The limited role of serum neurofilament light chain in predicting pain severity of patients with diabetic polyneuropathy.

Pain is one of many complaints expressed by patients with diabetic polyneuropathy. However, no objective measure for pain severity has been available. Neurofilament light chains have been widely used for assessing axonal damage in the neuronal system. Hence, we sought to investigate whether neurofilament light chains can serve as a marker reflecting pain severity in diabetic polyneuropathy. We enrolled the patients with diabetic polyneuropathy. Serum concentrations of neurofilament light chain were then measured using a single-molecule array. Pain severity was evaluated using painDETECT and the Brief Pain Inventory. Moreover, laboratory results including, serum creatinine, HbA1c, and glomerular filtration rate. A correlation test was used to analyze each variable. A total of 42 patients were enrolled. Neurofilament light chain levels were unable to reflect current neuropathic pain severity. However, high levels of neurofilament light chain were a significant predictor of poor diabetes control (r = 0.41; p = 0.02) and kidney damage (r = 0.45; p = 0.01). Serum levels of neurofilament light chain could not reflect current pain severity but was strongly associated with kidney dysfunction and poor diabetes control. Other biomarkers that could predict pain severity need to be uncovered.

Circulating KRAS G12D but not G12V is associated with survival in metastatic pancreatic ductal adenocarcinoma.

While high circulating tumor DNA (ctDNA) levels are associated with poor survival for multiple cancers, variant-specific differences in the association of ctDNA levels and survival have not been examined. Here we investigate KRAS ctDNA (ctKRAS) variant-specific associations with overall and progression-free survival (OS/PFS) in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) for patients receiving chemoimmunotherapy ("PRINCE", NCT03214250), and an independent cohort receiving standard of care (SOC) chemotherapy. For PRINCE, higher baseline plasma levels are associated with worse OS for ctKRAS G12D (log-rank p = 0.0010) but not G12V (p = 0.7101), even with adjustment for clinical covariates. Early, on-therapy clearance of G12D (p = 0.0002), but not G12V (p = 0.4058), strongly associates with OS for PRINCE. Similar results are obtained for the SOC cohort, and for PFS in both cohorts. These results suggest ctKRAS G12D but not G12V as a promising prognostic biomarker for mPDAC and that G12D clearance could also serve as an early biomarker of response.

Improving access to buprenorphine for rural veterans in a learning health care system.

OBJECTIVE: To describe a learning health care system research process designed to increase buprenorphine prescribing for the treatment of opioid use disorder (OUD) in rural primary care settings within U.S. Department of Veterans Affairs (VA) treatment facilities. DATA SOURCES AND STUDY SETTING: Using national administrative data from the VA Corporate Data Warehouse, we identified six rural VA health care systems that had improved their rate of buprenorphine prescribing within primary care from 2015 to 2020 (positive deviants). We conducted qualitative interviews with leaders, clinicians, and staff involved in buprenorphine prescribing within primary care from these sites to inform the design of an implementation strategy. STUDY DESIGN: Qualitative interviews to inform implementation strategy development. DATA COLLECTION/EXTRACTION METHODS: Interviews were audio-recorded, transcribed verbatim, and coded by a primary coder and secondary reviewer. Analysis utilized a mixed inductive/deductive approach. To develop an implementation strategy, we matched clinical needs identified within interviews with resources and strategies participants had utilized to address these needs in their own sites. PRINCIPAL FINDINGS: Interview participants (n = 30) identified key clinical needs and strategies for implementing buprenorphine in rural, primary care settings. Common suggestions included the need for clinical mentorship or a consult service, buprenorphine training, and educational resources. Building upon interview findings and in partnership with a clinical team, we developed an implementation strategy composed of an engaging case-based training, an audit and feedback process, and educational resources (e.g., Buprenorphine Frequently Asked Questions, Rural Care Model Infographic). CONCLUSIONS: We describe a learning health care system research process that leveraged national administrative data, health care provider interviews, and clinical partnership to develop an implementation strategy to encourage buprenorphine prescribing in rural primary care settings.

Empagliflozin attenuates epithelial to mesenchymal transition through senescence in peritoneal dialysis.

BACKGROUND: Epithelial to mesenchymal transition (EMT) is considered as one of the senescence processes; reportedly, anti-senescence therapies effectively reduce EMT. Some models have shown anti-senescence effects with the use of sodium-glucose cotransporter-2 (SGLT2) inhibitor. Therefore, our study investigated the anti-senescence effects of empagliflozin as a SGLT2 inhibitor in a peritoneal fibrosis model and their impact on EMT inhibition. METHODS: For in vitro study, human peritoneal mesothelial cells (HPMCs) were isolated and grown in a 96-well plate. The cell media were exchanged with serum-free M199 medium with D-Glucose, with or without empagliflozin. All animal experiments were carried out in male mice. Mice were randomly classified into three treatment groups based on peritoneal dialysis (PD) or empagliflozin. We evaluated changes in senescence and EMT markers in HPMCs and PD model. RESULTS: HPMCs treated with glucose transformed from cobble stone to spindle shape, resulting in EMT. Empagliflozin attenuated these morphologic changes. Reactive oxygen species production, DNA damage, senescence, and EMT markers were increased by glucose treatment; however, co-treatment with glucose and empagliflozin attenuated these changes. For the mice with PD, an increase in thickness, collagen deposition, staining for senescence or EMT markers of the parietal peritoneum was observed, which however, was attenuated by co-treatment with empagliflozin. p53, p21, and p16 increased in mice with PD compared to that in the control group; however, these changes were decreased by empagliflozin. CONCLUSION: Empagliflozin effectively attenuated glucose-induced EMT in HPMCs through a decrease in senescence. Co-treatment with empagliflozin improved peritoneal thickness and fibrosis in PD.

Highly Durable, Stretchable Multielectrode Array for Electro-mechanical Co-stimulation of Cells.

Electro-mechanical co-stimulation of cells can be a useful cue for tissue engineering. However, reliable co-stimulation platforms still have limitations due to low durability of the components and difficulty in optimizing the stimulation parameters. Although various electro-mechanical co-simulation systems have been explored, integrating materials and components with high durability is still limited. To tackle this problem, we designed an electro-mechanical co-stimulation system that facilitates uniaxial cyclic stretching, electrical stimulation, and optical monitoring. This system utilizes a robust and autoclavable stretchable multielectrode array housed within a compact mini-incubator. To illustrate its effectiveness, we conducted experiments that highlighted how electro-mechanical co-stimulation using this system can enhance the maturation of cardiomyocytes derived from human induced pluripotent stem cells. The results showed great potential of our co-stimulation platform as an effective tool for tissue engineering.

Spondylodiscitis: Understanding pathophysiology, surgical strategies, and postoperative management - A single-center study.

Background: Spondylodiscitis (SD) is an inflammatory condition affecting the intervertebral discs and adjacent structures, often leading to serious complications, including epidural abscesses. This study aimed to differentiate postoperative SD from spontaneous cases caused by osteoporotic defects and associated pathologies, evaluating the frequency of SD in spinal diseases at a single center. Materials and Methods: A retrospective observational study involving 25 patients was conducted, analyzing variations between postoperative revisions in SD patients and spontaneous SD due to concurrent pathology and osteoporotic defects. The effects of postoperative wound healing following transforaminal lumbar interbody fusion and decompressive hemilaminectomy with pedicle screws were also investigated. Ethical guidelines were strictly followed during the study, conducted from January 2023 to September 2023 at Moscow City Clinical Hospital No. 68, Demikhova V.P. Results: Among the 25 patients with spontaneous SD, 15 females and 10 males were included, with only two undergoing surgical revision. Predominant purulent inflammatory foci were observed at specific spinal levels, and demographics revealed prevalent comorbidities such as arterial hypertension (80%) and type 2 diabetes mellitus (60%). Postoperative complications included paravertebral abscesses and wound-related issues. Structural observations indicated vertebral destruction, joint gaps, and localized spinal canal narrowing, revealing complexities in SD cases. Conclusion: Surgical intervention remains crucial for addressing SD-related vertebral complications, while antimicrobial therapy tailored to specific pathogens is pivotal. Concurrent conditions necessitate comprehensive management, often involving cardiological interventions. Postoperatively, a combined approach of conservative therapy and calcium phosphate adjuncts is recommended, especially considering the observed low bone density, aiming to optimize patient recovery and spinal stability.

Tumor-localized interleukin-2 and interleukin-12 combine with radiation therapy to safely potentiate regression of advanced malignant melanoma in pet dogs.

PURPOSE: Interleukin-2 and -12 cytokines have potent anti-cancer activity, but suffer a narrow therapeutic window due to off-tumor immune cell activation. Engineering cytokines with the ability to bind and associate with tumor collagen after intratumoral injection potentiated response without toxicity in mice, and was previously safe in pet dogs with sarcoma. Here we sought to test the efficacy of this approach with in dogs with advanced melanoma. EXPERIMENTAL DESIGN: This study examined fifteen client-owned dogs with histologically- or cytologically-confirmed malignant melanoma who received a single 9 Gray fraction of radiation therapy, followed by six cycles of combined collagen-anchored IL-2 and IL-12 therapy Q2W. Cytokine dosing followed a 3+3 dose escalation design, with the initial cytokine dose chosen from prior evaluation in canine sarcomas. No exclusion criteria for tumor stage or metastatic burden, age, weight, or neuter status were applied for this trial. RESULTS: Median survival regardless of tumor stage or dose level was 256 days and 10/13 (76.9%) dogs that completed treatment had CT-measured tumor regression at the treated lesion. In dogs with metastatic disease, 8/13 (61.5%) dogs had partial responses across their combined lesions, evidence of locoregional response. Profiling by Nanostring of treatment-resistant dogs revealed that B2m loss was predictive of poor response to this therapy. CONCLUSIONS: Collectively, these results confirm the ability of locally administered tumor-anchored cytokines to potentiate responses at regional disease sites when combined with radiation. This evidence supports the clinical translation of this approach and highlights the utility of comparative investigation in canine cancers.

Digital outcome measures are associated with brain atrophy in patients with multiple sclerosis.

BACKGROUND: Digital monitoring of people with multiple sclerosis (PwMS) using smartphone-based monitoring tools is a promising method to assess disease activity and progression. OBJECTIVE: To study cross-sectional and longitudinal associations between active and passive digital monitoring parameters and MRI volume measures in PwMS. METHODS: In this prospective study, 92 PwMS were included. Clinical tests [Expanded Disability Status Scale (EDSS), Timed 25 Foot Walk test (T25FW), 9-Hole Peg Test (NHPT), and Symbol Digit Modalities Test (SDMT)] and structural MRI scans were performed at baseline (M0) and 12-month follow-up (M12). Active monitoring included the smartphone-based Symbol Digit Modalities Test (sSDMT) and 2 Minute Walk Test (s2MWT), while passive monitoring was based on smartphone keystroke dynamics (KD). Linear regression analyses were used to determine cross-sectional and longitudinal relations between digital and clinical outcomes and brain volumes, with age, disease duration and sex as covariates. RESULTS: In PwMS, both sSDMT and SDMT were associated with thalamic volumes and lesion volumes. KD were related to brain, ventricular, thalamic and lesion volumes. No relations were found between s2MWT and MRI volumes. NHPT scores were associated with lesion volumes only, while EDSS and T25FW were not related to MRI. No longitudinal associations were found for any of the outcome measures between M0 and M12. CONCLUSION: Our results show clear cross-sectional correlations between digital biomarkers and brain volumes in PwMS, which were not all present for conventional clinical outcomes, supporting the potential added value of digital monitoring tools.

Ubiquitin: Not just a one-way ticket to the proteasome, but a therapeutic dial to fine-tune the molecular landscape of disease.

Recently, there is a rise in studies that recognize the importance of targeting ubiquitin and related molecular machinery in various therapeutic contexts. Here we briefly discuss the history of ubiquitin, its biological roles in protein degradation and beyond, as well as the current state of ubiquitin-targeting therapeutics across diseases. We conclude that targeting ubiquitin machinery is approaching a renaissance, and tapping its full potential will require embracing a wholistic perspective of ubiquitin's multifaceted roles.

Impact of Transition Metal Layer Vacancy on the Structure and Performance of P2 Type Layered Sodium Cathode Material.

This study explores the impact of introducing vacancy in the transition metal layer of rationally designed Na0.6[Ni0.3Ru0.3Mn0.4]O2 (NRM) cathode material. The incorporation of Ru, Ni, and vacancy enhances the structural stability during extensive cycling, increases the operation voltage, and induces a capacity increase while also activating oxygen redox, respectively, in Na0.7[Ni0.2VNi0.1Ru0.3Mn0.4]O2 (V-NRM) compound. Various analytical techniques including transmission electron microscopy, X-ray absorption near edge spectroscopy, operando X-ray diffraction, and operando differential electrochemical mass spectrometry are employed to assess changes in the average oxidation states and structural distortions. The results demonstrate that V-NRM exhibits higher capacity than NRM and maintains a moderate capacity retention of 81% after 100 cycles. Furthermore, the formation of additional lone-pair electrons in the O 2p orbital enables V-NRM to utilize more capacity from the oxygen redox validated by density functional calculation, leading to a widened dominance of the OP4 phase without releasing O2 gas. These findings offer valuable insights for the design of advanced high-capacity cathode materials with improved performance and sustainability in sodium-ion batteries.

Integration of Germline Genetic Testing Into Routine Clinical Practice for Patients With Pancreatic Adenocarcinoma.

PURPOSE: Germline genetic testing (GT) is recommended for all patients with pancreatic ductal adenocarcinoma (PDAC), but the traditional clinical genetics infrastructure is limited in addressing the unique needs of this population. We describe the integration of point of care (POC) GT into routine clinical practice for all patients with PDAC at an academic medical center. METHODS: We developed a clinical POC workflow that leverages electronic health record (EHR) tools and behavioral nudges to enhance the sustainability and scalability of our previously described research-based POC model. For each of the research and clinical POC cohorts, we calculated the percentage of eligible patients who underwent GT. We used Wilcoxon rank-sum and Pearson's chi-squared tests to compare patients who did and did not undergo GT. We conducted surveys among oncology clinicians to evaluate the acceptability, appropriateness, and feasibility of the clinical POC model. RESULTS: The research POC cohort included 905 patients, of whom 694 (76.7%) underwent GT. The clinical POC cohort included 148 patients, of whom 126 (85.1%) underwent GT. Patients who underwent GT in the research POC cohort were significantly younger (median age, 67.0 v 70.9 years; P = .031) and more likely to be White (82.1% v 68.7%; P < .001) and commercially insured (41.8% v 28.0%; P < .001) compared with those who did not; there were no significant differences between GT groups in the clinical POC cohort. Oncology clinicians found the clinical POC model to be acceptable (mean 4.4/5), appropriate (4.6/5), feasible (4.0/5), and have a positive impact on their patients (4.9/5). CONCLUSION: A clinical POC model leveraging EHR tools and behavioral nudges is acceptable, appropriate, feasible, and associated with a >85% GT rate among patients with PDAC.

Neuronal distribution in colorectal cancer: associations with clinicopathological parameters and survival.

Over the last years, insights in the cancer neuroscience field increased rapidly and a potential role for neurons in colorectal carcinogenesis has been recognized. However, knowledge on the neuronal distribution, subtypes, origin and associations with clinicopathological characteristics in human studies is sparse. In this study, colorectal tumor tissues from the Netherlands Cohort Study on diet and cancer (n=490) and an in-cohort validation population (n=529) were immunohistochemically stained for the pan-neuronal markers neurofilament (NF) and protein gene product 9.5 (PGP9.5) to study the association between neuronal marker expression and clinicopathological characteristics. In addition, tumor and healthy colon tissue were stained for neuronal subtype markers and their immunoreactivity in colorectal cancer (CRC) stroma was analyzed. NF and PGP9.5 positive nerve fibers were found within the tumor stroma and were mostly characterized by the neuronal subtype markers vasoactive intestinal protein (VIP) and neuronal nitric oxide synthase (nNOS), suggesting that inhibitory neurons are the most prominent neuronal subtype in CRC. NF and PGP9.5 protein expression were not consistently associated with tumor stage, sublocation, differentiation grade and median survival. NF immunoreactivity was associated with a worse CRC-specific survival in the study cohort (p=0.025), independent of other prognostic factors (HR=2.31; 95% CI 1.33-4.03; p=0.003), but these results were not observed in the in-cohort validation group. PGP9.5 on the other hand, was associated with a worse CRC-specific survival in the in-cohort validation (p=0.046) but not in the study population. This effect disappeared in multivariate analyses (HR=0.81; 95% CI 0.50-1.32; p=0.393) indicating that this effect was dependent on other prognostic factors. This study demonstrates that the tumor stroma of CRC patients mainly harbors inhibitory neurons and that NF as a single marker is significantly associated with a poorer CRC-specific survival in the study cohort but necessitates future validation.

The power of animation: encouraging doctors to access support for psychological wellbeing.

The COVID-19 pandemic has exacerbated already high rates of poor psychological wellbeing in doctors. Many doctors perceive a stigma associated with acknowledging psychological wellbeing concerns, resulting in a reluctance to seek support for those concerns. The aim of this study was to develop a theoretically-informed and evidence-based composite narrative animation (CNA) to encourage doctors to access support for psychological wellbeing, and to evaluate the acceptability of the CNA.A composite narrative was developed from an evidence-base of interviews with 27 GP participants across Scotland (May-July 2020). The Behaviour Change Wheel was used to identify behaviour change techniques (BCTs) to be embedded within the CNA. The narrative was turned into a script in collaboration with an animation company. A brief animation 'Jane the GP' was developed reflecting specific BCTs.Scottish doctors (n = 83) were asked for their views on acceptability of the CNA concept, and subsequently asked to provide views on the acceptability of the CNA after viewing it. Participants thought the concept of a CNA was novel but may not appeal to all. After viewing the CNA, the widespread view was that it portrayed an authentic experience, could reduce stigma around seeking support for psychological wellbeing, and highlighted formal routes to access such support.CNAs are a novel and acceptable intervention method for encouraging doctors to access support for psychological wellbeing. The use of a theory driven intervention development framework to create the CNA facilitates the link between theory and practice.

Effectiveness and safety of secukinumab updosing in patients with moderate to severe plaque psoriasis: data from the PURE registry.

Secukinumab is a fully human IgG1 antibody that selectively binds to and neutralizes the proinflammatory cytokine interleukin-17A. Secukinumab is an effective and well-tolerated treatment for plaque psoriasis. There is a limited real-word evidence for dose optimisation of secukinumab based on clinical response. PURE is a multi-national, prospective, observational study in patients with moderate to severe chronic plaque psoriasis in Canada and Latin America, assessing the real-world safety and effectiveness of secukinumab and other indicated therapies. The aim of the current snapshot analysis was to evaluate the effectiveness and safety of on-label dose and updosed secukinumab in patients with plaque psoriasis enrolled in the PURE study. At the time of analysis, 676 patients received secukinumab, of which 84.6% (n = 572) remained on the on-label dose, while 15.4% (n = 104) were updosed. With on-label secukinumab, the absolute Psoriasis Area and Severity Index (PASI) score was reduced from 13.6 at baseline to 1.2 over 36 months, with treatment persistence of 73% at 40 months. At Month 36, 73.2% of the patients receiving on-label secukinumab achieved Investigator's Global Assessment (IGA) 0/1. With updosed secukinumab (300 mg every 2 weeks, 300 mg every 3 weeks, 450 mg every 4 weeks, or 450 mg every 3 weeks), 57.9% of the patients showed improvement in the absolute PASI score at the first visit after updosing, with treatment persistence of 50% at 12 months after updosing. At Month 15, 40% of patients receiving updosed secukinumab achieved IGA 0/1. Patients with previous biologic exposure (odds ratio [OR]: 3.25; 95% confidence interval [CI]: 2.03, 5.18, p < 0.0001) were more likely to be updosed while those with a body weight < 90 kg (OR: 0.49; 95% CI [0.31, 0.77], p = 0.0019) were less likely to be updosed. Previous biologic exposure (HR [hazard ratio]: 1.47; 95% CI [1.24, 1.75], p < 0.0001) and current biologic exposure (secukinumab vs. other indicated therapies: HR 0.57; 95% CI [0.43, 0.75], p = 0.0001) were significantly associated with time to secukinumab updosing. No new or unexpected safety signals were observed with updosed secukinumab. Secukinumab updosing was efficacious and well-tolerated in patients with psoriasis who failed to respond to the approved on-label regimen, suggesting that updosing may be a useful therapeutic option for approved dose non-responders.

Regulation of the RhoA exchange factor GEF-H1 by pro-fibrotic stimuli through a positive feedback loop involving RhoA, MRTF and Sp1.

RhoA and its effectors, the transcriptional coactivators Myocardin-Related Transcription Factor (MRTF) and Serum Response Factor (SRF), control epithelial phenotype and are indispensable for profibrotic epithelial reprogramming during fibrogenesis. Context-dependent control of RhoA and fibrosis-associated changes in its regulators, however, remain incompletely characterized. We previously identified the guanine nucleotide exchange factor GEF-H1 as a central mediator of RhoA activation in renal tubular cells exposed to inflammatory or fibrotic stimuli. Here we found that GEF-H1 expression and phosphorylation were strongly elevated in two animal models of fibrosis. In the Unilateral Ureteral Obstruction mouse kidney fibrosis model, GEF-H1 was upregulated predominantly in the tubular compartment. GEF-H1 was also elevated and phosphorylated in a rat pulmonary artery banding model of right ventricular fibrosis. Prolonged stimulation of LLC-PK1 tubular cells with tumor necrosis factor-α or transforming growth factor ß1 increased GEF-H1 expression and activated a luciferase-coupled GEF-H1 promoter. Knockdown and overexpression studies revealed that these effects were mediated by RhoA, cytoskeleton remodeling and MRTF, indicative of a positive feed-back cycle. Indeed, silencing endogenous GEF-H1 attenuated activation of the GEF-H1 promoter. Importantly, inhibition of MRTF using CCG-1423 prevented GEF-H1 upregulation in both animal models. MRTF-dependent increase in GEF-H1 was prevented by inhibition of the transcription factor Sp1, and mutating putative Sp1 binding sites in the GEF-H1 promoter eliminated its MRTF-dependent activation. Since the GEF-H1/RhoA axis is key for fibrogenesis, this novel MRTF/Sp1-dependent regulation of GEF-H1 abundance represents a potential target for reducing renal and cardiac fibrosis.

[Regulation of Retrotransposons in Drosophila melanogaster Somatic Tissues].

Regulation of retrotransposon activity in somatic tissues is a complex mechanism that has still not been studied in detail. It is strongly believed that siRNA interference is main mechanism of retrotransposon activity regulation outside the gonads, but recently was demonstrated that piRNA interference participates in retrotransposon repression during somatic tissue development. In this work, using RT-PCR, we demonstrated that during ontogenesis piRNA interference determinates retrotransposon expression level on imago stage and retrotransposons demonstrate tissue-specific expression. The major factor of retrotransposon tissue-specific expression is presence of transcription factor binding sites in their regulatory regions.

Triglyceride-Catabolizing Lactiplantibacillus plantarum GBCC_F0227 Shows an Anti-Obesity Effect in a High-Fat-Diet-Induced C57BL/6 Mouse Obesity Model.

Given the recognized involvement of the gut microbiome in the development of obesity, considerable efforts are being made to discover probiotics capable of preventing and managing obesity. In this study, we report the discovery of Lactiplantibacillus plantarum GBCC_F0227, isolated from fermented food, which exhibited superior triglyceride catabolism efficacy compared to L. plantarum WCSF1. Molecular analysis showed elevated expression levels of α/ß hydrolases with lipase activity (abH04, abH08_1, abH08_2, abH11_1, and abH11_2) in L. plantarum GBCC_F0227 compared to L. plantarum WCFS1, demonstrating its enhanced lipolytic activity. In a high-fat-diet (HFD)-induced mouse obesity model, the administration of L. plantarum GBCC_F0227 mitigated weight gain, reduced blood triglycerides, and diminished fat mass. Furthermore, L. plantarum GBCC_F0227 upregulated adiponectin gene expression in adipose tissue, indicative of favorable metabolic modulation, and showed robust growth and low cytotoxicity, underscoring its industrial viability. Therefore, our findings encourage the further investigation of L. plantarum GBCC_F0227's therapeutic applications for the prevention and treatment of obesity and associated metabolic diseases.

Dapagliflozin reduces systemic inflammation in patients with type 2 diabetes without known heart failure.

OBJECTIVE: Sodium glucose cotransporter 2 (SGLT2) inhibitors significantly improve cardiovascular outcomes in diabetic patients; however, the mechanism is unclear. We hypothesized that dapagliflozin improves cardiac outcomes via beneficial effects on systemic and cardiac inflammation and cardiac fibrosis. RESEARCH AND DESIGN METHODS: This randomized placebo-controlled clinical trial enrolled 62 adult patients (mean age 62, 17% female) with type 2 diabetes (T2D) without known heart failure. Subjects were randomized to 12 months of daily 10 mg dapagliflozin or placebo. For all patients, blood/plasma samples and cardiac magnetic resonance imaging (CMRI) were obtained at time of randomization and at the end of 12 months. Systemic inflammation was assessed by plasma IL-1B, TNFα, IL-6 and ketone levels and PBMC mitochondrial respiration, an emerging marker of sterile inflammation. Global myocardial strain was assessed by feature tracking; cardiac fibrosis was assessed by T1 mapping to calculate extracellular volume fraction (ECV); and cardiac tissue inflammation was assessed by T2 mapping. RESULTS: Between the baseline and 12-month time point, plasma IL-1B was reduced (- 1.8 pg/mL, P = 0.003) while ketones were increased (0.26 mM, P = 0.0001) in patients randomized to dapagliflozin. PBMC maximal oxygen consumption rate (OCR) decreased over the 12-month period in the placebo group but did not change in patients receiving dapagliflozin (- 158.9 pmole/min/106 cells, P = 0.0497 vs. - 5.2 pmole/min/106 cells, P = 0.41), a finding consistent with an anti-inflammatory effect of SGLT2i. Global myocardial strain, ECV and T2 relaxation time did not change in both study groups. GOV REGISTRATION: NCT03782259.

Sudden cardiac death due to ventricular arrhythmia in diabetes mellitus: A bench to bedside review.

Diabetes mellitus (DM) confers an increased risk of sudden cardiac death (SCD) independent of its associated cardiovascular comorbidities. DM induces adverse structural, electrophysiologic, and autonomic cardiac remodeling that can increase one's risk of ventricular arrhythmias and SCD. Although glycemic control and prevention of microvascular and macrovascular complications are cornerstones in the management of DM, they are not adequate for the prevention of SCD. In this narrative review, we describe the contribution of DM to the pathophysiologic mechanism of SCD beyond its role in atherosclerotic cardiovascular disease and heart failure. On the basis of this pathophysiologic framework, we outline potential preventive and therapeutic strategies to mitigate the risk of SCD in this population of high-risk patients.