Inhibition of EZH2 Reduces Aging-Related Decline in Interstitial Cells of Cajal of the Mouse Stomach.

BACKGROUND & AIMS: Restricted gastric motor functions contribute to aging-associated under-nutrition, sarcopenia, and frailty. We previously identified a decline in interstitial cells of Cajal (ICC, gastrointestinal pacemaker and neuromodulator cells) and their stem cells (ICC-SC) as a key factor of gastric aging. Altered functionality of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) is central to organismal aging. Here, we investigated the role of EZH2 in the aging-related loss of ICC/ICC-SC. METHODS: klotho mice, a model of accelerated aging, were treated with the most clinically advanced EZH2 inhibitor, EPZ6438 (tazemetostat; 160 mg/kg i.p. BID for 3 weeks). Gastric ICC were analyzed by western blotting (WB) and immunohistochemistry. ICC and ICC-SC were quantified by flow cytometry. Gastric slow wave activity was assessed by intracellular electrophysiology. Ezh2 was deactivated in ICC by treating KitcreERT2/+;Ezh2fl/fl mice with tamoxifen. TRP53, a key mediator of aging-related ICC loss, was induced with nutlin 3a in gastric muscle organotypic cultures and an ICC-SC line. RESULTS: In klotho mice, EPZ6438 treatment mitigated the decline in the ICC growth factor KIT ligand/stem cell factor and gastric ICC. EPZ6438 also improved gastric slow wave activity and mitigated the reduced food intake and impaired body weight gain characteristic of this strain. Conditional genomic deletion of Ezh2 in Kit-expressing cells also prevented ICC loss. In organotypic cultures and ICC-SC, EZH2 inhibition prevented the aging-like effects of TRP53 stabilization on ICC/ICC-SC. CONCLUSIONS: Inhibition of EZH2 with EPZ6438 mitigates aging-related ICC/ICC-SC loss and gastric motor dysfunction, improving slow wave activity and food intake in klotho mice.

Characterisation of an Adult Zebrafish Model for SDHB-Associated Phaeochromocytomas and Paragangliomas.

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours arising from chromaffin cells. Pathogenic variants in the gene succinate dehydrogenase subunit B (SDHB) are associated with malignancy and poor prognosis. When metastases arise, limited treatment options are available. The pathomechanism of SDHB-associated PPGL remains largely unknown, and the lack of suitable models hinders therapy development. Germline heterozygous SDHB pathogenic variants predispose to developing PPGLs with a life-long penetrance of around 50%. To mimic the human disease phenotype, we characterised adult heterozygous sdhb mutant zebrafish as a potential model to study SDHB-related PPGLs. Adult sdhb mutant zebrafish did not develop an obvious tumour phenotype and were anatomically and histologically like their wild-type siblings. However, sdhb mutants showed significantly increased succinate levels, a major hallmark of SDHB-related PPGLs. While basal activity was increased during day periods in mutants, mitochondrial complex activity and catecholamine metabolite levels were not significantly different. In conclusion, we characterised an adult in vivo zebrafish model, genetically resembling human carriers. Adult heterozygous sdhb mutants mimicked their human counterparts, showing systemic elevation of succinate levels despite the absence of a tumour phenotype. This model forms a promising basis for developing a full tumour phenotype and gaining knowledge of the pathomechanism behind SDHB-related PPGLs.

Bringing online adaptive radiotherapy to a standard C-arm linac.

Current online adaptive radiotherapy (oART) workflows require dedicated equipment. Our aim was to develop and implement an oART workflow for a C-arm linac which can be performed using standard clinically available tools. A workflow was successfully developed and implemented. Three patients receiving palliative radiotherapy for bladder cancer were treated, with 33 of 35 total fractions being delivered with the cone-beam computed tomography (CBCT)-guided oART workflow. Average oART fraction duration was 24 min from start of CBCT acquisition to end of beam on. This work shows how oART could be performed without dedicated equipment, broadening oART availability for application at existing treatment machines.

Obesity-driven mitochondrial dysfunction in human adipose tissue-derived mesenchymal stem/stromal cells involves epigenetic changes.

Obesity exacerbates tissue degeneration and compromises the integrity and reparative potential of mesenchymal stem/stromal cells (MSCs), but the underlying mechanisms have not been sufficiently elucidated. Mitochondria modulate the viability, plasticity, proliferative capacity, and differentiation potential of MSCs. We hypothesized that alterations in the 5-hydroxymethylcytosine (5hmC) profile of mitochondria-related genes may mediate obesity-driven dysfunction of human adipose-derived MSCs. MSCs were harvested from abdominal subcutaneous fat of obese and age/sex-matched non-obese subjects (n = 5 each). The 5hmC profile and expression of nuclear-encoded mitochondrial genes were examined by hydroxymethylated DNA immunoprecipitation sequencing (h MeDIP-seq) and mRNA-seq, respectively. MSC mitochondrial structure (electron microscopy) and function, metabolomics, proliferation, and neurogenic differentiation were evaluated in vitro, before and after epigenetic modulation. hMeDIP-seq identified 99 peaks of hyper-hydroxymethylation and 150 peaks of hypo-hydroxymethylation in nuclear-encoded mitochondrial genes from Obese- versus Non-obese-MSCs. Integrated hMeDIP-seq/mRNA-seq analysis identified a select group of overlapping (altered levels of both 5hmC and mRNA) nuclear-encoded mitochondrial genes involved in ATP production, redox activity, cell proliferation, migration, fatty acid metabolism, and neuronal development. Furthermore, Obese-MSCs exhibited decreased mitochondrial matrix density, membrane potential, and levels of fatty acid metabolites, increased superoxide production, and impaired neuronal differentiation, which improved with epigenetic modulation. Obesity elicits epigenetic changes in mitochondria-related genes in human adipose-derived MSCs, accompanied by structural and functional changes in their mitochondria and impaired fatty acid metabolism and neurogenic differentiation capacity. These observations may assist in developing novel therapies to preserve the potential of MSCs for tissue repair and regeneration in obese individuals.

Natural selection and evolution: evolving concepts.

Many recent studies in evolutionary biology have expanded and refined definitions of biological evolution and natural selection. Current evolutionary models incorporate different adaptive and non-adaptive processes based on molecular genetic changes and how DNA is modified over time in unicellular species, or in germline versus somatic cells in metazoan species. Cogent arguments can be raised for the view that natural selection should be considered a biological law, consistent with quantitative mathematical equations that describe the fitness of individuals, as well as variations within and among populations. Evolution is an overarching framework that incorporates the laws of natural selection and clarifies why phenotypic variation can increase in prevalence and result in species adaptations. The conceptual framework for biological evolution incorporates many cohesive principles that collectively have a predictive value. This framework will continue to evolve with improvements in high-resolution technologies that enable us to examine both adaptive and non-adaptive changes that drive biological phenotypes.

Transcriptomic responses of peripheral blood leukocytes to cardiac surgery after acute inflammation, and three months recovery.

Traumatic perioperative conditions may trigger early systemic responses, activate leukocytes and reprogram the immune system. We hypothesize that leukocyte activation may not revert to pre-surgical states, and that protracted activation may emerge with increased risks of comorbidities. We tested this concept by examining the transcriptomes of monocytes and T cells in a representative observational cohort of patients (n = 13) admitted for elective cardiac surgery. Transcriptomes in T cells and monocytes were compared from before surgery (t0), and monocytes were analyzed longitudinally after acute (t24hr), and convalescent (t3m) time points. Monocytes and T cells expressed distinct transcriptomes, reflected by statistically significant differential expression of 558 T cell related genes. Monocytes expressed genes related to protein degradation and presented atypical activation of surface markers and cytoplasmic functions over time. Additionally, monocytes exhibited limited transcriptomic heterogeneity prior to surgery, and long-term patterns of gene expression associated with atherosclerosis showed three temporally distinct signatures. These data establish that post-cardiac surgery transcriptomes of monocytes differ even at three months compared to baselines, which may reflect latent ('smoldering') inflammation and persistent progression of tissue degenerative processes that should inform clinical care.

Fundamentals and Translational Applications of Stem Cells and Biomaterials in Dental, Oral and Craniofacial Regenerative Medicine.

Regenerative dental medicine continuously expands to improve treatments for prevalent clinical problems in dental and oral medicine. Stem cell based translational opportunities include regenerative therapies for tooth restoration, root canal therapy, and inflammatory processes (e.g., periodontitis). The potential of regenerative approaches relies on the biological properties of dental stem cells. These and other multipotent somatic mesenchymal stem cell (MSC) types can in principle be applied as either autologous or allogeneic sources in dental procedures. Dental stem cells have distinct developmental origins and biological markers that determine their translational utility. Dental regenerative medicine is supported by mechanistic knowledge of the molecular pathways that regulate dental stem cell growth and differentiation. Cell fate determination and lineage progression of dental stem cells is regulated by multiple cell signaling pathways (e.g., WNTs, BMPs) and epigenetic mechanisms, including DNA modifications, histone modifications, and non-coding RNAs (e.g., miRNAs and lncRNAs). This review also considers a broad range of novel approaches in which stem cells are applied in combination with biopolymers, ceramics, and composite materials, as well as small molecules (agonistic or anti-agonistic ligands) and natural compounds. Materials that mimic the microenvironment of the stem cell niche are also presented. Promising concepts in bone and dental tissue engineering continue to drive innovation in dental and non-dental restorative procedures.

Inflammatory Markers Involved in the Pathogenesis of Dupuytren's Contracture.

Dupuytren's disease is a common fibroproliferative disease that can result in debilitating hand deformities. Partial correction and return of deformity are common with surgical or clinical treatments at present. While current treatments are limited to local procedures for relatively late effects of the disease, the pathophysiology of this connective tissue disorder is associated with both local and systemic processes (e.g., fibrosis, inflammation). Hence, a better understanding of the systemic circulation of Dupuytren related cytokines and growth factors may provide important insights into disease progression. In addition, systemic biomarker analysis could yield new concepts for treatments of Dupuytren that attenuate circulatory factors (e.g., anti-inflammatory agents, neutralizing antibodies). Progress in the development of any disease modifying biologic treatment for Dupuytren has been hampered by the lack of clinically useful biomarkers. The characterization of nonsurgical Dupuytren biomarkers will permit disease staging from diagnostic and prognostic perspectives, as well as allows evaluation of biologic responses to treatment. Identification of such markers may transcend their use in Dupuytren treatment, because fibrotic biological processes fundamental to Dupuytren are relevant to fibrosis in many other connective tissues and organs with collagen-based tissue compartments. There is a wide range of potential Dupuytren biomarker categories that could be informative, including disease determinants linked to genetics, collagen metabolism, as well as immunity and inflammation (e.g., cytokines, chemokines). This narrative review provides a broad overview of previous studies and emphasizes the importance of inflammatory mediators as candidate circulating biomarkers for monitoring Dupuytren's disease.

Liver Steatosis is Prevalent in Lean People With HIV and Associated With Exposure to Antiretroviral Treatment-A Cross-sectional Study.

Background: Steatotic liver disease is suggested to have a higher prevalence and severity in people with HIV (PHIV), including in those with a normal body mass index (BMI). In this study, we used data from the 2000HIV cohort to (1) assess the prevalence of liver steatosis and fibrosis in lean versus overweight/obese PHIV and (2) assess associations in these subgroups between steatosis and fibrosis with traditional risk factors and HIV-specific characteristics. Methods: The 2000HIV study cohort comprises 1895 virally suppressed PHIV that were included between 2019 and 2021 in 4 HIV treatment centers in the Netherlands. The majority (58.5%) underwent vibration-controlled transient elastography for the assessment of liver steatosis and fibrosis. The prevalence of steatosis (controlled attenuation parameter ≥263 dB/m) and fibrosis (liver stiffness measurement ≥7.0 kPa) was estimated. Multiple factors including HIV characteristics and antiretroviral drugs were tested in a logistic regression model for association with steatosis and fibrosis. Analyses were performed separately for lean (Asian descent: BMI < 23 kg/m2, other descent: BMI < 25 kg/m2) and overweight/obese (other BMI) participants. Results: Of 1050 PHIV including 505 lean and 545 overweight/obese PHIV, liver steatosis was observed in 37.7% of the overall study population, 19.7% of lean, and 54% of overweight/obese PHIV, whereas fibrosis was observed in 9.0% of the overall study population, 5.9% of lean, and 12.0% of overweight/obese PHIV.All associations with fibrosis and most associations with steatosis concerned metabolic factors such as type 2 diabetes mellitus (overall population: adjusted odds ratio [aOR] for steatosis: 2.3 [1.21-4.4], P = .011; aOR for fibrosis: 3.7 [1.82-7.53], P < .001). Furthermore, in lean PLHIV, liver steatosis was associated with CD4 and CD8 counts at enrollment, dual therapy, and history of treatment with raltegravir (aOR: 3.6 [1.53-8.47], P = .003), stavudine (aOR: 3.73 [1.69-8.2], P = .001), and indinavir (aOR: 3.86 [1.59-9.37], P = .003). These associations were not observed in overweight/obese PHIV. Conclusions: Liver steatosis was highly prevalent, affecting approximately one-fifth of lean PHIV and half of overweight/obese PHIV. Fibrosis was observed in a minority. Both steatosis and fibrosis were associated with traditional metabolic risk factors. In addition, (prior) exposure to specific antiretroviral drugs was associated liver steatosis in lean, but not in overweight/obese PHIV. Implementing increased screening protocols could enhance the identification of steatotic liver disease in lean PHIV.

Artifactually increased serum bicarbonate in a cat with rhabdomyolysis.

A 3-year-old male neutered domestic shorthair cat presented with lethargy, hyporexia, and pyrexia of unknown origin. Biochemical analysis using a Beckman Coulter AU480 demonstrated marked increases in creatine kinase and aspartate aminotransferase, indicative of severe muscle injury, with concurrent presumptive myoglobinuria on urinalysis. A marked, non-physiologic increase in measured bicarbonate and resultant negative anion gap was documented; however, calculated bicarbonate obtained via a point-of-care blood gas analyzer was within normal limits. Laboratory error due to interference by lactate dehydrogenase was suspected and supported by the results of subsequent biochemical testing. Artifactual increases in bicarbonate have been documented in cases of rhabdomyolysis in horses, cows, and a bird. However, to the best of the authors' knowledge, this is the first report to demonstrate this spurious change in a cat.

In vitro IL-15-activated human naïve CD8+ T cells down-modulate the CD8ß chain and become CD8αα T cells.

Antigen-driven human effector-memory CD8+ T cells expressing low levels of the CD8ß chain have been previously described. However, little is known on a possible antigen-independent trigger. We have examined the impact that IL-15 has on the expression of CD8ß on purified human naïve CD8+ T cells after CFSE labeling and culture with IL-15. As expected, IL-15 induced naïve CD8+ T cells to proliferate and differentiate. Remarkably, the process was associated with a cell-cycle dependent down-modulation of CD8ß from the cell surface, leading to the generation of CD8αßlow and CD8αß- (i.e., CD8αα) T cells. In contrast, expression of the CD8α chain remained steady or even increased. Neither IL-2 nor IL-7 reproduced the effect of IL-15. Determination of mRNA levels for CD8α and CD8ß isoforms by qPCR revealed that IL-15 promoted a significant decrease in mRNA levels of the CD8ß M-4 isoform, while levels of the M-1/M-2 isoforms and of CD8α increased. Noteworthy, CD8+ T cell blasts obtained after culture of CD8+ T cells with IL-15 showed a cell-cycle dependent increase in the level of the tyrosine kinase Lck, when compared to CD8+ T cells at day 0. This study has shown for the first time that IL-15 generates CD8αα+αßlow and CD8αα+αß- T cells containing high levels of Lck, suggesting that they may be endowed with unique functional features.

Entorhinal vessel density correlates with phosphorylated tau and TDP-43 pathology.

INTRODUCTION: The entorhinal cortex (EC) and perirhinal cortex (PC) are vulnerable to Alzheimer's disease. A triggering factor may be the interaction of vascular dysfunction and tau pathology. METHODS: We imaged post mortem human tissue at 100 µm3 with 7 T magnetic resonance imaging and manually labeled individual blood vessels (mean = 270 slices/case). Vessel density was quantified and compared per EC subfield, between EC and PC, and in relation to tau and TAR DNA-binding protein 43 (TDP-43) semiquantitative scores. RESULTS: PC was more vascularized than EC and vessel densities were higher in posterior EC subfields. Tau and TDP-43 strongly correlated with vasculature density and subregions with severe tau at the preclinical stage had significantly greater vessel density than those with low tau burden. DISCUSSION: These data impact cerebrovascular maps, quantification of subfield vasculature, and correlation of vasculature and pathology at early stages. The ordered association of vessel density, and tau or TDP-43 pathology, may be exploited in a predictive context. HIGHLIGHTS: Vessel density correlates with phosphorylated tau (p-tau) burden in entorhinal and perirhinal cortices. Perirhinal area 35 and posterior entorhinal cortex showed greatest p-tau burden but also the highest vessel density in the preclinical phase of Alzheimer's disease. We combined an ex vivo magnetic resonance imaging model and histopathology to demonstrate the 3D reconstruction of intracortical vessels and its spatial relationship to the pathology.

Do efficacy results obtained from randomized controlled trials translate to effectiveness data from observational studies for relapsing-remitting multiple sclerosis?

BACKGROUND: Randomized controlled trials are considered the gold standard in regulatory decision making, as observational studies are known to have important methodological limitations. However, real-world evidence may be helpful in specific situations. This review investigates how the effect estimates obtained from randomized controlled trials compare to those obtained from observational studies, using drug therapy for relapsing-remitting multiple sclerosis as an example. STUDY DESIGN AND SETTING: A systematic review of randomized controlled trials and observational studies was conducted. The primary outcome was the annualized relapse rate. Using (network) meta-analysis together with posterior predictive distributions, the drug-specific rate ratios from the network of randomized controlled trials were compared with those from the network of observational studies. RESULTS: Effect estimates from 26 observational studies showed greater magnitudes and were less precise compared to estimates obtained from 21 randomized controlled trials. Twenty of the 28 treatment comparisons between designs had similar rate ratios. Seven inconsistencies in observed rate ratios could be attributed to two specific disease-modifying therapies. CONCLUSION: In this case study, estimates from observational studies predominantly agreed with estimates from randomized controlled trials given their posterior predictive distributions. Multiple observational studies together may therefore supplement additional pivotal randomized controlled trials in relapsing-remitting multiple sclerosis, for instance facilitating the extrapolation of trial results to the broader patient population.

Finite element analysis of kangaroo astragali: A new angle on the ankle.

Using finite element analysis on the astragali of five macropodine kangaroos (extant and extinct hoppers) and three sthenurine kangaroos (extinct proposed bipedal striders) we investigate how the stresses experienced by the ankle in similarly sized kangaroos of different hypothesized/known locomotor strategy compare under different simulation scenarios, intended to represent the moment of midstance at different gaits. These tests showed a clear difference between the performance of sthenurines and macropodines with the former group experiencing lower stress in simulated bipedal strides in all species compared with hopping simulations, supporting the hypothesis that sthenurines may have utilized this gait. The Pleistocene macropodine Protemnodon also performed differently from all other species studied, showing high stresses in all simulations except for bounding. This may support the hypothesis of Protemnodon being a quadrupedal bounder.

HIV immunological non-responders are characterized by extensive immunosenescence and impaired lymphocyte cytokine production capacity.

Introduction: Immunological non-responders (INR) are people living with HIV (PLHIV) who fail to fully restore CD4+ T-cell counts despite complete viral suppression with antiretroviral therapy (ART). INR are at higher risk for non-HIV related morbidity and mortality. Previous research suggest persistent qualitative defects. Methods: The 2000HIV study (clinical trials NTC03994835) enrolled 1895 PLHIV, divided in a discovery and validation cohort. PLHIV with CD4 T-cell count <350 cells/mm3 after ≥2 years of suppressive ART were defined as INR and were compared to immunological responders (IR) with CD4 T-cell count >500 cells/mm3. Logistic and rank based regression were used to analyze clinical data, extensive innate and adaptive immunophenotyping, and ex vivo monocyte and lymphocyte cytokine production after stimulation with various stimuli. Results: The discovery cohort consisted of 62 INR and 1224 IR, the validation cohort of 26 INR and 243 IR. INR were older, had more advanced HIV disease before starting ART and had more frequently a history of non-AIDS related malignancy. INR had lower absolute CD4+ T-cell numbers in all subsets. Activated (HLA-DR+, CD38+) and exhausted (PD1+) subpopulations were proportionally increased in CD4 T-cells. Monocyte and granulocyte immunophenotypes were comparable. INR lymphocytes produced less IL-22, IFN-γ, IL-10 and IL-17 to stimuli. In contrast, monocyte cytokine production did not differ. The proportions of CD4+CD38+HLA-DR+ and CD4+PD1+ subpopulations showed an inversed correlation to lymphocyte cytokine production. Conclusions: INR compared to IR have hyperactivated and exhausted CD4+ T-cells in combination with lymphocyte functional impairment, while innate immune responses were comparable. Our data provide a rationale to consider the use of anti-PD1 therapy in INR.

An extension of the Walsh-Hadamard transform to calculate and model epistasis in genetic landscapes of arbitrary shape and complexity.

Accurate models describing the relationship between genotype and phenotype are necessary in order to understand and predict how mutations to biological sequences affect the fitness and evolution of living organisms. The apparent abundance of epistasis (genetic interactions), both between and within genes, complicates this task and how to build mechanistic models that incorporate epistatic coefficients (genetic interaction terms) is an open question. The Walsh-Hadamard transform represents a rigorous computational framework for calculating and modeling epistatic interactions at the level of individual genotypic values (known as genetical, biological or physiological epistasis), and can therefore be used to address fundamental questions related to sequence-to-function encodings. However, one of its main limitations is that it can only accommodate two alleles (amino acid or nucleotide states) per sequence position. In this paper we provide an extension of the Walsh-Hadamard transform that allows the calculation and modeling of background-averaged epistasis (also known as ensemble epistasis) in genetic landscapes with an arbitrary number of states per position (20 for amino acids, 4 for nucleotides, etc.). We also provide a recursive formula for the inverse matrix and then derive formulae to directly extract any element of either matrix without having to rely on the computationally intensive task of constructing or inverting large matrices. Finally, we demonstrate the utility of our theory by using it to model epistasis within both simulated and empirical multiallelic fitness landscapes, revealing that both pairwise and higher-order genetic interactions are enriched between physically interacting positions.

Four Tendinous Slips of Flexor Hallucis Longus Tendon: A Case Report.

Interindividual variability presents a rich field of study in medical sciences. During a cadaveric dissection at Louisiana State University Health Sciences Center, a rare anatomical variation was discovered in the pedal anatomy of a female cadaver. Medical students, while dissecting the sole of the foot, identified a variant tendinous structure. This aberrant tendinous slip from the flexor hallucis longus (FHL) extended to the lateral four tendons of flexor digitorum longus (FDL) along the plantar aspect of the foot. The discovery suggested that the FHL shares a functional relationship with the FDL. Application of tension to the FHL was found to result in simultaneous flexion motion in the lesser toes, from the second to the fifth digit. The presence of this anatomical variant holds considerable importance for surgical interventions, especially as a potential graft source in tendon reconstructions, warranting its documentation in this report.

Age-dependent association of cannabis use with risk of psychotic disorder.

BACKGROUND: Epidemiologic research suggests that youth cannabis use is associated with psychotic disorders. However, current evidence is based heavily on 20th-century data when cannabis was substantially less potent than today. METHODS: We linked population-based survey data from 2009 to 2012 with records of health services covered under universal healthcare in Ontario, Canada, up to 2018. The cohort included respondents aged 12-24 years at baseline with no prior psychotic disorder (N = 11 363). The primary outcome was days to first hospitalization, ED visit, or outpatient visit related to a psychotic disorder according to validated diagnostic codes. Due to non-proportional hazards, we estimated age-specific hazard ratios during adolescence (12-19 years) and young adulthood (20-33 years). Sensitivity analyses explored alternative model conditions including restricting the outcome to hospitalizations and ED visits to increase specificity. RESULTS: Compared to no cannabis use, cannabis use was significantly associated with psychotic disorders during adolescence (aHR = 11.2; 95% CI 4.6-27.3), but not during young adulthood (aHR = 1.3; 95% CI 0.6-2.6). When we restricted the outcome to hospitalizations and ED visits only, the strength of association increased markedly during adolescence (aHR = 26.7; 95% CI 7.7-92.8) but did not change meaningfully during young adulthood (aHR = 1.8; 95% CI 0.6-5.4). CONCLUSIONS: This study provides new evidence of a strong but age-dependent association between cannabis use and risk of psychotic disorder, consistent with the neurodevelopmental theory that adolescence is a vulnerable time to use cannabis. The strength of association during adolescence was notably greater than in previous studies, possibly reflecting the recent rise in cannabis potency.

Underuse of GLP-1 receptor agonists in the management of type 2 diabetes despite a favorable benefit-safety profile.

INTRODUCTION: Patients with type 2 diabetes (T2DM) are at high risk of atherosclerotic cardiovascular disease (ASCVD) and cardiovascular death. Cardiovascular protection is a key objective in T2DM. AREAS COVERED: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have proven their efficacy in reducing major cardiovascular events in high-risk patients with T2DM in placebo-controlled trials, a finding confirmed in observational studies compared with other glucose-lowering agents. Overall, GLP-1RAs have a good safety profile associated with a favorable benefit/risk ratio for the management of T2DM, even if their cost-effectiveness might be questionable. International guidelines recommend GLP-1RAs as preferred glucose-lowering agents in patients with ASCVD and as a valuable alternative in overweight/obese patients with T2DM. However, real-life studies worldwide revealed that only a minority of patients receive a GLP-1RA, despite a positive trend for increased prescriptions in recent years. Surprisingly, however, fewer patients with established ASCVD are treated with these cardioprotective antihyperglycemic agents versus patients without ASCVD. EXPERT OPINION: The reasons for GLP-1RA underuse in clinical practice are multiple. Multifaceted and coordinated interventions targeting all actors of the health-care system must be implemented to stimulate the adoption of GLP-1RAs as part of routine cardiovascular care among patients with T2DM, especially in those with ASCVD.

Patients with type 2 diabetes are at high risk of atherosclerotic cardiovascular disease, especially myocardial infarction and ischemic stroke. Cardiovascular protection should be considered as a key objective when treating those patients. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), an injectable therapy for the treatment of hyperglycemia, have proven their efficacy in reducing major cardiovascular events (cardiovascular mortality, myocardial infarction, ischemic stroke) both in controlled trials compared to placebo and in real-life studies compared with other glucose-lowering agents. These consistent findings profoundly influence international guidelines which recommend GLP-1RAs as preferred glucose-lowering agents in patients with atherosclerotic cardiovascular disease or at high risk of developing this complication. However, real-life studies worldwide revealed that only a minority of patients receive a GLP-1RA. An even more surprising finding was that GLP-1RAs are less prescribed in patients with established atherosclerotic cardiovascular disease, including antecedents of coronary heart disease and cerebrovascular disease, than in patients without such cardiovascular complications. The reasons for GLP-1RA underuse in clinical practice are multiple and concern physicians, patients, and health-care system. Bridging the gap between evidence-based cardiovascular protection with GLP-1RAs and their underuse in daily clinical practice in patients with type 2 diabetes at high risk is crucial from a public health viewpoint.

Serum NfL and GFAP as biomarkers of progressive neurodegeneration in TBI.

BACKGROUND: We examined spatial patterns of brain atrophy after mild, moderate, and severe traumatic brain injury (TBI), the relationship between progression of brain atrophy with initial traumatic axonal injury (TAI), cognitive outcome, and with serum biomarkers of brain injury. METHODS: A total of 143 patients with TBI and 43 controls were studied cross-sectionally and longitudinally up to 5 years with multiple assessments, which included brain magnetic resonance imaging, cognitive testing, and serum biomarkers. RESULTS: TBI patients showed progressive volume loss regardless of injury severity over several years, and TAI was independently associated with accelerated brain atrophy. Cognitive performance improved over time. Higher baseline serum neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) were associated with greater rate of brain atrophy over 5 years. DISCUSSSION: Spatial patterns of atrophy differ by injury severity and TAI is associated with the progression of brain atrophy. Serum NfL and GFAP show promise as non-invasive prognostic biomarkers of progressive neurodegeneration in TBI. HIGHLIGHTS: In this longitudinal study of patient with mild, moderate, and severe traumatic brain injury (TBI) who were assessed with paired magnetic resonance imaging (MRI), blood biomarkers, and cognitive assessments, we found that brain atrophy after TBI is progressive and continues for many years even after a mild head trauma without signs of brain injury on conventional MRI. We found that spatial pattern of brain atrophy differs between mild, moderate, and severe TBI, where in patients with mild TBI , atrophy is mainly seen in the gray matter, while in those with moderate to severe brain injury atrophy is predominantly seen in the subcortical gray matter and whiter matter. Cognitive performance improves over time after a TBI. Serum measures of neurofilament light or glial fibrillary acidic protein are associated with progression of brain atrophy after TBI.