well as those who had been treated for more than 3 months (n/N=17/31, 55% vs n/N=7/29, 24%; χ22 [N=60]=6.5, P=.04, Cramer V=0.329). Acceptance of telemedicine showed a moderate positive correlation with satisfaction (rs{58}=0.41, P

Abstract The impact of investigative interviews by police and Child Protective Services (CPS) on abused children can be profound, making effective training vital. Quality in these interviews often falls short and current training programs are insufficient in enabling adherence to best practice. We present a system for simulating an interactive environment with alleged abuse victims using a child avatar. The purpose of the system is to improve the quality of investigative interviewing by providing a realistic and engaging training experience for police and CPS personnel. We conducted a user study to assess the efficacy of four interactive platforms: VR, 2D desktop, audio, and text chat. CPS workers and child welfare students rated the quality of experience (QoE), realism, responsiveness, immersion, and flow. We also evaluated perceived learning impact, engagement in learning, self-efficacy, and alignment with best practice guidelines. Our findings indicate VR as superior in four out of five quality aspects, with 66% participants favoring it for immersive, realistic training. Quality of questions posed is crucial to these interviews. Distinguishing between appropriate and inappropriate questions, we achieved 87% balanced accuracy in providing effective feedback using our question classification model. Furthermore, CPS professionals demonstrated superior interview quality compared to non-professionals, independent of the platform.

Abstract ENSO's atmospheric teleconnections drive anomalous North Pacific sea surface temperatures through changes in surface heat fluxes (“the atmospheric bridge”). Previous research focusing on the bridge as a seasonal phenomenon did not consider how ENSO‐related changes in synoptic variability might also impact surface turbulent heat fluxes (STHF). In this study, we find that while well over half of ENSO's impact on STHF occurs on low‐frequency (>8 days) time scales, up to 20% of its impact arises on high‐frequency (

Diabetes is associated with numerous comorbidities, one of which is increased vulnerability to infections. This review will focus on how diabetes mellitus (DM) affects the immune system and its various components, leading to the impaired proliferation of immune cells and the induction of senescence. We will explore how the pathology of diabetes-induced immune dysfunction may have similarities to the pathways of “inflammaging”, a persistent low-grade inflammation common in the elderly. Inflammaging may increase the likelihood of conditions such as rheumatoid arthritis (RA) and periodontitis at a younger age. Diabetes affects bone marrow composition and cellular senescence, and in combination with advanced age also affects lymphopoiesis by increasing myeloid differentiation and reducing lymphoid differentiation. Consequently, this leads to a reduced immune system response in both the innate and adaptive phases, resulting in higher infection rates, reduced vaccine response, and increased immune cells’ senescence in diabetics. We will also explore how some diabetes drugs induce immune senescence despite their benefits on glycemic control.

The limited supply and rising demand for kidney transplantation has led to the use of allografts more susceptible to ischemic reperfusion injury (IRI) and oxidative stress to expand the donor pool. Organ preservation and procurement techniques, such as machine perfusion (MP) and normothermic regional perfusion (NRP), have been developed to preserve allograft function, though their long-term outcomes have been more challenging to investigate. We performed a systematic review and meta-analysis to examine the benefits of MP and NRP compared to traditional preservation techniques. PubMed (MEDLINE), Embase, Cochrane, and Scopus databases were queried, and of 13,794 articles identified, 54 manuscripts were included (n = 41 MP; n = 13 NRP). MP decreased the rates of 12-month graft failure (OR 0.67; 95%CI 0.55, 0.80) and other perioperative outcomes such as delayed graft function (OR 0.65; 95%CI 0.54, 0.79), primary nonfunction (OR 0.63; 95%CI 0.44, 0.90), and hospital length of stay (15.5 days vs. 18.4 days) compared to static cold storage. NRP reduced the rates of acute rejection (OR 0.48; 95%CI 0.35, 0.67) compared to in situ perfusion. Overall, MP and NRP are effective techniques to mitigate IRI and play an important role in safely expanding the donor pool to satisfy the increasing demands of kidney transplantation.

Diabetes mellitus (DM) is a chronic endocrine disorder that affects more than 20 million people in the United States. DM-related complications affect multiple organ systems and are a significant cause of morbidity and mortality among people with DM. Of the numerous acute and chronic complications, atherosclerosis due to diabetic dyslipidemia is a condition that can lead to many life-threatening diseases, such as stroke, coronary artery disease, and myocardial infarction. The nuclear erythroid 2-related factor 2 (Nrf2) signaling pathway is an emerging antioxidative pathway and a promising target for the treatment of DM and its complications. This review aims to explore the Nrf2 pathway’s role in combating diabetic dyslipidemia. We will explore risk factors for diabetic dyslipidemia at a cellular level and aim to elucidate how the Nrf2 pathway becomes a potential therapeutic target for DM-related atherosclerosis.

Abstract Electronic coaching (eCoach) facilitates goal-focused development for individuals to optimize certain human behavior. However, the automatic generation of personalized recommendations in eCoaching remains a challenging task. This research paper introduces a novel approach that combines deep learning and semantic ontologies to generate hybrid and personalized recommendations by considering “Physical Activity” as a case study. To achieve this, we employ three methods: time-series forecasting, time-series physical activity level classification, and statistical metrics for data processing. Additionally, we utilize a naïve-based probabilistic interval prediction technique with the residual standard deviation used to make point predictions meaningful in the recommendation presentation. The processed results are integrated into activity datasets using an ontology called OntoeCoach, which facilitates semantic representation and reasoning. To generate personalized recommendations in an understandable format, we implement the SPARQL Protocol and RDF Query Language (SPARQL). We evaluate the performance of standard time-series forecasting algorithms [such as 1D Convolutional Neural Network Model (CNN1D), autoregression, Long Short-Term Memory (LSTM), and Gated Recurrent Units (GRU)] and classifiers [including Multilayer Perceptron (MLP), Rocket, MiniRocket, and MiniRocketVoting] using state-of-the-art metrics. We conduct evaluations on both public datasets (e.g., PMData) and private datasets (e.g., MOX2-5 activity). Our CNN1D model achieves the highest prediction accuracy of 97 $$\%$$ % , while the MLP model outperforms other classifiers with an accuracy of 74 $$\%$$ % . Furthermore, we evaluate the performance of our proposed OntoeCoach ontology model by assessing reasoning and query execution time metrics. The results demonstrate that our approach effectively plans and generates recommendations on both datasets. The rule set of OntoeCoach can also be generalized to enhance interpretability.

Diabetes is a chronic disease that induces many comorbidities, including cardiovascular disease, nephropathy, and liver damage. Many mechanisms have been suggested as to how diabetes leads to these comorbidities, of which increased oxidative stress in diabetic patients has been strongly implicated. Limited knowledge of antioxidative antidiabetic drugs and substances that can address diabetic comorbidities through the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway calls for detailed investigation. This review will describe how diabetes increases oxidative stress, the general impact of that oxidative stress, and how oxidative stress primarily contributes to diabetic comorbidities. It will also address how treatments for diabetes, especially focusing on their effects on the Nrf2 antioxidative pathway, have been shown to similarly affect the Nrf2 pathway of the heart, kidney, and liver systems. This review demonstrates that the Nrf2 pathway is a common pathogenic component of diabetes and its associated comorbidities, potentially identifying this pathway as a target to guide future treatments.

Subcutaneous polymer scaffolds have shown potential for creating an optimal transplantation site in cellular replacement therapy, e.g., when transplanting insulin-producing cells to cure type 1 diabetes. Imperative for these scaffolds is a high degree of vascularization to guarantee long-term functional cellular survival. In this study, the effect of the nitric oxide (NO) donor S-nitroso-N-acetyl-dl-penicillamine (SNAP) on the vascularization degree of a subcutaneous poly(d,l-lactide-co-ε-caprolactone) (PDLLCL) scaffold was investigated. To this end, scaffolds were implanted under the skin of C57BL/6 mice. Each mouse received a control scaffold and a scaffold containing SNAP. At day 7, 14, and 28, the oxygen percentage within the scaffolds was measured and at day 28, the vascularization degree was determined with lectin infusion and gene expression analysis. We measured lower oxygen percentages within the scaffolds containing the NO-donor up to day 14 compared to the control scaffolds, but no differences were found at day 28. Although blood vessels in the scaffolds were well perfused, no differences between the groups were found in the lectin staining and gene expression of vascular markers, such as CD31, CD105, and VEGFa. To conclude, in this biomaterial setting, addition of a NO-donor did not improve the vascularization degree of the subcutaneous scaffold.

IntroductionDeficits in emotional perception are common in autistic people, but it remains unclear to which extent these perceptual impairments are linked to specific sensory modalities, specific emotions or multisensory facilitation.MethodsThis study aimed to investigate uni- and bimodal perception of emotional cues as well as multisensory facilitation in autistic (n = 18, mean age: 36.72 years, SD: 11.36) compared to non-autistic (n = 18, mean age: 36.41 years, SD: 12.18) people using auditory, visual and audiovisual stimuli.ResultsLower identification accuracy and longer response time were revealed in high-functioning autistic people. These differences were independent of modality and emotion and showed large effect sizes (Cohen’s d 0.8–1.2). Furthermore, multisensory facilitation of response time was observed in non-autistic people that was absent in autistic people, whereas no differences were found in multisensory facilitation of accuracy between the two groups.DiscussionThese findings suggest that processing of auditory and visual components of audiovisual stimuli is carried out more separately in autistic individuals (with equivalent temporal demands required for processing of the respective unimodal cues), but still with similar relative improvement in accuracy, whereas earlier integrative multimodal merging of stimulus properties seems to occur in non-autistic individuals.

The Erasmus+ project “Death Education for Palliative Psychology” (DE4PP) under the coordination of the University of Padua investigated the effects of teaching palliative psychology with psychodrama and arts therapies, as positive effects on students’ attitudes towards life and death were suspected through the use of these forms of treatment. Five countries participated in this project funded by the European Commission (Austria, Israel, Italy, Poland, and Romania). In Klagenfurt (Austria), 34 students from the University of Klagenfurt completed the pilot course entitled “Palliative Psychology” generated by the project partners. Course participants filled out psychological and satisfaction questionnaires at the beginning and end of the course, to measure the impact of teaching palliative psychology with psychodrama and arts therapies. The research involved a control group. In addition, six participants in the course participated in a focus group interview at the end, which included questions about their experience of the course; the impact of arts therapies and psychodrama techniques; experiences of verbal and artistic processing of death anxiety; and the meaning of life and death, representation of death, and associated feelings. The results, in summary, showed that processing of life and death had occurred in the participants due to the course they had completed. As part of the course, creative arts and psychodrama were bridges to death. Filling out satisfaction questionnaires, photovoice assignments, role reversal, and visualizing a personal social atom were seen by students in Klagenfurt as particularly effective methods for self-reflection.

The scourge of type-1 diabetes (T1D) is the morbidity and mortality it and its complications cause at a younger age. This propels the constant search for better diagnostic, treatment, and management strategies, with the ultimate quest being a cure for T1D. Recently, the therapeutic potential of exosomes has generated a lot of interest. Among the characteristics of exosomes of particular interest are (a) their regenerative capacity, which depends on their “origin”, and (b) their “content”, which determines the cell communication and crosstalk they influence. Other functional capacities, including paracrine and endocrine homeostatic regulation, pathogenic response ability resulting in insulin secretory defects or β-cell death under normal metabolic conditions, immunomodulation, and promotion of regeneration, have also garnered significant interest. Exosome “specificity” makes them suitable as biomarkers or predictors, and their “mobility” and “content” lend credence to drug delivery and therapeutic suitability. This review aims to highlight the functional capacities of exosomes and their established as well as novel contributions at various pathways in the onset and progression of T1D. The pathogenesis of T1D involves a complex crosstalk between insulin-secreting pancreatic β-cells and immune cells, which is partially mediated by exosomes. We also examine the potential implications for type 2 diabetes (T2D), as the link in T2D has guided T1D exploration. The collective landscape presented is expected to help identify how a deeper understanding of exosomes (and their cargo) can provide a framework for actionable solutions to prevent, halt, or change the very course of T1D and its complications.

The improvement of the sports technique is premised on comparing the values of the motor movement, this must be characterized to correct errors detected as part of the sports training management process. Emphasis is placed on highly technical sports, such as bodybuilding training. In this sense, the present research aimed to analyze the half-squat technique in professional and amateur bodybuilders as an empirical method (sport-specific measurement). The research is descriptive-explanatory of correlational order. Six variables of interest are correlated (X1: shoulder joint angle; X2: hip joint angle; X3: maximum speed reached; X4: maximum acceleration reached; X5: center of gravity in X; X6: center of gravity in Y). The means establish differences between independent groups, both in variable X1 (Group 1: ≈66°; Group 2: ≈70°; p=0.247 ), X2 (Group 1: ≈73°; Group 2: ≈86°; p=0.002 ), X3 (Group 1: ≈1.03m/s; Group 2: ≈1.36m/s; p=0.017 ), X4 (Group 1: ≈2.93m/s 2 ; Group 2: ≈4.78m /s 2 ; p=0.011 ), X5 (Group 1: ≈0.43m; Group 2: ≈0.65m; p=0.000 ), and X6 (Group 1: ≈0.61m; Group 2: ≈0.83m; p =0.000 ). Group 1 has a more effective technique, while the amateurs have less efficiency in biomechanical movement due to their inexperience, high values are shown in speed and acceleration, movement angles such as hip angles are included.

BackgroundWhen receiving mismatching nonverbal and verbal signals, most people tend to base their judgment regarding the current emotional state of others primarily on nonverbal information. However, individuals with high-functioning autism (HFA) have been described as having difficulties interpreting nonverbal signals. Recognizing emotional states correctly is highly important for successful social interaction. Alterations in perception of nonverbal emotional cues presumably contribute to misunderstanding and impairments in social interactions.MethodsTo evaluate autism-specific differences in the relative impact of nonverbal and verbal cues, 18 adults with HFA (14 male and four female subjects, mean age 36.7 years (SD 11.4) and 18 age, gender and IQ-matched typically developed controls [14 m/4 f, mean age 36.4 years (SD 12.2)] rated the emotional state of speakers in video sequences with partly mismatching emotional signals. Standardized linear regression coefficients were calculated as a measure of the reliance on the nonverbal and verbal components of the videos for each participant. Regression coefficients were then compared between groups to test the hypothesis that autistic adults base their social evaluations less strongly on nonverbal information. Further exploratory analyses were performed for differences in valence ratings and response times.ResultsCompared to the typically developed control group, nonverbal cue reliance was reduced in adults with high-functioning autism [t(23.14) = −2.44, p = 0.01 (one-sided)]. Furthermore, the exploratory analyses showed a tendency to avoid extreme answers in the HFA group, observable via less positive as well as less negative valence ratings in response to emotional expressions of increasingly strong valence. In addition, response time was generally longer in HFA compared to the control group [F (1, 33) = 10.65, p = 0.004].ConclusionThese findings suggest reduced impact of nonverbal cues and longer processing times in the analysis of multimodal emotional information, which may be associated with a subjectively lower relevance of this information and/or more processing difficulties for people with HFA. The less extreme answering tendency may indicate a lower sensitivity for nonverbal valence expression in HFA or result from a tendency to avoid incorrect answers when confronted with greater uncertainty in interpreting emotional states.

Background. Islet transplantation is a promising treatment for type 1 diabetes. It has the potential to improve glycemic control, particularly in patients suffering from hypoglycemic unawareness and glycemic instability. As most islet grafts do not function permanently, efforts are needed to create an accessible and replaceable site, for islet grafts or for insulin-producing cells obtained from replenishable sources. To this end, we designed and tested an artificial, polymeric subcutaneous transplantation site that allows repeated transplantation of islets. Methods. In this study, we developed and compared scaffolds made of poly(D,L,-lactide-co-ε-caprolactone) (PDLLCL) and polycaprolactone (PCL). Efficacy was first tested in mice‚ and then, as a proof of principle for application in a large animal model, the scaffolds were tested in pigs, as their skin structure is similar to that of humans. Results. In mice, islet transplantation in a PCL scaffold expedited return to normoglycemia in comparison to PDLLCL (7.7 ± 3.7 versus 16.8 ± 6.5 d), but it took longer than the kidney capsule control group. PCL also supported porcine functional islet survival in vitro. Subcutaneous implantation of PDLLCL and PCL scaffolds in pigs revealed that PCL scaffolds were more stable and was associated with less infiltration by immune cells than PDLLCL scaffolds. Prevascularized PCL scaffolds were therefore used to demonstrate the functional survival of allogenic islets under the skin of pigs. Conclusions. To conclude, a novel PCL scaffold shows efficacy as a readily accessible and replaceable, subcutaneous transplantation site for islets in mice and demonstrated islet survival after a month in pigs.

Stem cell therapy is an attractive treatment for diseases in companion animals that cannot be treated by conventional veterinary medicine practices. The unique properties of stem cells, particularly the ability to differentiate into specific cell types, makes them a focal point in regenerative medicine treatments. Stem cell transplantation, especially using mesenchymal stem cells, has been proposed as a means to treat a wide range of injuries and ailments, resulting in tissue regeneration or repair. This review aims to summarize the veterinary use of stem cells for treating age-related and joint diseases, which are common conditions in pets. While additional research is necessary and certain limitations exist, the potential of stem cell therapy for companion animals is immense.

The current gold standard for extracting highlight clips from soccer games is the use of manual annotations and clippings, where human operators define the start and end of an event and trim away the unwanted scenes. This is a tedious, time-consuming, and expensive task, to the extent of being rendered infeasible for use in lower league games. In this paper, we aim to automate the process of highlight generation using logo transition detection, scene boundary detection, and optional scene removal. We experiment with various approaches, using different neural network architectures on different datasets, and present two models that automatically find the appropriate time interval for extracting goal events. These models are evaluated both quantitatively and qualitatively, and the results show that we can detect logo and scene transitions with high accuracy and generate highlight clips that are highly acceptable for viewers. We conclude that there is considerable potential in automating the overall soccer video clipping process.

Detecting events in videos is a complex task, and many different approaches, aimed at a large variety of use-cases, have been proposed in the literature. Most approaches, however, are unimodal and only consider the visual information in the videos. This paper presents and evaluates different approaches based on neural networks where we combine visual features with audio features to detect (spot) and classify events in soccer videos. We employ model fusion to combine different modalities such as video and audio, and test these combinations against different state-of-the-art models on the SoccerNet dataset. The results show that a multimodal approach is beneficial. We also analyze how the tolerance for delays in classification and spotting time, and the tolerance for prediction accuracy, influence the results. Our experiments show that using multiple modalities improves event detection performance for certain types of events.

Abstract The public sphere is a meeting space. Various identities meet and interact. Each carries its pattern: instrumental-hierarchical, strategic monological, or mutual-communicative. Equality in the last pattern is the basis for building relationships that are oriented towards realizing common goals which are formulated from the synthesis of ideas. This research shows that there is a gap between the idea of inter-particularities equality and the tendency of the respondents to prioritize group identities over efforts to create common welfare. This gap can be traced back to the design of the lectionary sermon which found a lack of discussion on the themes of the public space. Therefore, the author proposes an alternative paradigmatic model that integrates all personal dimensions into the global-public dimension. A participatory approach that raises experiences in the context of community life is used as a starting point to mobilize the active participation of the people in testing the sermons relevance in the public space. Abstrak Ruang publik merupakan ruang perjumpaan. Berbagai identitas bertemu dan berinteraksi. Masing-masing membawa polanya: instrumental-hierarkis, strategis-monologis, atau mutual-komunikatif. Kesetaraan dalam pola terakhir merupakan dasar untuk menjalin relasi yang berorientasi pada upaya mewujudkan tujuan bersama yang dirumuskan dari sintesa gagasan-gagasan. Penelitian ini menunjukkan terdapatnya kesenjangan antara gagasan kesetaraan antarpartikularitas dengan kecenderungan umat responden yang mengutamakan identitas kelompok di atas upaya mewujudkan kemaslahatan bersama. Kesenjangan tersebut selanjutnya dirunut kembali pada rancangan khotbah leksionari dan dijumpai minimnya pembahasan mengenai tema-tema ruang publik. Oleh sebab itu, penulis mengusulkan sebuah model paradigmatik alternatif yang mengintegrasikan seluruh dimensi personal ke dalam dimensi publik global. Pendekatan partisipatori yang mengangkat pengalaman dalam konteks hidup bermasyarakat dipergunakan sebagai titik tolak guna memobilisir partisipasi aktif umat dalam mengujicobakan relevansi berita mimbar di ruang publik.

One very prominent context of the Pre-Christian history of Armenia of course lies with its relations with the great neighbouring empires of Parthia and Rome. These relations were mainly the result of Armenia’s geopolitical location between the two empires, its natural resources and its control of strategic long-distance routes. From a Roman point of view, Armenia certainly was the most important geopolitical concern in the East. Roman-Armenian relations therefore are a vast and complex subject, and their history extends over many centuries. In the years between 114 and 117 AD these relations assumed an extraordinary albeit short-lived condition when the kingdom of Greater Armenia became a Roman province. The present contribution reviews the Roman inscriptions that can be dated to this period, as well as the historical evidence they provide for the history of Greater Armenia as a Roman province.

Physiologic insulin secretion consists of an oscillating pattern of secretion followed by distinct trough periods that stimulate ligand and receptor activation. Apart from the large postprandial bolus release of insulin, β cells also secrete small amounts of insulin every 4–8 min independent of a meal. Insulin resistance is associated with a disruption in the normal cyclical pattern of insulin secretion. In the case of type-2 diabetes, β-cell mass is reduced due to apoptosis and β cells secrete insulin asynchronously. When ligand/receptors are constantly exposed to insulin, a negative feedback loop down regulates insulin receptor availability to insulin, creating a relative hyperinsulinemia. The relative excess of insulin leads to insulin resistance (IR) due to decreased receptor availability. Over time, progressive insulin resistance compromises carbohydrate metabolism, and may progress to type-2 diabetes (T2D). In this review, we discuss insulin resistance pathophysiology and the use of dynamic exogenous insulin administration in a manner consistent with more normal insulin secretion periodicity to reverse insulin resistance. Administration of insulin in such a physiologic manner appears to improve insulin sensitivity, lower HgbA1c, and, in some instances, has been associated with the reversal of end-organ damage that leads to complications of diabetes. This review outlines the rationale for how the physiologic secretion of insulin orchestrates glucose metabolism, and how mimicking this secretion profile may serve to improve glycemic control, reduce cellular inflammation, and potentially improve outcomes in patients with diabetes.

Abstract Background The denial of death in Western society deprives young people of the tools to derive meaning from experiences of death and dying. Literature shows that death education may allow them to become familiar with this topic without causing negative effects. This article describes the effects of a death education course with adolescents, wherein participants were given the opportunity to meet palliative doctors and palliative psychologists at school and in a hospice, where they were able to converse with the families of the dying. Methods This study used mixed methods and included an evaluation of a death education intervention with longitudinal follow-up of outcomes. The course involved 87 secondary school students (experimental group) aged between 16 and 20 years. We also recruited a control group of 76 similarly-aged students to observe differences. The variables we examined were: alexithymia, representation of death, value attributed to life and spirituality. These were measured with the following instruments: the Toronto Alexithymia Scale-20, the Testoni Death Representation Scale, the Personal Meaning Profile and the Spiritual Orientation Inventory, respectively. To better understand how the students perceived the experience, we asked the experimental group to answer some open-ended questions. Their answers were analysed through thematic analysis. Results The study showed that death education and the hospice experience did not produce negative effects, but rather allowed students to decrease alexithymia, improving their ability to recognise and express emotions. Thematic analysis revealed that all participants perceived the experience as very positive. Conclusions Our findings affirm that death education programs can be successfully implemented in high schools, and that they can usefully involve local hospices and palliative care professionals, especially physicians and psychologists.

The number of applications that run over mobile networks, expecting bounded end-to-end delay, is increasing steadily. However, the stochastic and shared nature of the wireless medium makes providing such guarantees challenging. Using several network interfaces simultaneously can help address fluctuating delays, provided that transport protocols can switch between them in a timely manner. Today’s protocols are mostly closed-loop and thus require at least one round trip before reacting to increased delay. This paper examines whether jumps in round trip times (RTTs) have a pattern that can be predicted beforehand. Using per second RTT measurements from hundreds of probes in two Long Term Evolution (LTE) cellular networks, we train an ensemble of classifiers to detect increases in delay. We construct a parsimonious explainable model that provides an accuracy of 80% and does not appear to be specific to a particular mobile operator. Further, we examine whether our model can be extended to 5G using a small dataset with extra 5G metadata, resulting in an accuracy of 88%. Our model indicates that RTTs are long-range correlated and shows that radio measurements of channel occupancy are accurate predictors of the onset of high delays. These results suggest that it is feasible to build an open-loop control system for multiplexing among several interfaces to proactively bound delays.

Changes in motor activity are core symptoms of mood episodes in bipolar disorder. The manic state is characterized by increased variance, augmented complexity and irregular circadian rhythmicity when compared to healthy controls. No previous studies have compared mania to euthymia intra-individually in motor activity. The aim of this study was to characterize differences in motor activity when comparing manic patients to their euthymic selves. Motor activity was collected from 16 bipolar inpatients in mania and remission. 24-h recordings and 2-h time series in the morning and evening were analyzed for mean activity, variability and complexity. Lastly, the recordings were analyzed with the similarity graph algorithm and graph theory concepts such as edges, bridges, connected components and cliques. The similarity graph measures fluctuations in activity reasonably comparable to both variability and complexity measures. However, direct comparisons are difficult as most graph measures reveal variability in constricted time windows. Compared to sample entropy, the similarity graph is less sensitive to outliers. The little-understood estimate Bridges is possibly revealing underlying dynamics in the time series. When compared to euthymia, over the duration of approximately one circadian cycle, the manic state presented reduced variability, displayed by decreased standard deviation (p = 0.013) and augmented complexity shown by increased sample entropy (p = 0.025). During mania there were also fewer edges (p = 0.039) and more bridges (p = 0.026). Similar significant changes in variability and complexity were observed in the 2-h morning and evening sequences, mainly in the estimates of the similarity graph algorithm. Finally, augmented complexity was present in morning samples during mania, displayed by increased sample entropy (p = 0.015). In conclusion, the motor activity of mania is characterized by altered complexity and variability when compared within-subject to euthymia.

El objetivo de la presente investigación consiste en diseñar una estrategia metodológica que facilite la inte-gración de un sistema de gestión ambiental basado en la norma ISO 14001:2015 en un sistema de gestión de la ca-lidad ISO 9001:2015 de una Universidad con Modalidad Abierta y a Distancia en Colombia. La Institución cuenta con 23 sedes a nivel nacional denominados Centros de Atención Universitaria (CAU). Se diseñaron dos instru-mentos, el primero fue el “Diagnóstico ISO 14001” y el segundo una “Lista de chequeo gestión ambiental” con los cuales se obtuvieron las condiciones ambientales ini-ciales de la institución y a partir del resultado obtenido se diseñó una guía metodológica para integrar el SGA orientado por la estructura de alto nivel. Se realizó la validación de la guía por medio de un grupo de expertos y se obtuvo una calificación de 0.97 en la escala de V de Aiken, lo que demostró que la herramienta meto-dológica cuenta con una validez de contenido bastante significativa. Esta investigación busca contribuir con la responsabilidad social de las empresas para promover la gestión ambiental y el cuidado del medio ambiente sin importar sus modalidades de trabajo o la cobertura organizacional que se posea, garantizando la efectividad de sus procesos.

We present a rare case of a patient who presented with complete and rapid wear-through of a ceramic femoral head through a polyethylene liner and titanium acetabular cup. In addition, this patient exhibited significantly elevated serum titanium ion levels, which may serve as a marker of severe metallosis in cases where the preoperative plain radiographs underestimate signs of periarticular metal debris. The unique findings of this case include the rapid (less than 1 year time) wear-through of the femoral head in interval radiographs and the dramatic progression of metallosis and pelvic and femoral osteolysis that required both component revision. In addition, the markedly elevated titanium levels secondary to cup wear-through are also of interest and demonstrate a systemic manifestation of abrasive wear of a titanium alloy component. Keywords: Total hip arthroplasty, Revision arthroplasty, Wear-through cup failure, Catastrophic failure, Osteolysis, Ceramic on poly

The memoir about personal meetings with Ezra Pound in Rapallo in 1962 and 1963, at T. S. Eliot’s memorial service in London in 1965, and finally in Venice in the later 1960s, dwells also on the reception of the poet’s work in postwar Britain and in the USA. In the 1960s England largely forgot Pound; his role was historic, his name and his presence faded: in a version of literary history current in British universities in 1960, Ezra Pound figured as “the precursor of Eliot”. In the USA, on the contrary, his breakthrough in modernist poetry as well as his anti-Semitism and admiration for Italian Fascism were well recognized, thanks to the controversy over the award of the Bollingen Prize to Pound’s Pisan Cantos. The memoir shows how a name from literary history becomes a part of personal experience after meeting the man himself, and how it leads to a new understanding of the poet’s legacy – against wider historical, cultural, and literary background. The memoir also provides interesting facts that stimulate reflections on the literary canon, its constant change and flux despite its apparently stable nature.

Os fungos são o objeto de estudo de uma ciência conhecida por Micologia e, em virtude de seu papel na história da vida no planeta e de sua importância ecológica e econômica, compõem o saber escolar da disciplina de Biologia no Ensino Médio. Sendo assim, nesse trabalho objetivamos realizar uma análise descritiva dos conteúdos de Micologia presentes nas dez coleções de Biologia aprovadas na edição de 2018 do Programa Nacional do Livro Didático. A análise revelou que, apesar de melhorias em termos conceituais e de abordagem metodológica, as ilustrações presentes nos livros analisados ainda apresentam eventuais erros que podem prejudicar a compreensão do conteúdo. Outro fator potencialmente problemático é a ausência de contextualização com os demais aspectos ecológicos, saúde humana e relações com outros seres vivos, tornando os tópicos sobre Micologia reduzidos a uma abordagem desconexa com a realidade dos estudantes. Assim sendo, concluímos que seja relevante que se continue a investigar a temática da Micologia nos livros didáticos de Biologia.

Immune cell therapeutics are increasingly applied in oncology. Especially chimeric antigen receptor (CAR) T cells are successfully used to treat several B cell malignancies. Efforts to engineer CAR T cells for improved activity against solid tumors include co-delivery of pro-inflammatory cytokines in addition to CARs, via either constitutive cytokine expression or inducible cytokine expression triggered by CAR recognition of its target antigen—so-called “T cells redirected for universal cytokine-mediated killing” (TRUCKs) or fourth-generation CARs. Here, we tested the hypothesis that TRUCK principles could be expanded to improve anticancer functions of NK cells. A comparison of the functionality of inducible promoters responsive to NFAT or NFκB in NK cells showed that, in contrast to T cells, the inclusion of NFκB-responsive elements within the inducible promoter construct was essential for CAR-inducible expression of the transgene. We demonstrated that GD2CAR-specific activation induced a tight NFκB-promoter-driven cytokine release in NK-92 and primary NK cells together with an enhanced cytotoxic capacity against GD2+ target cells, also shown by increased secretion of cytolytic cytokines. The data demonstrate biologically relevant differences between T and NK cells that are important when clinically translating the TRUCK concept to NK cells for the treatment of solid malignancies.

The purpose of this article is twofold: first, we show how algorithms have become increasingly central to financial credit scoring; second, we draw on this to further develop the anthropological study of algorithmic governance. As such, we describe the literature on credit scoring and then discuss ethnographic examples from two regulatory and commercial contexts: the US and Denmark. From these empirical cases, we carve out main developments of algorithmic governance in credit scoring and elucidate social and cultural logics behind algorithmic governance tools. Our analytical framework builds on critical algorithm studies and anthropological studies where money and payment infrastructures are viewed as embedded in their specific cultural contexts (Bloch and Parry 1989; Maurer 2015). The comparative analysis shows how algorithmic credit scoring takes different forms hence raising different issues in the two cases. Danish banks seem to have developed a system of intensive, yet hidden credit scoring based on surveillance and harvesting of behavioural data, which, however, due to GDPR takes place in restricted silos. Credit scores are hidden to customers, and therefore there has been virtually no public debate regarding the algorithmic models behind scores. In the US, fewer legal restrictions on data trading combined with both widespread and visible credit scoring has led to the development of a credit data market and widespread use of credit scoring by ‘affiliation’ on the one hand, but also to increasing public and political critique on scoring models on the other.

The systematic removal of death from social life in the West has exposed people living in areas affected by COVID-19 to the risk of being unable to adequately manage the anxiety caused by mortality salience. Death education is a type of intervention that helps people manage their fear of death by offering them effective strategies to deal with loss and anxiety. To that end, a path of death education has been carried out with University students of psychology. The main purpose of the research is to understand how students who participated in the death education course perceive the lockdown experience in light of course teachings. The research was carried out at a University in northern Italy in an area severely affected by COVID-19, during the first year of the pandemic. The group of participants included 38 students, 30 women and 8 men, with an average age of 25.45 years (SD = 7). At the end of the course, the students could respond on an optional basis to the request to comment on the training experience according to what they experienced during the pandemic. A thematic analysis was subsequently carried out on the texts, which made it possible to identify the most relevant thematic areas for the students. The qualitative analyses permitted recognition of three main forms of discovery: the removal of death in contemporary culture; the importance of community, ritual and funeral, and spirituality; and the significance of death education for future health professionals. The texts have highlighted how the removal of these issues exposes people to the risk of being unable to handle extremely painful events such as those related to dying. The results show the positivity of death education pathways conducted at the University level to help students reflect on these issues and manage the related anguish.

Melon is very popular among Indonesians because of its sweet taste and rich in nutrients and also very potential as export comodities. Every export comodities including melon need proper handlings of quarantine to disinfestation pests / diseases. One of quarantine technique which is appliable for melon is vapor heat treatment (VHT). Aims of this research are to make a simulation of heat distribution during VHT process inside melons, to observe VHT technique effects on melon qualities during storage, and to determine the optimum time of VHT process for melon. Finite difference method is used in designing the simulation using Visual Basic 6.0. To observe melon qualities, this research used complete randomized design (CRD) with 4 level of treatment based on VHT process duration which was 10 minutes, 20 minutes, 30 minutes and control every 4 days for 24 days. The result showed that finite difference method can be used for simulating heat distribution inside melon during VHT with coefficient determination (R2) value of 0.9903. Beside that, the result also showed that there were no signifficant difference between each treatments. Based on these results, VHT with 46.5oC temperature and 10 minutes duration time considered as the best treatment.

on having treated as one of the taxes that major revenue generates to the territory, the industry and trade, notices and boards tax, iCA, it turns out to be transcendental in the maintenance of the public finance of the Capital district. for such a reason, this investigation determines the benefits that the charge grants to the development of the city, analyzing the behavior of the collection and the budget execution of the 2012 – 2015 period. nevertheless, by means of the use of the criterion of pearson’s correlation, the direct relation that the income of the charge presents with the district Gdp is identified, as well as its rate of growth in relation with the resources of the state, keeping levels of debt lower than the established ones for the law. in this sense, this article maintains a qualitative approach that uses documentary analysis and data collection techniques, using record and consistency matrices

ABSTRACT: Background: Traditional insulin treatment for diabetes mellitus with insulin administered subcutaneously yields nonpulsatile plasma insulin concentrations that represent a fraction of normal portal vein levels. Oral hypoglycemic medications result in the same lack of pulsatile insulin response to blood glucose levels. Intensive treatments of significant complications of diabetes are not recommended due to complicated multidrug regimens, significant weight gain, and the high risk of hypoglycemic complications. Consequently, advanced complications of diabetes do not have an effective treatment option because conventional therapy is not sufficient. Intensive insulin therapy (IIT) simulates normal pancreatic function by closely matching the periodicity and amplitude of insulin secretion in healthy subjects; however, the mechanisms involved with the observed improvement are not clearly understood. Objective: The current review aims to analyze the pathophysiology of insulin secretion, discuss current therapies for the management of diabetes, provides an updates on the recent advancements of IIT, and proposes its mechanism of action. Methods: A literature search on PubMed, MEDLINE, Embase, and CrossRef databases was performed on multiple key words regarding the history and current variations of pulsatile and IIT for diabetes treatment. Articles reporting the physiology of insulin secretion, advantages of pulsatile insulin delivery in patients with diabetes patients, efficacy and adverse effects of current conventional insulin therapies for the management of diabetes, benefits and shortcomings of pancreas and islet transplantation, or clinical trials on patients with diabetes treated with pulsed insulin therapy or advanced IIT were included for a qualitative analysis and categorized into the following topics: mechanism of insulin secretion in normal subjects and patients with diabetes and current therapies for the management of diabetes, including oral hypoglycemic agents, insulin therapy, pancreas and islet transplantation, pulsed insulin therapy, and advances in IIT. Results: Our review of the literature shows that IIT improves the resolution of diabetic ulcers, neuropathy, and nephropathy, and reduces emergency room visits. The likely mechanism responsible for this improvement is increased insulin sensitivity from adipocytes, as well as increased insulin receptor expression. Conclusions: Recent advancements show that IIT is an effective option for both type 1 diabetes mellitus and type 2 diabetes mellitus patient populations. This treatment resembles normal pancreatic function so closely that it has significantly reduced the effects of relatively common complications of diabetes in comparison to standard treatments. Thus, this new treatment is a promising advancement in the management of diabetes. (Curr Ther Res Clin Exp. 2019; 80:XXX–XXX). Keywords: Diabetes, Complications, Infusion, Insulin, Intravenous

Video monitoring and surveillance of commercial fisheries in world oceans has been proposed by the governing bodies of several nations as a response to crimes such as overfishing. Traditional video monitoring systems may not be suitable due to limitations in the offshore fishing environment, including low bandwidth, unstable satellite network connections and issues of preserving the privacy of crew members. In this paper, we present Áika, a robust system for executing distributed Artificial Intelligence (AI) applications on the edge. Áika provides engineers and researchers with several building blocks in the form of Agents, which enable the expression of computation pipelines and distributed applications with robustness and privacy guarantees. Agents are continuously monitored by dedicated monitoring nodes, and provide applications with a distributed checkpointing and replication scheme. Áika is designed for monitoring and surveillance in privacy-sensitive and unstable offshore environments, where flexible access policies at the storage level can provide privacy guarantees for data transfer and access.

Islet cell transplantation has become a favorable therapeutic approach in the treatment of Type 1 Diabetes due to the lower surgical risks and potential complications compared to conventional pancreas transplantation. Despite significant improvements in islet cell transplantation outcomes, several limitations hamper long-term graft survival due to tremendous damage and loss of islet cells during the islet cell transplantation process. Oxidative stress has been identified as an omnipresent stressor that negatively affects both the viability and function of isolated islets. Furthermore, it has been established that at baseline, pancreatic β cells exhibit reduced antioxidative capacity, rendering them even more susceptible to oxidative stress during metabolic stress. Thus, identifying antioxidants capable of conferring protection against oxidative stressors present throughout the islet transplantation process is a valuable approach to improving the overall outcomes of islet cell transplantation. In this review we discuss the potential application of antioxidative therapy during each step of islet cell transplantation.

Chronic kidney disease is generally progressive and currently has no reliable treatment to reverse a decline in kidney function or to slow the progression of the disease. Diabetic nephropathy is one of the leading causes of end-stage kidney failure. Kidney damage in diabetic nephropathy is largely attributed to the increased oxidative stress, affecting its metabolic activity, metabolic pathways, and hemodynamic pathways. In diabetic patients, hyperglycemia causes an increase in the production of reactive oxygen species that further increase oxidative stress. These reactive oxygen species are created through a variety of pathways, providing the opportunity for treatment using anti-oxidative defense mechanisms to prevent vascular injury. This review will give an overview of oxidative stress, along with the current treatments and limitations of diabetic nephropathy. We will also discuss the potential of antioxidative therapies, with an emphasis on the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway.

The origins of low-temperature tissue storage research date back to the late 1800s. Over half a century later, osmotic stress was revealed to be a main contributor to cell death during cryopreservation. Consequently, the addition of cryoprotective agents (CPAs) such as dimethyl sulfoxide (DMSO), glycerol (GLY), ethylene glycol (EG), or propylene glycol (PG), although toxic to cells at high concentrations, was identified as a necessary step to protect against rampant cell death during cryopreservation. In addition to osmotic stress, cooling and thawing rates were also shown to have significant influence on cell survival during low temperature storage. In general, successful low-temperature cell preservation consists of the addition of a CPA (commonly 10% DMSO), alone or in combination with additional permeating or non-permeating agents, cooling rates of approximately 1ºC/min, and storage in either liquid or vapor phase nitrogen. In addition to general considerations, cell-specific recommendations for hepatocytes, pancreatic islets, sperm, oocytes, and stem cells should be observed to maximize yields. For example, rapid cooling is associated with better cryopreservation outcomes for oocytes, pancreatic islets, and embryonic stem cells while slow cooling is recommended for cryopreservation of hepatocytes, hematopoietic stem cells, and mesenchymal stem cells. Yields can be further maximized by implementing additional pre-cryo steps such as: pre-incubation with glucose and anti-oxidants, alginate encapsulation, and selecting cells within an optimal age range and functional ability. Finally, viability and functional assays are critical steps in determining the quality of the cells post-thaw and improving the efficiency of the current cryopreservation methods.

As part of a European Erasmus Plus project entitled Death Education for Palliative Psychology, this study assessed the ways in which Master’s Degree students in psychology and the creative arts therapies self-rated their confidence and interest in death education and palliative and bereavement care. In five countries (Austria, Israel, Italy, Poland, Romania), 344 students completed an online questionnaire, and 37 students were interviewed to better understand their views, interest, and confidence. The results revealed some significant differences between countries, and showed that older respondents with previous experience as formal caregivers for end-of-life clients showed greater interest in obtaining practical clinical competence in these fields. A mediation analysis indicated that students’ previous care experiences and past loss experiences were related to students’ current interest in death education and palliative and bereavement care through the mediation of their sense of confidence in this field. The qualitative findings identified five shared themes: life and death, learning about death, the psychological burden, personal experience and robust training, and four key training needs. Overall, students’ interest in studying and working with terminal illness and death are rooted in internal resources, a preliminary sense of confidence, but also external requirements.

This study was designed as an action research aimed to help students to elaborate their feelings of traumatic grief, due to a car accident and a suicide of two of their classmates, in an Italian high school. A death education project was realized in order to prevent the Werther effect. The intervention was based on psychodramatic techniques and meditation with Tibetan bells to encourage reflection on the suffering of traumatic loss, the sense of life, and their future. A total of 89 students from four classes (46 in the experimental group: two classes, 43 in the control groups: two classes) participated in the study, among which 82 (45 in the experimental group, 37 in the control group) completed the pre- and post-test survey. The intervention consisted of eight 2-h meetings, during which the themes of death and loss were dealt with through theoretical discussions, dramatization, and meditation. Two other classes which participated in the assessment as a control group did not attend the activities. The following instruments were used: Death Attitude Profile-Revised, which measures individual attitudes toward death; Psychological Well-being Scale, which measures a person’s psychological well-being; Resilience Scale for Adolescents, which measures the construct of resilience in adolescents; Self-Transcendence Scale, which measures self-transcendence; and Testoni Death Representation Scale, which measures the ontological representations of death. The results demonstrated that in the experimental group, there was a reduction in the fear of death and its avoidance, and that the students normalized the representation of death as something natural, thus improving their well-being. It is consequently possible to say that well-being is not simply the absence of suffering and worries, but rather, is rooted in the possibility of thinking of creative solutions to the trauma.

For the advancement of porcine xenotransplantation for clinical use in type 1 diabetes mellitus, the concerns of a sustainable and safe digestion enzyme blend must be overcome. Incorporating good manufacturing practices (GMP) can facilitate this through utilizing GMP-grade enzymes. In conjunction, still taking into account the cost-effectiveness, a wide concern. We evaluated how GMP-grade enzyme blends impact our piglet islets and their long-term effects. Preweaned porcine islets (PPIs) were isolated from 8- to 10-day-old pigs. Digestion enzyme blends, collagenase type V (Type V), collagenase AF-1 GMP-grade with collagenase NB 6 GMP-grade (AF-1 and NB 6), and collagenase AF-1 GMP-grade with collagenase neutral protease AF GMP-grade (AF-1 and NP AF) were compared. Islet quality control assessments, islet yield, viability, and function, were performed on days 3 and 7, and cell content was performed on day 7. GMP-grade AF-1 and NB 6 (17,209 ± 2,730 islet equivalent per gram of pancreatic tissue [IE/g] on day 3, 9,001 ± 1,034 IE/g on day 7) and AF-1 and NP AF (17,214 ± 3,901 IE/g on day 3, 8,833 ± 2,398 IE/g on day 7) showed a significant increase in islet yield compared to Type V (4,618 ± 1,240 IE/g on day 3, 1,923 ± 704 IE/g on day 7). Islet size, viability, and function showed comparable results in all enzyme blends. There was no significant difference in islet cellular content between enzyme blends. This study demonstrated a comparison of GMP-grade collagenase enzyme blends and a standard crude collagenase enzyme in preweaned-aged porcine, a novel topic in this age. GMP-grade enzyme blends of AF-1 and NB 6 and AF-1 and NP AF resulted in substantially higher yields and as effective PPIs compared to Type V. In the long run, considering costs, integrity, and sustainability, GMP-grade enzyme blends are more favorable for clinical application due to high reproducibility in comparison to undefined manufacturing processes of standard enzymes.

Access to functional high-quality pancreatic human islets is critical to advance diabetes research. The Integrated Islet Distribution Program (IIDP), a major source for human islet distribution for over 15 years, conducted a study to evaluate the most advantageous times to ship islets postisolation to maximize islet recovery. For the evaluation, three experienced IIDP Islet Isolation Centers each provided samples from five human islet isolations, shipping 10,000 islet equivalents (IEQ) at four different time periods postislet isolation (no 37°C culture and shipped within 0 to 18 hours; or held in 37°C culture for 18 to 42, 48 to 96, or 144 to 192 hours). A central evaluation center compared samples for islet quantity, quality, and viability for each experimental condition preshipment and postshipment, as well as post 37°C culture 18 to 24 hours after shipment receipt. Additional evaluations included measures of functional potency by static glucose-stimulated insulin release (GSIR), represented as a stimulation index. Comparing the results of the four preshipment holding periods, the greatest IEQ loss postshipment occurred with the shortest preshipment times. Similar patterns emerged when comparing preshipment to postculture losses. In vitro islet function (GSIR) was not adversely impacted by increased tissue culture time. These data indicate that allowing time for islet recovery postisolation, prior to shipping, yields less islet loss during shipment without decreasing islet function.

Prevalence of type 2 diabetes increased from 2.5% of the US population in 1990 to 10.5% in 2018. This creates a major public health problem, due to increases in long-term complications of diabetes, including neuropathy, retinopathy, nephropathy, skin ulcers, amputations, and atherosclerotic cardiovascular disease. In this review, we evaluated the scientific basis that supports the use of physiologic insulin resensitization. Insulin resistance is the primary cause of type 2 diabetes. Insulin resistance leads to increasing insulin secretion, leading to beta-cell exhaustion or burnout. This triggers a cascade leading to islet cell destruction and the long-term complications of type 2 diabetes. Concurrent with insulin resistance, the regular bursts of insulin from the pancreas become irregular. This has been treated by the precise administration of insulin more physiologically. There is consistent evidence that this treatment modality can reverse the diabetes-associated complications of neuropathy, diabetic ulcers, nephropathy, and retinopathy, and that it lowers HbA1c. In conclusion, physiologic insulin resensitization has a persuasive scientific basis, significant treatment potential, and likely cost benefits.

Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia as a result of insufficient insulin levels and/or impaired function as a result of autoimmune destruction or insulin resistance. While Type 1 DM (T1DM) and Type 2 DM (T2DM) occur through different pathological processes, both result in β-cell destruction and/or dysfunction, which ultimately lead to insufficient β-cell mass to maintain normoglycemia. Therefore, therapeutic agents capable of inducing β-cell proliferation is crucial in treating and reversing diabetes; unfortunately, adult human β-cell proliferation has been shown to be very limited (~0.2% of β-cells/24 h) and poorly responsive to many mitogens. Furthermore, diabetogenic insults result in damage to β cells, making it ever more difficult to induce proliferation. In this review, we discuss β-cell mass/proliferation pathways dysregulated in diabetes and current therapeutic agents studied to induce β-cell proliferation. Furthermore, we discuss possible combination therapies of proliferation agents with immunosuppressants and antioxidative therapy to improve overall long-term outcomes of diabetes.