Lower Risks of New-Onset Hepatocellular Carcinoma in Patients With Type 2 Diabetes Mellitus Treated With SGLT2 Inhibitors Versus DPP4 Inhibitors.

BACKGROUND: Type 2 diabetes mellitus (T2DM) may be a risk factor for development of hepatocellular carcinoma (HCC). The association between risk of developing HCC and treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP4i) is currently unknown. This study aimed to compare the risk of new-onset HCC in patients treated with SGLT2i versus DPP4i. METHODS: This was a retrospective cohort study of patients with T2DM in Hong Kong receiving either SGLT2i or DPP4i between January 1, 2015, and December 31, 2020. Patients with concurrent DPP4i and SGLT2i use were excluded. Propensity score matching (1:1 ratio) was performed by using the nearest neighbor search. Multivariable Cox regression was applied to identify significant predictors. RESULTS: A total of 62,699 patients were included (SGLT2i, n=22,154; DPP4i, n=40,545). After matching (n=44,308), 166 patients (0.37%) developed HCC: 36 in the SGLT2i group and 130 in the DPP4i group over 240,269 person-years. Overall, SGLT2i use was associated with lower risks of HCC (hazard ratio [HR], 0.42; 95% CI, 0.28-0.79) compared with DPP4i after adjustments. The association between SGLT2i and HCC development remained significant in patients with cirrhosis or advanced fibrosis (HR, 0.12; 95% CI, 0.04-0.41), hepatitis B virus (HBV) infection (HR, 0.32; 95% CI, 0.17-0.59), or hepatitis C virus (HCV) infection (HR, 0.41; 95% CI, 0.22-0.80). The results were consistent in different risk models, propensity score approaches, and sensitivity analyses. CONCLUSIONS: SGLT2i use was associated with a lower risk of HCC compared with DPP4i use after adjustments, and in the context of cirrhosis, advanced fibrosis, HBV infection, and HCV infection.

Older adults use fewer muscles to overcome perturbations during a seated locomotor task.

Locomotor perturbations provide insights into humans' response to motor errors. We investigated the differences in motor adaptation and muscle cocontraction between young and older adults during perturbed-arm and -leg recumbent stepping. We hypothesized that besides prolonged adaptation due to use-dependent learning, older adults would exhibit greater muscle cocontraction than young adults in response to the perturbations. Perturbations were brief increases in resistance applied during each stride at the extension onset or midextension of the left or right leg. Seventeen young adults and eleven older adults completed four 10-min perturbed stepping tasks. Subjects were instructed to follow a visual pacing cue, step smoothly, and use all their limbs to drive the stepper. Results showed that young and older adults did not decrease their errors with more perturbation experience, and errors did not wash out after perturbations were removed. Interestingly, older adults consistently had smaller motor errors than young adults in response to the perturbations. Older adults used fewer muscles to drive the stepper and had greater cocontraction than young adults. The results suggest that, despite similar motor error responses, young and older adults use distinctive muscle recruitment patterns to perform the motor task. Age-related motor strategies help track motor changes across the human life span and are a baseline for rehabilitation and performance assessment.NEW & NOTEWORTHY Older adults often demonstrate greater cocontraction and motor errors than young adults in response to motor perturbations. We demonstrated that older adults reduced their motor errors more than young adults with brief perturbations during recumbent stepping while maintaining greater muscle cocontraction. In doing so, older adults largely used one muscle pair to drive the stepper, tibialis anterior and soleus, whereas young adults used all muscles. These two muscles are crucial for maintaining upright balance.

The common p.Ile291Val variant of ERLIN1 enhances TM6SF2 function and is associated with protection against MASLD.

BACKGROUND: The ERLIN1 p.Ile291Val single-nucleotide polymorphism (rs2862954) is associated with protection from steatotic liver disease (SLD), but effects of this variant on metabolic phenotypes remain uncertain. METHODS: Metabolic phenotypes and outcomes associated with ERLIN1 p.Ile291Val were analyzed by using a genome-first approach in the UK Biobank (UKB), Penn Medicine BioBank (PMBB), and All of Us cohort. FINDINGS: ERLIN1 p.Ile291Val carriers exhibited significantly lower serum levels of alanine aminotransferase and aspartate aminotransferase as well as higher levels of triglycerides, low-density lipoprotein cholesterol, Apolipoprotein B, high-density lipoprotein cholesterol, and Apolipoprotein A1 in UKB, and these values were affected by ERLIN1 p.Ile291Val in an allele-dose-dependent manner. Homozygous ERLIN1 p.Ile291Val carriers had a significantly reduced risk of developing metabolic dysfunction-associated SLD (MASLD, adjusted odds ratio [aOR] = 0.92, 95% confidence interval [CI], 0.88-0.96). The protective effect of this variant was enhanced in patients with alcoholic liver disease. Our results were replicated in PMBB and the All of Us cohort. Strikingly, the protective effects of ERLIN1 p.Ile291Val were not apparent in individuals carrying the TM6SF2 p.Glu167Lys variant associated with increased risk of SLD. We analyzed the effects of predicted loss-of-function ERLIN1 variants and found that they had opposite effects, namely reduced plasma lipids, suggesting that ERLIN1 p.Ile291Val may be a gain-of-function variant. CONCLUSION: Our study contributes to a better understanding of ERLIN1 by investigating a coding variant that has emerged as a potential gain-of-function mutation with protective effects against MASLD development.

Whose Signals Are Being Amplified? Toward a More Equitable Clinical Psychophysiology.

Research using psychophysiological methods holds great promise for refining clinical assessment, identifying risk factors, and informing treatment. Unfortunately, unique methodological features of existing approaches limit inclusive research participation and, consequently, generalizability. This brief overview and commentary provides a snapshot of the current state of representation in clinical psychophysiology, with a focus on the forms and consequences of ongoing exclusion of Black participants. We illustrate issues of inequity and exclusion that are unique to clinical psychophysiology, considering intersections among social constructions of Blackness and biased design of current technology used to measure electroencephalography, skin conductance, and other signals. We then highlight work by groups dedicated to quantifying and addressing these limitations. We discuss the need for reflection and input from a wider variety of stakeholders to develop and refine new technologies, given the risk of further widening disparities. Finally, we provide broad recommendations for clinical psychophysiology research.

The noncanonical NFκB pathway: Regulatory mechanisms in health and disease.

The noncanonical NFκB signaling pathway mediates the biological functions of diverse cell survival, growth, maturation, and differentiation factors that are important for the development and maintenance of hematopoietic cells and immune organs. Its dysregulation is associated with a number of immune pathologies and malignancies. Originally described as the signaling pathway that controls the NFκB family member RelB, we now know that noncanonical signaling also controls NFκB RelA and cRel. Here, we aim to clarify our understanding of the molecular network that mediates noncanonical NFκB signaling and review the human diseases that result from a deficient or hyper-active noncanonical NFκB pathway. It turns out that dysregulation of RelA and cRel, not RelB, is often implicated in mediating the resulting pathology. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology Cancer > Molecular and Cellular Physiology Immune System Diseases > Stem Cells and Development.

The advent of RNA-based therapeutics for metabolic syndrome and associated conditions: a comprehensive review of the literature.

Metabolic syndrome (MetS) is a prevalent and intricate health condition affecting a significant global population, characterized by a cluster of metabolic and hormonal disorders disrupting lipid and glucose metabolism pathways. Clinical manifestations encompass obesity, dyslipidemia, insulin resistance, and hypertension, contributing to heightened risks of diabetes and cardiovascular diseases. Existing medications often fall short in addressing the syndrome's multifaceted nature, leading to suboptimal treatment outcomes and potential long-term health risks. This scenario underscores the pressing need for innovative therapeutic approaches in MetS management. RNA-based treatments, employing small interfering RNAs (siRNAs), microRNAs (miRNAs), and antisense oligonucleotides (ASOs), emerge as promising strategies to target underlying biological abnormalities. However, a summary of research available on the role of RNA-based therapeutics in MetS and related co-morbidities is limited. Murine models and human studies have been separately interrogated to determine whether there have been recent advancements in RNA-based therapeutics to offer a comprehensive understanding of treatment available for MetS. In a narrative fashion, we searched for relevant articles pertaining to MetS co-morbidities such as cardiovascular disease, fatty liver disease, dementia, colorectal cancer, and endocrine abnormalities. We emphasize the urgency of exploring novel therapeutic avenues to address the intricate pathophysiology of MetS and underscore the potential of RNA-based treatments, coupled with advanced delivery systems, as a transformative approach for achieving more comprehensive and efficacious outcomes in MetS patients.

Prevalence of at-risk MASH, MetALD and alcohol-associated steatotic liver disease in the general population.

BACKGROUND: The prevalence of at-risk metabolic dysfunction-associated steatohepatitis (at-risk MASH) has not been systematically assessed. AIM: To delineate the prevalence of at-risk MASH in a large population-based cohort. METHODS: We conducted a cross-sectional analysis of 40,189 patients in the UK Biobank who underwent liver MRI. Hepatic steatosis was determined by proton density fat fraction (PDFF) ≥5%. Based on AASLD criteria, participants were classified as alcohol-associated steatotic liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), combined metabolic alcoholic liver disease (MetALD) and at-risk MASH. RESULTS: Among 40,189 patients, 10,886 (27.0%) had a PDFF ≥5%, indicating SLD. Among patients with SLD, 1% had ALD, 89.0% had MASLD, 7.9% had MetALD and 2.2% had at-risk MASH. The at-risk MASH group, which included 0.6% of the general population, had the highest mean liver fat on MRI and the highest BMI. Serum biomarkers highlighted increased inflammation and metabolic changes in at-risk MASH. The prevalence of MASLD was significantly higher among men with a BMI ≥30 kg/m2. Non-obese women showed only a 12% risk of MASLD. Conversely, MetALD had similar prevalence in obese men and women and was absent in non-obese women. CONCLUSIONS: MASLD is prevalent among patients with elevated PDFF on MRI. There are different sex- and BMI-specific prevalence of different steatotic liver disorders. At-risk MASH demonstrates the most severe metabolic and inflammatory profiles. This study provides novel estimates for the at-risk MASH population that will be eligible for treatment with pharmacologic therapy when approved by regulatory authorities.

Advancements and progress in juvenile idiopathic arthritis: A Review of pathophysiology and treatment.

Juvenile idiopathic arthritis (JIA) is a chronic clinical condition characterized by arthritic features in children under the age of 16, with at least 6 weeks of active symptoms. The etiology of JIA remains unknown, and it is associated with prolonged synovial inflammation and structural joint damage influenced by environmental and genetic factors. This review aims to enhance the understanding of JIA by comprehensively analyzing relevant literature. The focus lies on current diagnostic and therapeutic approaches and investigations into the pathoaetiologies using diverse research modalities, including in vivo animal models and large-scale genome-wide studies. We aim to elucidate the multifactorial nature of JIA with a strong focus towards genetic predilection, while proposing potential strategies to improve therapeutic outcomes and enhance diagnostic risk stratification in light of recent advancements. This review underscores the need for further research due to the idiopathic nature of JIA, its heterogeneous phenotype, and the challenges associated with biomarkers and diagnostic criteria. Ultimately, this contribution seeks to advance the knowledge and promote effective management strategies in JIA.

Exploring Health Care Disparities in Genetic Testing and Research for Hereditary Cardiomyopathy: Current State and Future Perspectives.

Background Hereditary cardiomyopathies are commonly occurring myocardial conditions affecting heart structure and function with a genetic or familial association, but the etiology is often unknown. Cardiomyopathies are linked to significant mortality, requiring robust risk stratification with genetic testing and early diagnosis. Hypothesis We hypothesized that health care disparities exist in genetic testing for hereditary cardiomyopathies within clinical practice and research studies. Methods In a narrative fashion, we conducted a literature search with online databases such as PubMed/MEDLINE, Google Scholar, EMBASE, and Science Direct on papers related to hereditary cardiomyopathies. A comprehensive analysis of findings from articles in English on disparities in diagnostics and treatment was grouped into four categories. Results Racial and ethnic disparities in research study enrollment and health care delivery favor White populations and higher socioeconomic status, resulting in differences in the development and implementation of effective genetic screening. Such disparities have shown to be detrimental, as minorities often suffer from disease progression to heart failure and sudden cardiac death. Barriers related to clinical genetic testing included insurance-related issues and health illiteracy. The underrepresentation of minority populations extends to research methodologies, as testing in ethnic minorities resulted in a significantly lower detection rate and diagnostic yield, as well as a higher likelihood of misclassification of variants. Conclusions Prioritizing minority-based participatory research programs and screening protocols can address systemic disparities. Diversifying research studies can improve risk stratification strategies and impact clinical practice.

Mass spectrometry imaging highlights dynamic patterns of lipid co-expression with Aß plaques in mouse and human brains.

Lipids play crucial roles in the susceptibility and brain cellular responses to Alzheimer's disease (AD) and are increasingly considered potential soluble biomarkers in cerebrospinal fluid (CSF) and plasma. To delineate the pathological correlations of distinct lipid species, we conducted a comprehensive characterization of both spatially localized and global differences in brain lipid composition in AppNL-G-F mice with spatial and bulk mass spectrometry lipidomic profiling, using human amyloid-expressing (h-Aß) and WT mouse brains controls. We observed age-dependent increases in lysophospholipids, bis(monoacylglycerol) phosphates, and phosphatidylglycerols around Aß plaques in AppNL-G-F mice. Immunohistology-based co-localization identified associations between focal pro-inflammatory lipids, glial activation, and autophagic flux disruption. Likewise, in human donors with varying Braak stages, similar studies of cortical sections revealed co-expression of lysophospholipids and ceramides around Aß plaques in AD (Braak stage V/VI) but not in earlier Braak stage controls. Our findings in mice provide evidence of temporally and spatially heterogeneous differences in lipid composition as local and global Aß-related pathologies evolve. Observing similar lipidomic changes associated with pathological Aß plaques in human AD tissue provides a foundation for understanding differences in CSF lipids with reported clinical stage or disease severity.

Exploring the Landscape of Intracranial Aneurysms in South America: A Comprehensive Narrative Review Intracranial Aneurysms in South America.

Exploring the landscape of intracranial aneurysms in South America unravels a complex interplay of epidemiological factors, clinical manifestations, and therapeutic challenges. The study methodically conducts a comprehensive literature review spanning the years 2003 to 2023, focusing on English-language articles obtained from diverse databases to elucidate the multifaceted nature of intracranial aneurysms in the region. Results and discussions categorize outcomes into positive domains, emphasizing successful treatments, favorable recoveries, and high survival rates, while also shedding light on negative aspects such as residual aneurysms and complications. The research illuminates significant gaps in pathological typing of intracranial aneurysms and exposes challenges in healthcare accessibility, notably the disparities in neurosurgical resources. Management challenges, including constrained infrastructure access, a neurosurgeon shortage, and gender disparities, are underscored. Transitioning to future prospects, the study advocates for strategic interventions, proposing expanded neurosurgical training, multidisciplinary approaches, improved funding, enhanced access to care, and fostering international collaborations. The study concludes by emphasizing the pivotal role of collaborative efforts, intensified training programs, and global partnerships in propelling intracranial aneurysm management forward in South America, ultimately contributing to enhanced patient outcomes across the region.

Hereditary spastic paraplegia: Novel insights into the pathogenesis and management.

Hereditary spastic paraplegia is a genetically heterogeneous neurodegenerative disorder characterised primarily by muscle stiffness in the lower limbs. Neurodegenerative disorders are conditions that result from cellular and metabolic abnormalities, many of which have strong genetic ties. While ageing is a known contributor to these changes, certain neurodegenerative disorders can manifest early in life, progressively affecting a person's quality of life. Hereditary spastic paraplegia is one such condition that can appear in individuals of any age. In hereditary spastic paraplegia, a distinctive feature is the degeneration of long nerve fibres in the corticospinal tract of the lower limbs. This degeneration is linked to various cellular and metabolic processes, including mitochondrial dysfunction, remodelling of the endoplasmic reticulum membrane, autophagy, abnormal myelination processes and alterations in lipid metabolism. Additionally, hereditary spastic paraplegia affects processes like endosome membrane trafficking, oxidative stress and mitochondrial DNA polymorphisms. Disease-causing genetic loci and associated genes influence the progression and severity of hereditary spastic paraplegia, potentially affecting various cellular and metabolic functions. Although hereditary spastic paraplegia does not reduce a person's lifespan, it significantly impairs their quality of life as they age, particularly with more severe symptoms. Regrettably, there are currently no treatments available to halt or reverse the pathological progression of hereditary spastic paraplegia. This review aims to explore the metabolic mechanisms underlying the pathophysiology of hereditary spastic paraplegia, emphasising the interactions of various genes identified in recent network studies. By comprehending these associations, targeted molecular therapies that address these biochemical processes can be developed to enhance treatment strategies for hereditary spastic paraplegia and guide clinical practice effectively.

Refining mutanome-based individualised immunotherapy of melanoma using artificial intelligence.

Using the particular nature of melanoma mutanomes to develop medicines that activate the immune system against specific mutations is a game changer in immunotherapy individualisation. It offers a viable solution to the recent rise in resistance to accessible immunotherapy alternatives, with some patients demonstrating innate resistance to these drugs despite past sensitisation to these agents. However, various obstacles stand in the way of this method, most notably the practicality of sequencing each patient's mutanome, selecting immunotherapy targets, and manufacturing specific medications on a large scale. With the robustness and advancement in research techniques, artificial intelligence (AI) is a potential tool that can help refine the mutanome-based immunotherapy for melanoma. Mutanome-based techniques are being employed in the development of immune-stimulating vaccines, improving current options such as adoptive cell treatment, and simplifying immunotherapy responses. Although the use of AI in these approaches is limited by data paucity, cost implications, flaws in AI inference capabilities, and the incapacity of AI to apply data to a broad population, its potential for improving immunotherapy is limitless. Thus, in-depth research on how AI might help the individualisation of immunotherapy utilising knowledge of mutanomes is critical, and this should be at the forefront of melanoma management.

Cardiac amyloidosis and aortic stenosis: a state-of-the-art review.

Cardiac amyloidosis is caused by the extracellular deposition of amyloid fibrils in the heart, involving not only the myocardium but also any cardiovascular structure. Indeed, this progressive infiltrative disease also involves the cardiac valves and, specifically, shows a high prevalence with aortic stenosis. Misfolded protein infiltration in the aortic valve leads to tissue damage resulting in the onset or worsening of valve stenosis. Transthyretin cardiac amyloidosis and aortic stenosis coexist in patients > 65 years in about 4-16% of cases, especially in those undergoing transcatheter aortic valve replacement. Diagnostic workup for cardiac amyloidosis in patients with aortic stenosis is based on a multi-parametric approach considering clinical assessment, electrocardiogram, haematologic tests, basic and advanced echocardiography, cardiac magnetic resonance, and technetium labelled cardiac scintigraphy like technetium-99 m (99mTc)-pyrophosphate, 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid, and 99mTc-hydroxymethylene diphosphonate. However, a biopsy is the traditional gold standard for diagnosis. The prognosis of patients with coexisting cardiac amyloidosis and aortic stenosis is still under evaluation. The combination of these two pathologies worsens the prognosis. Regarding treatment, mortality is reduced in patients with cardiac amyloidosis and severe aortic stenosis after undergoing transcatheter aortic valve replacement. Further studies are needed to confirm these findings and to understand whether the diagnosis of cardiac amyloidosis could affect therapeutic strategies. The aim of this review is to critically expose the current state-of-art regarding the association of cardiac amyloidosis with aortic stenosis, from pathophysiology to treatment.

Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer.

Tumors are intrinsically heterogeneous and it is well established that this directs their evolution, hinders their classification and frustrates therapy1-3. Consequently, spatially resolved omics-level analyses are gaining traction4-9. Despite considerable therapeutic interest, tumor metabolism has been lagging behind this development and there is a paucity of data regarding its spatial organization. To address this shortcoming, we set out to study the local metabolic effects of the oncogene c-MYC, a pleiotropic transcription factor that accumulates with tumor progression and influences metabolism10,11. Through correlative mass spectrometry imaging, we show that pantothenic acid (vitamin B5) associates with MYC-high areas within both human and murine mammary tumors, where its conversion to coenzyme A fuels Krebs cycle activity. Mechanistically, we show that this is accomplished by MYC-mediated upregulation of its multivitamin transporter SLC5A6. Notably, we show that SLC5A6 over-expression alone can induce increased cell growth and a shift toward biosynthesis, whereas conversely, dietary restriction of pantothenic acid leads to a reversal of many MYC-mediated metabolic changes and results in hampered tumor growth. Our work thus establishes the availability of vitamins and cofactors as a potential bottleneck in tumor progression, which can be exploited therapeutically. Overall, we show that a spatial understanding of local metabolism facilitates the identification of clinically relevant, tractable metabolic targets.

Recurrent haemorrhagic pontine cavernoma resection via a retrosigmoid microsurgical approach.

BACKGROUND: Brainstem cavernomas occasionally require surgical treatment. Appropriate patient selection and thorough understanding of the anatomy and technical nuances involved in microsurgical resection is a pre-requisite in undertaking these challenging cases. CASE DESCRIPTION: We present a video case of a patient with a recurrent haemorrhagic pontine cavernoma. A step-by-step commentary of surgical footage is provided along with clinical, anatomical and technical learning points pertinent to the safe surgical management of these lesions.

Microsurgical clipping of ruptured supraclinoid internal carotid artery aneurysm with extradural clinoidectomy.

BACKGROUND: Supraclinoid Internal Carotid Artery (ICA) aneurysms require additional access to standard pterional craniotomy via extradural clinoidectomy. Existing texts and surgical videos lack clarity, explanation and a clear step by step process. CASE DESCRIPTION: We present a case of a ruptured supraclinoid ICA aneurysm and extradural clinoidectomy along with 3D reconstructed imaging of the case anatomy to guide its resection. Real-time unedited on table rerupture provides an example of management. CONCLUSION: Extradural Anterior Clinoidectomy is a key maneuver in cerebrovascular surgical armamentarium for clipping of supraclinoid aneurysms. Stereotypical Pathological or Surgical Anatomy, its application, and availability with 3D imaging should be facilitates the framing and learning of normal physiological anatomy.

Cardioprotective effect of antiviral therapy among hepatitis C infected patients: A meta-analysis.

Background: Hepatitis C (HCV) infections have been shown to be associated a with higher risk of atherosclerotic cardiovascular disease (CVD). However, the use of antiviral therapy (AVT) and the risk of CVD has not been well established with limited literature. Objective: We sought to evaluate the association between AVT use post-HCV infection and cardiovascular outcomes. Methods: We performed a systematic literature search using PubMed, Embase, and Scopus for relevant articles from inception until 10th March 2023. Primary clinical outcomes were the incidence of any CVD. Secondary endpoints were all-cause of mortality, stroke, myocardial infarction, and peripheral artery disease. Results: A total of 394,452 patients were included in the analysis (111,076 in the AVT group and 283,376 patients in the NAVT group). The mean age of patients among AVT and NAVT groups was comparable (58.7 vs 58.18). The pooled analysis of primary outcomes showed that AVT was associated with a significantly reduced risk of any CVD (HR, 0.55(95%CI: 0.41-0.75), P < 0.001) compared with the NAVT group of patients. Secondary outcomes including ACM (HR, 0.38(95%CI: 0.32-0.46), P < 0.001), MI (HR, 0.62(95%CI: 0.41-0.94), P = 0.02), and PAD (HR, 0.62(95%CI: 0.41-0.93), P = 0.02) were significantly lower among AVT groups compared with NAVT groups of patients with HCV infection. However, the risk of stroke was comparable between both groups of patients (HR, 0.79(95%CI: 0.58-1.07), P = 0.13). Conclusion: Our analysis shows HCV-infected patients post-AVT have a significantly lower risk of any CVD, MI, ACM, and PAD compared with NAVT groups of patients.

SGLT2 inhibitors among patients with heart failure with preserved ejection fraction: A meta-analysis of randomised controlled trials.

BACKGROUND: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been recommended in the practice guidelines for the treatment of patients with heart failure with reduced ejection fraction; however, their effects among patients with preserved ejection fraction have been debatable. OBJECTIVE: We aim to evaluate the SGLT2 inhibitor effect among patients with heart failure with reduced ejection fraction, including DELIVER and EMPEROR-Preserved trials. METHODS: We performed a systematic literature search using the PubMed, Embase, Scopus, and Cochrane libraries for relevant articles from inception until August 30th, 2022. Statistical analysis was performed by calculating hazard ratio (HR) using the random effect model with a 95% confidence interval (CI) and probability value (P). Statistical significance was met if 95% CI does not cross numeric "1" and P < .05. RESULTS: Six studies with a total of 15,989 total patients were included in the final analysis. The mean age of patients enrolled in SGLT2 inhibitors and placebo was 69.13 and 69.37 years, respectively. The median follow-up duration was 2.24 years. SGLT2 inhibitors reduced composite cardiovascular mortality or first hospitalization for heart failure (HR, 0.80 [95% CI: 0.74-0.87], P < .001, I2 = 0%), heart failure hospitalization (HR, 0.74 [95% CI: 0.67-0.82], P < .001, I2 = 0%) compared with placebo. However, all-cause mortality (HR, 0.97 [95% CI: 0.89-1.06], P = .54, I2 = 0%) and cardiovascular mortality (HR, 0.96 [95% CI: 0.82-1.13), P = .66, I2 = 35.09%] were comparable between both groups. CONCLUSION: Our study finding shows that SGLT2 inhibitors significantly reduced the risk of first HF hospitalization or cardiovascular death and HF hospitalization; however, all-cause mortality was comparable between the groups.

Large-scale identification of undiagnosed hepatic steatosis using natural language processing.

Background: Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity in people with and without diabetes, but it is underdiagnosed, posing challenges for research and clinical management. Here, we determine if natural language processing (NLP) of data in the electronic health record (EHR) could identify undiagnosed patients with hepatic steatosis based on pathology and radiology reports. Methods: A rule-based NLP algorithm was built using a Linguamatics literature text mining tool to search 2.15 million pathology report and 2.7 million imaging reports in the Penn Medicine EHR from November 2014, through December 2020, for evidence of hepatic steatosis. For quality control, two independent physicians manually reviewed randomly chosen biopsy and imaging reports (n = 353, PPV 99.7%). Findings: After exclusion of individuals with other causes of hepatic steatosis, 3007 patients with biopsy-proven NAFLD and 42,083 patients with imaging-proven NAFLD were identified. Interestingly, elevated ALT was not a sensitive predictor of the presence of steatosis, and only half of the biopsied patients with steatosis ever received an ICD diagnosis code for the presence of NAFLD/NASH. There was a robust association for PNPLA3 and TM6SF2 risk alleles and steatosis identified by NLP. We identified 234 disorders that were significantly over- or underrepresented in all subjects with steatosis and identified changes in serum markers (e.g., GGT) associated with presence of steatosis. Interpretation: This study demonstrates clear feasibility of NLP-based approaches to identify patients whose steatosis was indicated in imaging and pathology reports within a large healthcare system and uncovers undercoding of NAFLD in the general population. Identification of patients at risk could link them to improved care and outcomes. Funding: The study was funded by US and German funding sources that did provide financial support only and had no influence or control over the research process.