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.

Virulence phenotypes differ between toxigenic Vibrio parahaemolyticus isolated from western coasts of Europe.

Vibrio parahaemolyticus is the leading bacterial cause of gastroenteritis associated with seafood consumption worldwide. Not all members of the species are thought to be pathogenic, thus identification of virulent organisms is essential to protect public health and the seafood industry. Correlations of human disease and known genetic markers (e.g. thermostable direct hemolysin (TDH), TDH-related hemolysin (TRH)) appear complex. Some isolates recovered from patients lack these factors, while their presence has become increasingly noted in isolates recovered from the environment. Here, we used whole-genome sequencing in combination with mammalian and insect models of infection to assess the pathogenic potential of V. parahaemolyticus isolated from European Atlantic shellfish production areas. We found environmental V. parahaemolyticus isolates harboured multiple virulence-associated genes, including TDH and/or TRH. However, carriage of these factors did not necessarily reflect virulence in the mammalian intestine, as an isolate containing TDH and the genes coding for a type 3 secretion system (T3SS) 2α virulence determinant, appeared avirulent. Moreover, environmental V. parahaemolyticus lacking TDH or TRH could be assigned to groups causing low and high levels of mortality in insect larvae, with experiments using defined bacterial mutants showing that a functional T3SS1 contributed to larval death. When taken together, our findings highlight the genetic diversity of V. parahaemolyticus isolates found in the environment, their potential to cause disease and the need for a more systematic evaluation of virulence in diverse V. parahaemolyticus to allow better genetic markers.

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.

Advances with Platelet-Rich Plasma for Bone Healing.

Despite significant advances in the understanding and delivery of osteosynthesis, fracture non-union remains a challenging clinical problem in orthopaedic surgery. To bridge the gap, basic science characterization of fracture healing provides a platform to identify and target biological strategies to enhance fracture healing. Of immense interest, Platelet-rich plasma (PRP) is a point of care orthobiologic that has been extensively studied in bone and soft tissue healing given its relative ease of translation from the benchtop to the clinic. The aim of this narrative review is to describe and relate pre-clinical in-vitro and in-vivo findings to clinical observations investigating the efficacy of PRP to enhance bone healing for primary fracture management and non-union treatment. A particular emphasis is placed on the heterogeneity of PRP preparation techniques, composition, activation strategies, and delivery. In the context of existing data, the routine use of PRP to enhance primary fracture healing and non-union management cannot be supported. However, it is acknowledged that extensive heterogeneity of PRP treatments in clinical studies adds obscurity; ultimately, refinement (and consensus) of PRP treatments for specific clinical indications, including repetition studies are warranted.

A Large Ankle Mass in a Figure Skater: A Case Report.

A 19-year-old male competitive figure skater presented to clinic with a 3-year history of right ankle swelling. Exam demonstrated a ~6cm diameter mass over the medial malleolus. MRI revealed a well-circumscribed fluid-filled mass. After failing conservative management, the patient underwent surgical excision. Anatomic pathology revealed a pseudocyst with pseudosynovial metaplasia, consistent with malleolar bursitis. Competitive figure skaters can develop significant medial malleolar bursitis due to excessive shear forces from ill-fitting skates. If non-operative management is ineffective, patients can be managed successfully with surgical excision. The patient made a full recovery and has returned to competitive skating without recurrence.

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.

Detecting low-energy quasilocalized excitations in computer glasses.

Soft, quasilocalized excitations (QLEs) are known to generically emerge in a broad class of disordered solids and to govern many facets of the physics of glasses, from wave attenuation to plastic instabilities. In view of this key role of QLEs, shedding light upon several open questions in glass physics depends on the availability of computational tools that allow one to study QLEs' statistical mechanics. The latter is a formidable task since harmonic analyses are typically contaminated by hybridizations of QLEs with phononic excitations at low frequencies, obscuring a clear picture of QLEs' abundance, typical frequencies, and other important micromechanical properties. Here we present an efficient algorithm to detect the field of quasilocalized excitations in structural computer glasses. The algorithm introduced takes a computer-glass sample as input and outputs a library of QLEs embedded in that sample. We demonstrate the power of the algorithm by reporting the spectrum of glassy excitations in two-dimensional computer glasses featuring a huge range of mechanical stability, which is inaccessible using conventional harmonic analyses due to phonon hybridizations. Future applications are discussed.

Understanding diabetes heterogeneity: key steps towards precision medicine in diabetes.

Diabetes is a highly heterogeneous condition; yet, it is diagnosed by measuring a single blood-borne metabolite, glucose, irrespective of aetiology. Although pragmatically helpful, disease classification can become complex and limit advances in research and medical care. Here, we describe diabetes heterogeneity, highlighting recent approaches that could facilitate management by integrating three disease models across all forms of diabetes, namely, the palette model, the threshold model and the gradient model. Once diabetes has developed, further worsening of established diabetes and the subsequent emergence of diabetes complications are kept in check by multiple processes designed to prevent or circumvent metabolic dysfunction. The impact of any given disease risk factor will vary from person-to-person depending on their background, diabetes-related propensity, and environmental exposures. Defining the consequent heterogeneity within diabetes through precision medicine, both in terms of diabetes risk and risk of complications, could improve health outcomes today and shine a light on avenues for novel therapy in the future.

Impact of dipeptidyl peptidase-4 inhibitors on glucose-dependent insulinotropic polypeptide in type 2 diabetes mellitus: a systematic review and meta-analysis.

Aims: Glucose-dependent insulinotropic polypeptide (GIP) confers a variety of metabolic benefits in type 2 diabetes mellitus (T2DM). This meta-analysis was conducted to investigate the impact of dipeptidyl peptidase 4 (DPP4) inhibitors on GIP levels in T2DM patients. Methods: Medline (PubMed), CENTER (Cochrane Library), and Embase (Ovid) were searched and randomized controlled trials (RCTs) evaluating the impact of DPP4 inhibitors on fasting and postprandial GIP levels were obtained. For postprandial GIP, only studies with the data of GIP changes reported as the total area under the curve (AUCGIP) using a meal or oral glucose tolerance test were included. A random-effects model was used for data pooling after incorporating heterogeneity. Results: Overall, 14 RCTs with 541 T2DM patients were included. Compared to placebo/no treatment, the use of DPP4 inhibitors significantly increased the fasting GIP level (standard mean difference [SMD]: 0.77, 95% confidence interval [CI]: 0.48-1.05, P<0.001; I2 = 52%) and postprandial AUCGIP (SMD: 1.33, 95% CI: 1.02-1.64, P<0.001; I2 = 65%). Influence analysis by excluding one dataset at a time showed consistent results. Sensitivity analyses only including studies with radioimmunoassay showed also consistent results (fasting GIP: SMD: 0.75, 95% CI: 0.51-1.00, P<0.001; I2 = 0%; and postprandial AUCGIP: SMD: 1.48, 95% CI: 1.18-1.78, P<0.001; I2 = 54%). Further subgroup analyses demonstrated that the influence of DPP4 inhibitors on fasting and postprandial GIP levels in T2DM patients was not significantly changed by study characteristics such as study design, patient mean age, baseline glycated hemoglobin (HbA1c) concentration, body mass index (BMI), background treatment, treatment duration, or method for postprandial GIP measurement (all P for subgroup effects <0.05). Conclusion: The use of DPP4 inhibitors effectively increases the fasting and postprandial GIP concentrations in T2DM patients. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022356716.

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.

Comparison of Functional Outcomes After Acute Inpatient Rehabilitation After Acquired Brain Injury Before and During the COVID-19 Pandemic.

OBJECTIVE: The objective of this study was to characterize and compare functional outcomes of acquired brain injury patients in an inpatient rehabilitation facility in the year before (April 2019-March 2020) and during the first year (April 2020-March 2021) of the COVID-19 pandemic, when the most drastic changes in the delivery of health care occurred. DESIGN: In this retrospective single-center chart review study, functional outcomes, based on the Center for Medicare and Medicaid Services Inpatient Rehabilitation Facility-Patient Assessment Instrument, were obtained and analyzed for patients in acute inpatient rehabilitation with acquired brain injury. RESULTS: Data from 1330 patients were included for analysis. Functional outcomes of average self-care, bed mobility, and transfer scores were statistically, but not clinically, different between groups. More patients in the pandemic group were discharged home (prepandemic n = 454 [65.4%]; pandemic n = 461 [72.6%]; P = 0.011), although they had significantly longer lengths of stay (prepandemic median = 14.0 [interquartile range = 9.0-23.0]; pandemic = 16.0 [10.0-23.0]; P = 0.037). CONCLUSIONS: Despite the impact of hospital policies due to the COVID-19 pandemic, similar functional outcomes were obtained for those with acquired brain injury after inpatient rehabilitation.

Combination therapy with saxagliptin and vitamin D for the preservation of ß-cell function in adult-onset type 1 diabetes: a multi-center, randomized, controlled trial.

Disease modifying therapies aiming to preserve ß-cell function in patients with adult-onset autoimmune type 1 diabetes are lacking. Here, we conducted a multi-centre, randomized, controlled trial to assess the ß-cell preservation effects of saxagliptin alone and saxagliptin combined with vitamin D as adjunctive therapies in adult-onset autoimmune type 1 diabetes. In this 3-arm trial, 301 participants were randomly assigned to a 24-month course of the conventional therapy (metformin with or without insulin) or adjunctive saxagliptin or adjunctive saxagliptin plus vitamin D to the conventional therapy. The primary endpoint was the change from baseline to 24 months in the fasting C-peptide. The secondary endpoints included the area under the concentration-time curve (AUC) for C-peptide level in a 2-h mixed-meal tolerance test, glycemic control, total daily insulin use and safety, respectively. The primary endpoint was not achieved in saxagliptin plus vitamin D group (P = 0.18) and saxagliptin group (P = 0.26). However, compared with the conventional therapy, 2-h C-peptide AUC from 24 months to baseline decreased less with saxagliptin plus vitamin D (-276 pmol/L vs. -419 pmol/L; P = 0.01), and not to the same degree with saxagliptin alone (-314 pmol/L; P = 0.14). Notably, for participants with higher glutamic acid decarboxylase antibody (GADA) levels, the decline of ß-cell function was much lower in saxagliptin plus vitamin D group than in the conventional therapy group (P = 0.001). Insulin dose was significantly reduced in both active treatment groups than in the conventional therapy group despite all groups having similar glycemic control. In conclusion, the combination of saxagliptin and vitamin D preserves pancreatic ß-cell function in adult-onset autoimmune type 1 diabetes, an effect especially efficacious in individuals with higher GADA levels. Our results provide evidence for a novel adjunct to insulin and metformin as potential initial treatment for adult-onset type 1 diabetes. (ClinicalTrials.gov identifier: NCT02407899).

The autophagy receptor NBR1 directs the clearance of photodamaged chloroplasts.

The ubiquitin-binding NBR1 autophagy receptor plays a prominent role in recognizing ubiquitylated protein aggregates for vacuolar degradation by macroautophagy. Here, we show that upon exposing Arabidopsis plants to intense light, NBR1 associates with photodamaged chloroplasts independently of ATG7, a core component of the canonical autophagy machinery. NBR1 coats both the surface and interior of chloroplasts, which is then followed by direct engulfment of the organelles into the central vacuole via a microautophagy-type process. The relocalization of NBR1 into chloroplasts does not require the chloroplast translocon complexes embedded in the envelope but is instead greatly enhanced by removing the self-oligomerization mPB1 domain of NBR1. The delivery of NBR1-decorated chloroplasts into vacuoles depends on the ubiquitin-binding UBA2 domain of NBR1 but is independent of the ubiquitin E3 ligases SP1 and PUB4, known to direct the ubiquitylation of chloroplast surface proteins. Compared to wild-type plants, nbr1 mutants have altered levels of a subset of chloroplast proteins and display abnormal chloroplast density and sizes upon high light exposure. We postulate that, as photodamaged chloroplasts lose envelope integrity, cytosolic ligases reach the chloroplast interior to ubiquitylate thylakoid and stroma proteins which are then recognized by NBR1 for autophagic clearance. This study uncovers a new function of NBR1 in the degradation of damaged chloroplasts by microautophagy.

Genome Reference Assembly for Bottlenecked Southern Australian Koalas.

Koala populations show marked differences in inbreeding levels and in the presence or absence of the endogenous Koala retrovirus (KoRV). These genetic differences among populations may lead to severe disease impacts threatening koala population viability. In addition, the recent colonization of the koala genome by KoRV provides a unique opportunity to study the process of retroviral adaptation to vertebrate genomes and the impact this has on speciation, genome structure, and function. The genome build described here is from an animal from the bottlenecked Southern population free of endogenous and exogenous KoRV. It provides a more contiguous genome build than the previous koala reference derived from an animal from a more outbred Northern population and is the first koala genome from a KoRV polymerase-free animal.

Impaired emotional awareness is associated with childhood maltreatment exposure and positive symptoms in schizophrenia.

Objectives: Evidence suggests that emotional awareness-the ability to identify and label emotions-may be impaired in schizophrenia and related to positive symptom severity. Exposure to childhood maltreatment is a risk factor for both low emotional awareness and positive symptoms. Methods: The current investigation examines associations between a performance-based measure of emotional awareness, positive symptom severity, and childhood maltreatment exposure in 44 individuals with a schizophrenia-spectrum disorder and 48 healthy comparison participants using the electronic Levels of Emotional Awareness Scale (eLEAS), Positive and Negative Syndrome Scale (PANSS) and Childhood Trauma Questionnaire (CTQ). Results: Patients demonstrated significant deficits in emotional awareness overall, which was true for both self and others. In patients, lower emotional awareness was significantly associated with more severe positive symptoms. Emotional awareness was significantly impaired in patients with schizophrenia with self-reported maltreatment exposure, relative to other groups. Severity of maltreatment was not significantly associated with emotional awareness or positive symptoms when looking continuously, and there was no significant indirect effect. Conclusion: These data suggest that emotional awareness impairments observed in schizophrenia may be exacerbated by exposure to childhood maltreatment, possibly putting individuals at greater risk for experiencing positive symptoms of psychosis.

Unbiased proteomic and forward genetic screens reveal that mechanosensitive ion channel MSL10 functions at ER-plasma membrane contact sites in Arabidopsis thaliana.

Mechanosensitive (MS) ion channels are an evolutionarily conserved way for cells to sense mechanical forces and transduce them into ionic signals. The channel properties of Arabidopsis thaliana MscS-Like (MSL)10 have been well studied, but how MSL10 signals remains largely unknown. To uncover signaling partners of MSL10, we employed a proteomic screen and a forward genetic screen; both unexpectedly implicated endoplasmic reticulum-plasma membrane contact sites (EPCSs) in MSL10 function. The proteomic screen revealed that MSL10 associates with multiple proteins associated with EPCSs. Of these, only VAMP-associated proteins (VAP)27-1 and VAP27-3 interacted directly with MSL10. The forward genetic screen, for suppressors of a gain-of-function MSL10 allele (msl10-3G, MSL10S640L), identified mutations in the synaptotagmin (SYT)5 and SYT7 genes. We also found that EPCSs were expanded in leaves of msl10-3G plants compared to the wild type. Taken together, these results indicate that MSL10 associates and functions with EPCS proteins, providing a new cell-level framework for understanding MSL10 signaling. In addition, placing a mechanosensory protein at EPCSs provides new insight into the function and regulation of this type of subcellular compartment.

Effect of dipeptidyl peptidase-4 inhibitors on postprandial glucagon level in patients with type 2 diabetes mellitus: A systemic review and meta-analysis.

Aims: Hyperglucagonemia occurs in the pathogenesis of type 2 diabetes mellitus (T2DM). In this meta-analysis, we summarized the effects of DPP4 inhibitors on glucagon levels in patients with T2DM. Materials and methods: Randomized controlled trials (RCTs) comparing the influence of DPP4 inhibitors on circulating glucagon levels with placebo or other oral antidiabetic drugs (OADs) in patients with T2DM were identified by searches of Medline (PubMed), Embase (Ovid), and CENTER (Cochrane Library). Only studies reporting changes in glucagon level presented as total area under the curve (AUCglucagon) using a meal or oral glucose tolerance test were included. Results were combined using a random-effects model that incorporated potential heterogeneity among the included studies. Results: A total of 36 RCTs with moderate to high quality were included. Overall, the numbers of T2DM patients included for the meta-analyses comparing DPP4 inhibitors with placebo and other OADs were 4266 and 1652, respectively. Compared to placebo, DPP4 inhibitors significantly reduced circulating glucagon levels (standard mean difference [SMD]: -0.32, 95% CI: -0.40 to -0.24, P<0.001; I2 = 28%). Analysis of subgroups revealed that study characteristics had no significant effect on results, such as study design (parallel group or crossover), number of patients, mean patient age, proportion of men, baseline HbA1c, duration of diabetes, background therapy, treatment duration, or methods for glucagon measurement (all P for subgroup differences >0.05). Moreover, DPP4 inhibitors significantly reduced glucagon levels compared to other OADs (SMD: -0.35, 95% CI: -0.53 to -0.16, P<0.001; I2 = 66%), and the reduction in glucagon was greater in comparison with insulin secretagogues than in comparison with non-insulin secretagogues (P for subgroup difference =0.03). Systematic review registration: https://inplasy.com/, identifier INPLASY202280104. Conclusions: DPP4 inhibitors are effective at reducing the circulating postprandial glucagon level in T2DM patients.