Early clinical drug product shelf-life setting using accelerated predictive stability and metabolite data for impurity qualification: A case study.

This case study demonstrates how knowledge of degradation products together with predictions can establish a lean stability strategy using the accelerated predictive stability (APS) principles. Applying all available data for AZD4831, (R)-1-(2-(1-aminoethyl)-4-chlorobenzyl)-2-thioxo-2,3-dihydro-1H-pyrrolo[3,2-d]pyrimidin-4(5H)-one, a reliable predictive model was developed despite minor differences in technical batch tablet compositions. Early forced degradation studies were performed to map potential degradation pathways. The insights from these studies guided the design of an APS study, which in turn inform on a suitable clinical stability program, initial specification and shelf-life. The use of APS predictions of degradants as well as total impurities highlighted at an early stage, when designing the clinical stability program, the opportunity to identify which degradation product that would be shelf-life limiting. Hence, it was possible to guide the development stability activities and set an initial shelf-life of a tablet formulation. The presented study displays the importance of combining several sources of information in drug development, e.g., potential degradation pathways, accelerated stability, stability program design, metabolite data, and specification limits.

Using a customized telescoped stent complex in the percutaneous treatment of a residual superior sinus venosus defect.

The management of superior sinus venosus defects (SVD) via transcatheter covered stent (CS) placement is becoming an acceptable alternative to open heart surgery. Though the medium-term success of this procedure has been described, residual shunting from damage to the covering of the implanted stents, use of stents which are too short and unanticipated shortening of stents may result in immediate or short-term procedural failure. In such cases, placement of a second CS may be required to address a residual defect. Preprocedural prediction of the length of stent required for residual leak treatment may not be as accurate as predicting the required stent length in a native defect, meaning that compassionate use applications to facilitate acquiring non-standard stent and balloon combinations may not be practical. We present a successful case of residual SVD closure using a novel sutured telescoping stent technique. Further collaboration with industry should encourage regulatory approval of longer CS, to mitigate the need for potentially unpredictable modifications such as this.

Urinary anatalline and nicotelline cut-points to distinguish between exclusive and dual use of tobacco products.

OBJECTIVE: This study measured anatalline and nicotelline, two minor tobacco alkaloids, to discriminate between exclusive smokeless tobacco (SLT) use, exclusive electronic nicotine delivery systems (ENDS) use, exclusive cigarette use, dual SLT and cigarette use, and dual ENDS and cigarette use. METHODS: N = 664 urine samples from participants in the Population Assessment of Tobacco and Health Study were analyzed for anatalline and nicotelline. Geometric means and 95% confidence intervals were calculated for biomarker levels and their ratios. Non-parametric Receiver Operating Characteristic analyses were used to determine optimal cut-points of natural log-transformed biomarker ratios for distinguishing between tobacco use groups. RESULTS: The anatalline/nicotelline ratio distinguished exclusive cigarette from exclusive SLT use (threshold = 18.1, sensitivity = 89.3%, specificity = 86.4%, AUC = 0.90), and exclusive SLT from exclusive ENDS use (threshold = 12.8, sensitivity = 96.4%, specificity = 76.3%, AUC = 0.90) very well, but had reduced sensitivity and specificity when distinguishing exclusive cigarette from exclusive ENDS or any dual use with cigarettes. CONCLUSIONS: This research fills a gap in understanding the public health consequences of SLT and ENDS use by providing objective measures that can signal use of these products alone or in combination with cigarettes.

Dermatology Journal Advisory Boards and editorial independence.

Background: Dermatology journals play an essential role in the distribution and promotion of scientific and medical information. Despite this, there are little data on governance structure with respect to its editors, owners, and journal boards that oversee the day-to-day operations for these entities. Objective: This study aimed to explore the current governance structure of dermatology journals and best practice recommendations. Methods: The editors-in-chief of the major dermatology journals participated in an online survey of 29 questions to examine general statistics of each journal, open access model, governance structure, and process for editor selection or dismissal. Results: Of the 52 journal responses, 29 (55.8%) are society-owned journals with 19 (65.5%) primarily governed by a society board, while 18 (34.6%) have an advisory committee or alternative body. Most editor(s)-in-chief (56.9%) serve between 3- and 5-year terms, while 84.6% have the option of at least one renewal. Even though the selection, evaluation, and dismissal processes differed between the journals, generalized best practice recommendations were developed to help improve their overall organization and management. Conclusions: The oversight structure of dermatology journals varies, and some do not follow current best practice recommendations. Transparency regarding leadership, governance, and due process is needed to maintain editorial independence and integrity.

Pre-eclampsia and future cardiovascular disease risk: Assessing British clinicians' knowledge and practice.

OBJECTIVE: To explore UK-based clinicians' knowledge of long-term cardiovascular disease (CVD) risks after pre-eclampsia and capture current risk management practice. STUDY DESIGN: A voluntary online survey was designed to explore clinicians' perception and management of CVD risks after pre-eclampsia. Distribution occurred May-July 2022 via social media and email. The survey assessed awareness of pre-eclampsia's association with future CVD, knowledge of published guidelines on CVD risk management after pre-eclampsia, and current practice of risk-reduction counselling. Results were analysed descriptively. MAIN OUTCOME MEASURE: Clinician knowledge of postpartum cardiovascular risk and management following pre-eclampsia. RESULTS: Of 240 respondents, 72 were midwives, 46 obstetricians, 8 cardiologists, and 114 general practitioners (GPs). Most clinicians knew that pre-eclampsia increases the risk of chronic hypertension (89 %) and stroke (75 %). Awareness was worse for heart failure (47 %) and peripheral vascular disease (55 %). Obstetricians provide CVD risk-reduction counselling to women with pre-eclampsia most frequently: 43 % always counsel and 27 % often counsel. Most other clinicians never counsel patients (midwives: 76 %, cardiologists: 75 %, GPs: 62 %). Most clinicians (84 %) were not aware of CVD risk management guidance after pre-eclampsia and 75 % of cardiologists and GPs never consider pre-eclampsia when assessing cardiovascular risk. Almost all clinicians (91 %) wished for greater education on the topic. CONCLUSIONS: This study presents the first assessment of cardiovascular risk awareness after pre-eclampsia amongst UK-based clinicians. Although most knew pre-eclampsia increases CVD risk, patient counselling was limited. Targeted educational initiatives are needed to improve the knowledge-to-practice gap and reduce CVD prevalence after pre-eclampsia.

Multidisciplinary considerations for implementing Bayesian borrowing in basket trials.

Drug development has historically relied on phase I-III clinical trials including participants sharing the same disease. However, drug development has evolved as the discovery of mechanistic drivers of disease demonstrated that the same therapeutic target may provide benefits across different diseases. A basket trial condenses evaluation of one therapy among multiple related diseases into a single trial and presents an opportunity to borrow information across them rather than viewing each in isolation. Borrowing is a statistical tool but requires a foundation of clinical and therapeutic mechanistic justification. We review the Bayesian borrowing approach, including its assumptions, and provide a framework for how this approach can be evaluated for successful use in a basket trial for drug development.

Virtual Reality Remote Collaboration for Preprocedural Planning of Complex Percutaneous Congenital Interventions: A Case Series.

Virtual reality technology provides an environment for advanced 3-dimensional visualization of complex cardiac anatomy from cross-sectional imaging. Visualization and case planning with procedural simulation is very relevant and likely critical for overall procedural success in complex congenital interventions. We report this case series demonstrating the use of virtual reality to conduct remote, collaborative interinstitutional consultations on computed tomography angiography prior to congenital percutaneous interventions.

Transcatheter pulmonary valve replacement after arterial switch operation.

BACKGROUND: Patients with d-transposition of the great arteries (d-TGA) who have undergone an arterial switch operation (ASO) can develop right ventricular outflow tract (RVOT) dysfunction with pulmonary regurgitation (PR) or stenosis. In these patients, treatment may include transcatheter pulmonary valve replacement (TPVR). Coronary compression is a contraindication occurring in 5% of typical TPVR cases. After ASO, there are various anatomical considerations that can confound TPVR, including potential coronary artery compression. Our goal is to understand feasibility of TPVR in patients following ASO. METHODS: This was a retrospective multicenter cohort study of patients with RVOT dysfunction after ASO who underwent cardiac catheterization with intention to perform TPVR from 2008 to 2020. RESULTS: Across nine centers, 33 patients met inclusion criteria. TPVR was successful in 22 patients (66%), 19 receiving a Melody valve and 3 a SAPIEN valve. RVOT stenosis in isolation or with PR dictated need for TPVR in nearly all patients. One serious adverse event occurred with valve embolization. After TPVR, the RVOT peak gradient decreased from 43 to 9 mm Hg (p < 0.001); PR was trivial/none in all but one patient, in whom it was mild. Coronary compression prohibiting TPVR occurred in eight patients (24%) and two patients (6%) had severe aortic regurgitation from aortic root deformation precluding TPVR. Seven patients underwent RVOT reintervention with a median of 5.3 years post-TPVR. CONCLUSIONS: TPVR in patients with d-TGA after ASO is feasible, but in this cohort, coronary compression or aortic root distortion precluded TPVR in one-third of patients. The rate of RVOT reintervention after TPVR was higher in this cohort of ASO patients that in prior studies.

Computed tomography-derived normative values and z-scores of the pulmonary valve annulus and sino-tubular junction in the pediatric population.

BACKGROUND: Accurate assessment of the pulmonary valve can dictate clinical management of patients with right ventricular outflow tract (RVOT) anomalies. Comparisons with available normal reference values are essential for accurate evaluation. The aim of the study was to generate normative data for the pulmonary valve annulus and sino-tubular (ST) junction using CT measurements derived from a heterogeneous pediatric population and create z-scores useful for clinical practice. METHODS: Patients without heart disease who underwent cardiac CT between April 2014 and February 2021 â€‹at Children's Hospital Colorado were included. Minimum and maximum diameter (mm) and cross-sectional area (mm2) for the pulmonary valve annulus and ST junction were measured. Previously validated models were used to normalize the measurements and calculate z-scores. Each measurement was plotted against BSA, and z-score distributions were used as reference lines. RESULTS: Three-hundred-sixty-seven healthy patients with a mean age of 8.8 years (1-21), 56% male, and BSA of 1.1 â€‹m2 (0.4-2.1) were analyzed. The Haycock formula was used to present data as predicted values for a given BSA and within equations relating each measurement to BSA. Predicted values and z-score boundaries for all measurements are graphically re-presented. CONCLUSIONS: CT-derived normative data for the pulmonary valve annulus and ST junction is reported from a heterogenous cohort of healthy children.

Vitamin D Receptor Regulates Liver Regeneration After Partial Hepatectomy in Male Mice.

Vitamin D signals through the vitamin D receptor (VDR) to induce its end-organ effects. Hepatic stellate cells control development of liver fibrosis in response to stressors and vitamin D signaling decreases fibrogenesis. VDR expression in hepatocytes is low in healthy liver, and the role of VDR in hepatocyte proliferation is unclear. Hepatocyte-VDR null mice (hVDR) were used to assess the role of VDR and vitamin D signaling in hepatic regeneration. hVDR mice have impaired liver regeneration and impaired hepatocyte proliferation associated with significant differential changes in bile salts. Notably, mice lacking hepatocyte VDR had significant increases in expression of conjugated bile acids after partial hepatectomy, consistent with failure to normalize hepatic function by the 14-day time point tested. Real-time PCR of hVDR and control livers showed significant changes in expression of cell-cycle genes including cyclins D1 and E1 and cyclin-dependent kinase 2. Gene expression profiling of hepatocytes treated with vitamin D or control showed regulation of groups of genes involved in liver proliferation, hepatitis, liver hyperplasia/hyperproliferation, and liver necrosis/cell death. Together, these studies demonstrate an important functional role for VDR in hepatocytes during liver regeneration. Combined with the known profibrotic effects of impaired VDR signaling in stellate cells, the studies provide a mechanism whereby vitamin D deficiency would both reduce hepatocyte proliferation and permit fibrosis, leading to significant liver compromise.

De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5' splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.

Prospective Evaluation of Vitamin C, Vitamin D, and Zinc Deficiencies in Patients with Active Foot Ulceration.

Objective: This prospective cohort study aimed to determine the relationship between serum vitamin C, D, and zinc on foot wound healing and compare time to healing in individuals who are deficient versus those who have adequate levels. Approach: One hundred adults with foot wounds were recruited from Blacktown high-risk foot service with a follow-up period of 12 months. Serum vitamin C, D, and zinc as well as routine baseline blood testing was undertaken. Wounds were measured using a three-dimensional wound camera and classified using the Wound Ischemia and Foot Infection system at regular intervals. Results: Vitamin C deficiency was present in 75% of participants, 50% had vitamin D deficiency, and 38% had zinc deficiency. Diabetes was present in 91% of participants, and 50% had a history of previous amputation. Wound chronicity (p = 0.03) and toe pressures (p = 0.04) were predictive of wound healing. Serum vitamin C, D, and zinc were not associated with significant differences in wound healing or time to wound healing. Innovation: Deficiencies in vitamin C, D, and zinc were highly prevalent in participants with active foot ulceration. Wound chronicity was predictive of healing outcomes, highlighting the importance of rapid access to best practice care. Conclusion: This cohort had high deficiency rates of vitamin C, D, and zinc consistent with previous literature; however, there was no relationship between these deficiencies and wound healing or time to heal. Large randomized controlled trials are required to comprehensively determine if adequate levels of these nutrients improve wound healing outcomes.

Administration sequence- and formation-dependent vaccination using acid-degradable polymeric nanoparticles with high antigen encapsulation capability.

Vaccines aim to efficiently and specifically activate the immune system via a cascade of antigen uptake, processing, and presentation by antigen-presenting cells (APCs) to CD4 and CD8 T cells, which in turn drive humoral and cellular immune responses. The specific formulation of vaccine carriers can not only shield the antigens from premature sequestering before reaching APCs but also favorably promote intracellular antigen presentation and processing. This study compares two different acid-degradable polymeric nanoparticles that are capable of encapsulating a moderately immunogenic antigen, GFP, at nearly full efficacy via electrostatic interactions or molecular affinity between His tag and Ni-NTA-conjugated monomners. This resulted in GFP-encapsulating NPs composed of ketal monomers and crosslinkers (KMX/GFP NPs) and NTA-conjugated ketal monomers and crosslinkers (NKMX/GFP NPs), respectively. Encapsulated GFP was found to be released more rapidly from NKMX/GFP NPs (electrostatic encapsulation) than from KMX/GFP NPs (affinity-driven encapsulation). In vivo vaccination studies demonstrated that while repeated injections of either NP formulation resulted in poorer generation of anti-GFP antibodies than injections of the GFP antigen itself, sequential injections of NPs and GFP as prime and booster vaccines, respectively, restored the humoral response. We proposed that NPs primarily assist APCs in antigen presentation by T cells, and B cells need to be further stimulated by free protein antigens to produce antibodies. The findings of this study suggest that the immune response can be modulated by varying the chemistry of vaccine carriers and the sequences of vaccination with free antigens and antigen-encapsulating NPs.

Imbalance of APOB Lipoproteins and Large HDL in Type 1 Diabetes Drives Atherosclerosis.

BACKGROUND: Individuals with type 1 diabetes (T1D) generally have normal or even higher HDL (high-density lipoprotein)-cholesterol levels than people without diabetes yet are at increased risk for atherosclerotic cardiovascular disease (CVD). Human HDL is a complex mixture of particles that can vary in cholesterol content by >2-fold. To investigate if specific HDL subspecies contribute to the increased atherosclerosis associated with T1D, we created mouse models of T1D that exhibit human-like HDL subspecies. We also measured HDL subspecies and their association with incident CVD in a cohort of people with T1D. METHODS: We generated LDL receptor-deficient (Ldlr-/-) mouse models of T1D expressing human APOA1 (apolipoprotein A1). Ldlr-/-APOA1Tg mice exhibited the main human HDL subspecies. We also generated Ldlr-/-APOA1Tg T1D mice expressing CETP (cholesteryl ester transfer protein), which had lower concentrations of large HDL subspecies versus mice not expressing CETP. HDL particle concentrations and sizes and proteins involved in lipoprotein metabolism were measured by calibrated differential ion mobility analysis and targeted mass spectrometry in the mouse models of T1D and in a cohort of individuals with T1D. Endothelial transcytosis was analyzed by total internal reflection fluorescence microscopy. RESULTS: Diabetic Ldlr-/-APOA1Tg mice were severely hyperglycemic and hyperlipidemic and had markedly elevated plasma APOB levels versus nondiabetic littermates but were protected from the proatherogenic effects of diabetes. Diabetic Ldlr-/-APOA1Tg mice expressing CETP lost the atheroprotective effect and had increased lesion necrotic core areas and APOB accumulation, despite having lower plasma APOB levels. The detrimental effects of low concentrations of larger HDL particles in diabetic mice expressing CETP were not explained by reduced cholesterol efflux. Instead, large HDL was more effective than small HDL in preventing endothelial transcytosis of LDL mediated by scavenger receptor class B type 1. Finally, in humans with T1D, increased concentrations of larger HDL particles relative to APOB100 negatively predicted incident CVD independently of HDL-cholesterol levels. CONCLUSIONS: Our results suggest that the balance between APOB lipoproteins and the larger HDL subspecies contributes to atherosclerosis progression and incident CVD in the setting of T1D and that larger HDLs exert atheroprotective effects on endothelial cells rather than by promoting macrophage cholesterol efflux.

Oxidative stress biomarkers for fetal growth restriction in umbilical cord blood: A scoping review.

Fetal growth restriction and underlying placental insufficiency are associated with increased oxidative stress. Current diagnostics fail to identify all growth restricted fetuses and newborns, due to focus on small size. This scoping review aims to summarize the available evidence on usefulness of cord blood oxidative stress biomarkers for identification of growth restricted newborns in need of monitoring and support because of associated health risks. MEDLINE and EMBASE were searched from inception to May 2024. Studies were included if oxidative stress biomarkers were measured in cord blood collected immediately after delivery in newborns suspected to be growth restricted. Biomarkers were categorized based on the origin and/or biological function and their interrelationships. Oxidative stress was determined for each individual biomarker and category. Literature search identified 78 studies on 39 different biomarkers, with a total of 2707 newborns with suspected growth restriction, and 4568 controls. Total oxidant/antioxidant status, catalase, glutathione, ischemia-modified albumin, and nucleated red blood cells were most consistently associated with suspected growth restriction. Reactive oxygen species/reactive nitrogen species, factors in their production, antioxidant enzymes, non-enzymatic antioxidants, and products of oxidative stress were not consistently associated. This review collates the evidence of associations between cord blood oxidative stress biomarkers and growth restriction. Total oxidant/antioxidant status, catalase, glutathione, ischemia-modified albumin, and nucleated red blood cells could potentially be candidates for developing a cord blood diagnostic tool for future clinical use.

Reassessing the association: Evaluation of a polyalanine deletion variant of RUNX2 in non-syndromic sagittal and metopic craniosynostosis.

The RUNT-related transcription factor RUNX2 plays a critical role in osteoblast differentiation, and alterations to gene dosage cause distinct craniofacial anomalies. Uniquely amongst the RUNT-related family, vertebrate RUNX2 encodes a polyglutamine/polyalanine repeat (Gln23-Glu-Ala17 in humans), with the length of the polyalanine component completely conserved in great apes. Surprisingly, a frequent 6-amino acid deletion polymorphism, p.(Ala84_Ala89)del, occurs in humans (termed 11A allele), and a previous association study (Cuellar et al. Bone 137:115395;2020) reported that the 11A variant was significantly more frequent in non-syndromic sagittal craniosynostosis (nsSag; allele frequency [AF] = 0.156; 95% confidence interval [CI] 0.126-0.189) compared to non-syndromic metopic craniosynostosis (nsMet; AF = 0.068; 95% CI 0.045-0.098). However, the gnomAD v.2.1.1 control population used by Cuellar et al. did not display Hardy-Weinberg equilibrium, hampering interpretation. To re-examine this association, we genotyped the RUNX2 11A polymorphism in 225 individuals with sporadic nsSag as parent-child trios and 164 singletons with sporadic nsMet, restricting our analysis to individuals of European ancestry. We compared observed allele frequencies to the non-transmitted alleles in the parent-child trios, and to the genome sequencing data from gnomAD v.4, which display Hardy-Weinberg equilibrium. Observed AFs (and 95% CI) were 0.076 (0.053-0.104) in nsSag and 0.082 (0.055-0.118) in nsMet, compared with 0.062 (0.042-0.089) in non-transmitted parental alleles and 0.065 (0.063-0.067) in gnomAD v.4.0.0 non-Finnish European control genomes. In summary, we observed a non-significant excess, compared to gnomAD data, of 11A alleles in both nsSag (relative risk 1.18, 95% CI 0.83-1.67) and nsMet (relative risk 1.29, 95% CI 0.87-1.92), but we did not replicate the much higher excess of RUNX2 11A alleles in nsSag previously reported (p = 0.0001).

Advanced Imaging Guidance for Ductus Venosus Stenting in Obstructed Total Anomalous Pulmonary Venous Return.

Obstructed infracardiac total anomalous pulmonary venous return is nearly always a surgical emergency in which infants present in severe cardiopulmonary distress. Ductal venosus stenting can provide a temporizing option for premature, low birth weight infants with high risk for surgical complications. In challenging anatomic cases, virtual reality, 3D-printed models, and fusion image guidance can aid in procedural planning and provide support for successful intervention.

ACVIM consensus statement on the treatment of immune thrombocytopenia in dogs and cats.

Management of immune thrombocytopenia (ITP) in dogs and cats is evolving, but there are no evidence-based guidelines to assist clinicians with treatment decisions. Likewise, the overall goals for treatment of ITP have not been established. Immunosuppressive doses of glucocorticoids are the first line treatment, but optimal treatment regimens beyond glucocorticoids remain uncertain. Additional options include secondary immunosuppressive drugs such as azathioprine, modified cyclosporine, and mycophenolate mofetil, usually selected based on clinician preference. Vincristine, human IV immunoglobulin (hIVIg), and transfusion of platelet or red blood cell-containing products are often used in more severe cases. Splenectomy and thrombopoietin receptor agonists are usually reserved for refractory cases, but when and in which patient these modalities should be employed is under debate. To develop evidence-based guidelines for individualized treatment of ITP patients, we asked 20 Population Intervention Comparison Outcome (PICO) format questions. These were addressed by 17 evidence evaluators using a literature pool of 288 articles identified by a structured search strategy. Evidence evaluators, using panel-designed templates and data extraction tools, summarized evidence and created guideline recommendations. These were integrated by treatment domain chairs and then refined by iterative Delphi survey review to reach consensus on the final guidelines. In addition, 19 non-PICO questions covering scenarios in which evidence was lacking or of low quality were answered by expert opinion using iterative Delphi surveys with panelist integration and refinement. Commentary was solicited from multiple relevant professional organizations before finalizing the consensus. The rigorous consensus process identified few comparative treatment studies, highlighting many areas of ITP treatment requiring additional studies. This statement is a companion manuscript to the ACVIM Consensus Statement on the Diagnosis of Immune Thrombocytopenia in Dogs and Cats.

Elevated apolipoprotein C3 augments diabetic kidney disease and associated atherosclerosis in type 2 diabetes.

Diabetes increases the risk of both cardiovascular disease and kidney disease. Notably, most of the excess cardiovascular risk in people with diabetes is in those with kidney disease. Apolipoprotein C3 (APOC3) is a key regulator of plasma triglycerides, and it has recently been suggested to play a role in both type 1 diabetes-accelerated atherosclerosis and kidney disease progression. To investigate if APOC3 plays a role in kidney disease in people with type 2 diabetes, we analyzed plasma levels of APOC3 from the Veterans Affairs Diabetes Trial. Elevated baseline APOC3 levels predicted a greater loss of renal function. To mechanistically test if APOC3 plays a role in diabetic kidney disease and associated atherosclerosis, we treated black and tan, brachyury, WT and leptin-deficient (OB; diabetic) mice, a model of type 2 diabetes, with an antisense oligonucleotide (ASO) to APOC3 or a control ASO, all in the setting of human-like dyslipidemia. Silencing APOC3 prevented diabetes-augmented albuminuria, renal glomerular hypertrophy, monocyte recruitment, and macrophage accumulation, partly driven by reduced ICAM1 expression. Furthermore, reduced levels of APOC3 suppressed atherosclerosis associated with diabetes. This suggests that targeting APOC3 might benefit both diabetes-accelerated atherosclerosis and kidney disease.