First-in-human, double-blind, randomized phase 1b study of peptide immunotherapy IMCY-0098 in new-onset type 1 diabetes: an exploratory analysis of immune biomarkers.

BACKGROUND: IMCY-0098, a synthetic peptide developed to halt disease progression via elimination of key immune cells in the autoimmune cascade, has shown a promising safety profile for the treatment of type 1 diabetes (T1D) in a recent phase 1b trial. This exploratory analysis of data from that trial aimed to identify the patient biomarkers at baseline associated with a positive response to treatment and examined the associations between immune response parameters and clinical efficacy endpoints (as surrogates for mechanism of action endpoints) using an artificial intelligence-based approach of unsupervised explainable machine learning. METHODS: We conducted an exploratory analysis of data from a phase 1b, dose-escalation, randomized, placebo-controlled study of IMCY-0098 in patients with recent-onset T1D. Here, a panel of markers of T cell activation, memory T cells, and effector T cell response were analyzed via descriptive statistics. Artificial intelligence-based analyses of associations between all variables, including immune responses and clinical responses, were performed using the Knowledge Extraction and Management (KEM®) v 3.6.2 analytical platform. RESULTS: The relationship between all available patient data was investigated using unsupervised machine learning implemented in the KEM® environment. Of 15 associations found for the dose C group (450 µg subcutaneously followed by 3 × 225 µg subcutaneously), seven involved human leukocyte antigen (HLA) type, all of which identified improvement/absence of worsening of disease parameters in DR4+ patients and worsening/absence of improvement in DR4- patients. This association with DR4+ and non-DR3 was confirmed using the endpoints normalized area under the curve C-peptide from mixed meal tolerance tests where presence of DR4 HLA haplotype was associated with an improvement in both endpoints. Exploratory immune analysis showed that IMCY-0098 dose B (150 µg subcutaneously followed by 3 × 75 µg subcutaneously) and dose C led to an increase in presumed/potentially protective antigen-specific cytolytic CD4+ T cells and a decrease in pathogenic CD8+ T cells, consistent with the expected mechanism of action of IMCY-0098. The analysis identified significant associations between immune and clinical responses to IMCY-0098. CONCLUSIONS: Promising preliminary efficacy results support the design of a phase 2 study of IMCY-0098 in patients with recent-onset T1D. TRIAL REGISTRATION: ClinicalTrials.gov NCT03272269; EudraCT: 2016-003514-27.

Cardio-renal-metabolic disease in primary care setting.

In the primary care setting providers have more tools available than ever before to impact positively obesity, diabetes, and their complications, such as renal and cardiac diseases. It is important to recognise what is available for treatment taking into account diabetes heterogeneity. For those who develop type 2 diabetes (T2DM), effective treatments are available that for the first time have shown a benefit in reducing mortality and macrovascular complications, in addition to the well-established benefits of glucose control in reducing microvascular complications. Some of the newer medications for treating hyperglycaemia have also a positive impact in reducing heart failure (HF). Technological advances have also contributed to improving the quality of care in patients with diabetes. The use of technology, such as continuous glucose monitoring systems (CGM), has improved significantly glucose and glycated haemoglobin A1c (HbA1c) values, while limiting the frequency of hypoglycaemia. Other technological support derives from the use of predictive algorithms that need to be refined to help predict those subjects who are at great risk of developing the disease and/or its complications, or who may require care by other specialists. In this review we also provide recommendations for the optimal use of the new medications; sodium-glucose co-transporter-2 inhibitors (SGLT2i) and Glucagon-like peptide-receptor agonists 1 (GLP1RA) in the primary care setting considering the relevance of these drugs for the management of T2DM also in its early stage.

Connecting microscopic and mesoscopic mechanics in model structural glasses.

We present a novel formalism to characterize elastic heterogeneities in amorphous solids. In particular, we derive high-order strain-energy expansions for pairwise energies under athermal quasistatic dynamics. We then use the presented formalism to study the statistical properties of pairwise expansion coefficients and their link with the statistics of soft, quasilocalized modes, for a wide range of formation histories in both two- and three-dimensional systems. We further exploit the presented framework to access local yield stress maps by performing a non-linear stress-strain expansion within a cavity embedded in a frozen matrix. We show that our "bond micromechanics" compare well with the original "frozen matrix" method, with the caveat of overestimating large stress activations. We additionally show how local yield rules can be used as an input for a scalar elasto-plastic model (EPM) to predict the stress response of materials ranging from ductile to brittle. Finally, we highlight some of the limits of simple mesoscale models in capturing the aging dynamics of post-yielding systems. Intriguingly, we observe subdiffusive and diffusive shear band growths for particle-based simulations and EPMs, respectively.

First-in-human, double-blind, randomized phase 1b study of peptide immunotherapy IMCY-0098 in new-onset type 1 diabetes.

BACKGROUND: Type 1 diabetes (T1D) is a CD4+ T cell-driven autoimmune disease characterized by the destruction of insulin-producing pancreatic ß-cells by CD8+ T cells. Achieving glycemic targets in T1D remains challenging in clinical practice; new treatments aim to halt autoimmunity and prolong ß-cell survival. IMCY-0098 is a peptide derived from human proinsulin that contains a thiol-disulfide oxidoreductase motif at the N-terminus and was developed to halt disease progression by promoting the specific elimination of pathogenic T cells. METHODS: This first-in-human, 24-week, double-blind phase 1b study evaluated the safety of three dosages of IMCY-0098 in adults diagnosed with T1D < 6 months before study start. Forty-one participants were randomized to receive four bi-weekly injections of placebo or increasing doses of IMCY-0098 (dose groups A/B/C received 50/150/450 µg for priming followed by three further administrations of 25/75/225 µg, respectively). Multiple T1D-related clinical parameters were also assessed to monitor disease progression and inform future development. Long-term follow-up to 48 weeks was also conducted in a subset of patients. RESULTS: Treatment with IMCY-0098 was well tolerated with no systemic reactions; a total of 315 adverse events (AEs) were reported in 40 patients (97.6%) and were related to study treatment in 29 patients (68.3%). AEs were generally mild; no AE led to discontinuation of the study or death. No significant decline in C-peptide was noted from baseline to Week 24 for dose A, B, C, or placebo (mean change - 0.108, - 0.041, - 0.040, and - 0.012, respectively), suggesting no disease progression. CONCLUSIONS: Promising safety profile and preliminary clinical response data support the design of a phase 2 study of IMCY-0098 in patients with recent-onset T1D. TRIAL REGISTRATION: IMCY-T1D-001: ClinicalTrials.gov NCT03272269; EudraCT: 2016-003514-27; and IMCY-T1D-002: ClinicalTrials.gov NCT04190693; EudraCT: 2018-003728-35.

The influence of awareness on implicit visuomotor adaptation.

It is well documented that reaches are adapted when reaching with a visuomotor distortion (i.e., rotated cursor feedback). Less clear is the influence of awareness on visuomotor adaptation, where awareness encompasses knowledge of the changes in one's reaches and the visuomotor distortion itself. In the current experiment, we asked if awareness governs the magnitude of implicit (i.e., unconscious) visuomotor adaptation achieved, independent of how the distortion is introduced (i.e., abruptly vs. gradually introduced visuomotor distortion), and hence initial errors experienced. Participants were divided into two groups that differed with respect to how the visuomotor distortion was introduced (i.e., Abrupt vs. Gradual Groups) and reached in a virtual environment where a cursor on the screen misrepresented the position of their hand. Participants completed three blocks of 150 reach training trials in the following order: aligned cursor feedback (baseline), rotated cursor feedback (adaptation) and aligned cursor feedback (washout). For the Abrupt Group, the cursor was immediately rotated 45° clockwise (CW) relative to hand motion in the adaptation block, whereas in the Gradual Group, the 45° cursor rotation was gradually introduced over adaptation trials. Following reach training, participants' awareness of changes in their reaches and the visuomotor distortion were established based on a drawing task, where participants drew the path their hand took to get the cursor on target, as well as a post-experiment questionnaire. Participants were subsequently divided into the following 3 groups: Abrupt-Aware (n = 16), Gradual-Aware (n = 11) and Gradual-Unaware (n = 14). Results revealed that errors differed for the Gradual-Unaware Group at the end of adaptation training compared to the Gradual-Aware Group and at the start of the washout block compared to the Abrupt-Aware Group. Errors in the two aware groups did not differ from each other. These results suggest that awareness may lead to reduced implicit adaptation, regardless of the size of initial errors experienced.

Simple and Broadly Applicable Definition of Shear Transformation Zones.

Plastic deformation in amorphous solids is known to be carried by stress-induced localized rearrangements of a few tens of particles, accompanied by the conversion of elastic energy to heat. Despite their central role in determining how glasses yield and break, the search for a simple and generally applicable definition of the precursors of those plastic rearrangements-the so-called shear transformation zones (STZs)-is still ongoing. Here we present a simple definition of STZs-based solely on the harmonic approximation of a glass's energy. We explain why and demonstrate directly that our proposed definition of plasticity carriers in amorphous solids is more broadly applicable compared to anharmonic definitions put forward previously. Finally, we offer an open-source library that analyzes low-lying STZs in computer glasses and in laboratory materials such as dense colloidal suspensions for which the harmonic approximation is accessible. Our results constitute a physically motivated methodological advancement towards characterizing mechanical disorder in glasses, and understanding how they yield.

Simultaneous enrichment and separation of neutral and sialyl glycopeptides of SARS-CoV-2 spike protein enabled by dual-functionalized Ti-IMAC material.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a serious threat to human health all over the world. The development of effective vaccines has been focusing on the spike (S) glycoprotein, which mediates viral invasion to human cells through its interaction with the angiotensin-converting enzyme 2 (ACE2) receptor. In this work, we perform analytical characterization of N- and O-linked glycosylation of the SARS-CoV-2 S glycoprotein. We explore the novel use of dual-functionalized titanium (IV)-immobilized metal affinity chromatography (Ti-IMAC) material for simultaneous enrichment and separation of neutral and sialyl glycopeptides of a recombinant SARS-CoV-2 S glycoprotein from HEK293 cells. This strategy helps eliminate signal suppression from neutral glycopeptides for the detection of sialyl glycopeptides and improves the glycoform coverage of the S protein. We profiled 19 of its 22 potential N-glycosylated sites with 398 unique glycoforms using the dual-functional Ti-IMAC approach, which exhibited improvement of coverage by 1.6-fold compared to the conventional hydrophilic interaction chromatography (HILIC) glycopeptide enrichment method. We also identified O-linked glycosylation site that was not found using the conventional HILIC approach. In addition, we reported on the identification of mannose-6-phosphate (M6P) glycosylation, which substantially expands the current knowledge of the spike protein's glycosylation landscape and enables future investigation into the influence of M6P glycosylation of the spike protein on its cell entry.

Elastic moduli fluctuations predict wave attenuation rates in glasses.

The disorder-induced attenuation of elastic waves is central to the universal low-temperature properties of glasses. Recent literature offers conflicting views on both the scaling of the wave attenuation rate Γ(ω) in the low-frequency limit (ω → 0) and its dependence on glass history and properties. A theoretical framework-termed Fluctuating Elasticity Theory (FET)-predicts low-frequency Rayleigh scattering scaling in -d spatial dimensions, Γ(ω) ∼ γ ω -d+1, where γ = γ(Vc) quantifies the coarse-grained spatial fluctuations of elastic moduli, involving a correlation volume Vc that remains debated. Here, using extensive computer simulations, we show that Γ(ω) ∼ γω3 is asymptotically satisfied in two dimensions ( -d = 2) once γ is interpreted in terms of ensemble-rather than spatial-averages, where Vc is replaced by the system size. In doing so, we also establish that the finite-size ensemble-statistics of elastic moduli is anomalous and related to the universal ω4 density of states of soft quasilocalized modes. These results not only strongly support FET but also constitute a strict benchmark for the statistics produced by coarse-graining approaches to the spatial distribution of elastic moduli.

Does mesoscopic elasticity control viscous slowing down in glassforming liquids?

The dramatic slowing down of relaxation dynamics of liquids approaching the glass transition remains a highly debated problem, where the crux of the puzzle resides in the elusive increase in the activation barrier ΔE(T) with decreasing temperature T. A class of theoretical frameworks-known as elastic models-attribute this temperature dependence to the variations of the liquid's macroscopic elasticity, quantified by the high-frequency shear modulus G∞(T). While elastic models find some support in a number of experimental studies, these models do not take into account the spatial structures, length scales, and heterogeneity associated with structural relaxation in supercooled liquids. Here, we propose and test the possibility that viscous slowing down is controlled by a mesoscopic elastic stiffness κ(T), defined as the characteristic stiffness of response fields to local dipole forces in the liquid's underlying inherent structures. First, we show that κ(T)-which is intimately related to the energy and length scales characterizing quasilocalized, nonphononic excitations in glasses-increases more strongly with decreasing T than the macroscopic inherent structure shear modulus G(T) [the glass counterpart of liquids' G∞(T)] in several computer liquids. Second, we show that the simple relation ΔE(T) ∝ κ(T) holds remarkably well for some computer liquids, suggesting a direct connection between the liquid's underlying mesoscopic elasticity and enthalpic energy barriers. On the other hand, we show that for other computer liquids, the above relation fails. Finally, we provide strong evidence that what distinguishes computer liquids in which the ΔE(T) ∝ κ(T) relation holds from those in which it does not is that the latter feature highly fragmented/granular potential energy landscapes, where many sub-basins separated by low activation barriers exist. Under such conditions, it appears that the sub-basins do not properly represent the landscape properties relevant for structural relaxation.

Correction: Gill, R.D. Does Geometric Algebra Provide a Loophole to Bell's Theorem? Entropy 2020, 22, 61.

Corrections are made to my paper "Gill, R.D. Does Geometric Algebra Provide a Loophole to Bell's Theorem? Entropy 2020, 22, 61" [...].

Universality of the Nonphononic Vibrational Spectrum across Different Classes of Computer Glasses.

It has been recently established that the low-frequency spectrum of simple computer glass models is populated by soft, quasilocalized nonphononic vibrational modes whose frequencies ω follow a gapless, universal distribution D(ω)∼ω^{4}. While this universal nonphononic spectrum has been shown to be robust to varying the glass history and spatial dimension, it has so far only been observed in simple computer glasses featuring radially symmetric, pairwise interaction potentials. Consequently, the relevance of the universality of nonphononic spectra seen in simple computer glasses to realistic laboratory glasses remains unclear. Here, we demonstrate the emergence of the universal ω^{4} nonphononic spectrum in a broad variety of realistic computer glass models, ranging from tetrahedral network glasses with three-body interactions, through molecular glasses and glassy polymers, to bulk metallic glasses. Taken together with previous observations, our results indicate that the low-frequency nonphononic vibrational spectrum of any glassy solid quenched from a melt features the universal ω^{4} law, independently of the nature of its microscopic interactions.

Evaluation of resource utilization efficiency in obstetrics and gynecology units in China: A three-stage data envelopment analysis of the Shanxi province.

In China, health care resources for expectant mothers and children are still not utilized to full efficiency, with health requirements still not being met. The purpose of this study is to critically examine the efficiency of gynecology and obstetrics hospital (OB/GYN) units in Shanxi province of China, with the overarching objective of exploring methods for improving their efficiency. We employ the three-stage data envelopment analysis (DEA) model to measure the efficiency of 134 OB/GYN units in Shanxi. The results show that the technical efficiency and scale efficiency scores of the sample units were low (0.48 and 0.54, respectively). The efficiency of the OB/GYN units varies by region, city, and county and by type of unit. We conclude that the main reason for the low efficiency of OB/GYN units in Shanxi province lies in the unreasonable scale. The government should, therefore, allocate health resources more reasonably, improving the efficiency of different regions, cities, and counties, as well as different types of OB/GYN units.

The Triangle Wave Versus the Cosine: How Classical Systems Can Optimally Approximate EPR-B Correlations.

The famous singlet correlations of a composite quantum system consisting of two two-level components in the singlet state exhibit notable features of two kinds. One kind are striking certainty relations: perfect anti-correlation, and perfect correlation, under certain joint settings. The other kind are a number of symmetries, namely invariance under a common rotation of the settings, invariance under exchange of components, and invariance under exchange of both measurement outcomes. One might like to restrict attention to rotations in the plane since those are the ones most commonly investigated experimentally. One can then also further distinguish between the case of discrete rotations (e.g., only settings which are a whole number of degrees are allowed) and continuous rotations. We study the class of classical correlation functions, i.e., generated by classical physical systems, satisfying all these symmetries, in the continuous, planar, case. We call such correlation functions classical EPR-B correlations. It turns out that if the certainty relations and rotational symmetry holds at the level of the correlations, then rotational symmetry can be imposed "for free" on the underlying classical physical model by adding an extra randomisation level. The other binary symmetries are obtained "for free". This leads to a simple heuristic description of all possible classical EPR-B correlations in terms of a "spinning bi-coloured disk" model. We deliberately use the word "heuristic" because technical mathematical problems remain wide open concerning the transition from finite or discrete to continuous. The main purpose of this paper is to bring this situation to the attention of the mathematical community. We do show that the widespread idea that "quantum correlations are more extreme than classical physics would allow" is at best highly inaccurate, through giving a concrete example of a classical correlation which satisfies all the symmetries and all the certainty relations and which exceeds the quantum correlations over a whole range of settings. It is found by a search procedure in which we randomly generate classical physical models and, for each generated model, evaluate its properties in a further Monte-Carlo simulation of the model itself.

Genetic diversity of Koala retrovirus env gene subtypes: insights into northern and southern koala populations.

Koala retrovirus (KoRV) is a recently endogenized retrovirus associated with neoplasia and immunosuppression in koala populations. The virus is known to display sequence variability and to be present at varying prevalence in different populations, with animals in southern Australia displaying lower prevalence and viral loads than northern animals. This study used a PCR and next-generation sequencing strategy to examine the diversity of the KoRV env gene in both proviral DNA and viral RNA forms in two distinct populations representative of the 'northern' and 'southern' koala genotypes. The current study demonstrated that the full range of KoRV subtypes is present across both populations, and in both healthy and sick animals. KoRV-A was the predominant proviral subtype in both populations, but there was marked diversity of DNA and RNA subtypes within individuals. Many of the northern animals displayed a higher RNA viral diversity than evident in their proviral DNA, indicating relatively higher replication efficiency of non-KoRV-A subtypes. The southern animals displayed a lower absolute copy number of KoRV than the northern animals as reported previously and a higher preponderance of KoRV-A in individual animals. These discrepancies in viral replication and diversity remain unexplained but may indicate relative protection of the southern population from KoRV replication due to either viral or host factors and may represent an important protective effect for the host in KoRV's ongoing entry into the koala genome.

Identifying Common Methods Used by Drug Interaction Experts for Finding Evidence About Potential Drug-Drug Interactions: Web-Based Survey.

BACKGROUND: Preventing drug interactions is an important goal to maximize patient benefit from medications. Summarizing potential drug-drug interactions (PDDIs) for clinical decision support is challenging, and there is no single repository for PDDI evidence. Additionally, inconsistencies across compendia and other sources have been well documented. Standard search strategies for complete and current evidence about PDDIs have not heretofore been developed or validated. OBJECTIVE: This study aimed to identify common methods for conducting PDDI literature searches used by experts who routinely evaluate such evidence. METHODS: We invited a convenience sample of 70 drug information experts, including compendia editors, knowledge-base vendors, and clinicians, via emails to complete a survey on identifying PDDI evidence. We created a Web-based survey that included questions regarding the (1) development and conduct of searches; (2) resources used, for example, databases, compendia, search engines, etc; (3) types of keywords used to search for the specific PDDI information; (4) study types included and excluded in searches; and (5) search terms used. Search strategy questions focused on 6 topics of the PDDI information-(1) that a PDDI exists; (2) seriousness; (3) clinical consequences; (4) management options; (5) mechanism; and (6) health outcomes. RESULTS: Twenty participants (response rate, 20/70, 29%) completed the survey. The majority (17/20, 85%) were drug information specialists, drug interaction researchers, compendia editors, or clinical pharmacists, with 60% (12/20) having >10 years' experience. Over half (11/20, 55%) worked for clinical solutions vendors or knowledge-base vendors. Most participants developed (18/20, 90%) and conducted (19/20, 95%) search strategies without librarian assistance. PubMed (20/20, 100%) and Google Scholar (11/20, 55%) were most commonly searched for papers, followed by Google Web Search (7/20, 35%) and EMBASE (3/20, 15%). No respondents reported using Scopus. A variety of subscription and open-access databases were used, most commonly Lexicomp (9/20, 45%), Micromedex (8/20, 40%), Drugs@FDA (17/20, 85%), and DailyMed (13/20, 65%). Facts and Comparisons was the most commonly used compendia (8/20, 40%). Across the 6 attributes of interest, generic drug name was the most common keyword used. Respondents reported using more types of keywords when searching to identify the existence of PDDIs and determine their mechanism than when searching for the other 4 attributes (seriousness, consequences, management, and health outcomes). Regarding the types of evidence useful for evaluating a PDDI, clinical trials, case reports, and systematic reviews were considered relevant, while animal and in vitro data studies were not. CONCLUSIONS: This study suggests that drug interaction experts use various keyword strategies and various database and Web resources depending on the PDDI evidence they are seeking. Greater automation and standardization across search strategies could improve one's ability to identify PDDI evidence. Hence, future research focused on enhancing the existing search tools and designing recommended standards is needed.

Pearle's Hidden-Variable Model Revisited.

Pearle (1970) gave an example of a local hidden variables model which exactly reproduced the singlet correlations of quantum theory, through the device of data-rejection: particles can fail to be detected in a way which depends on the hidden variables carried by the particles and on the measurement settings. If the experimenter computes correlations between measurement outcomes of particle pairs for which both particles are detected, he or she is actually looking at a subsample of particle pairs, determined by interaction involving both measurement settings and the hidden variables carried in the particles. We correct a mistake in Pearle's formulas (a normalization error) and more importantly show that the model is simpler than first appears. We illustrate with visualizations of the model and with a small simulation experiment, with code in the statistical programming language R included in the paper. Open problems are discussed.

Does Geometric Algebra Provide a Loophole to Bell's Theorem?

In 2007, and in a series of later papers, Joy Christian claimed to refute Bell's theorem, presenting an alleged local realistic model of the singlet correlations using techniques from geometric algebra (GA). Several authors published papers refuting his claims, and Christian's ideas did not gain acceptance. However, he recently succeeded in publishing yet more ambitious and complex versions of his theory in fairly mainstream journals. How could this be? The mathematics and logic of Bell's theorem is simple and transparent and has been intensely studied and debated for over 50 years. Christian claims to have a mathematical counterexample to a purely mathematical theorem. Each new version of Christian's model used new devices to circumvent Bell's theorem or depended on a new way to misunderstand Bell's work. These devices and misinterpretations are in common use by other Bell critics, so it useful to identify and name them. I hope that this paper can serve as a useful resource to those who need to evaluate new "disproofs of Bell's theorem". Christian's fundamental idea is simple and quite original: he gives a probabilistic interpretation of the fundamental GA equation a · b = ( a b + b a ) / 2 . After that, ambiguous notation and technical complexity allows sign errors to be hidden from sight, and new mathematical errors can be introduced.

Modelling competing legal arguments using Bayesian model comparison and averaging.

Bayesian models of legal arguments generally aim to produce a single integrated model, combining each of the legal arguments under consideration. This combined approach implicitly assumes that variables and their relationships can be represented without any contradiction or misalignment, and in a way that makes sense with respect to the competing argument narratives. This paper describes a novel approach to compare and 'average' Bayesian models of legal arguments that have been built independently and with no attempt to make them consistent in terms of variables, causal assumptions or parameterization. The approach involves assessing whether competing models of legal arguments are explained or predict facts uncovered before or during the trial process. Those models that are more heavily disconfirmed by the facts are given lower weight, as model plausibility measures, in the Bayesian model comparison and averaging framework adopted. In this way a plurality of arguments is allowed yet a single judgement based on all arguments is possible and rational.