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22q11.2 deletion syndrome (22q11DS) is a highly penetrant and common genetic cause of neuropsychiatric disease. Here we generated induced pluripotent stem cells from 15 individuals with 22q11DS and 15 control individuals and differentiated them into three-dimensional (3D) cerebral cortical organoids. Transcriptional profiling across 100 days showed high reliability of differentiation and revealed changes in neuronal excitability-related genes. Using electrophysiology and live imaging, we identified defects in spontaneous neuronal activity and calcium signaling in both organoid- and 2D-derived cortical neurons. The calcium deficit was related to resting membrane potential changes that led to abnormal inactivation of voltage-gated calcium channels. Heterozygous loss of DGCR8 recapitulated the excitability and calcium phenotypes and its overexpression rescued these defects. Moreover, the 22q11DS calcium abnormality could also be restored by application of antipsychotics. Taken together, our study illustrates how stem cell derived models can be used to uncover and rescue cellular phenotypes associated with genetic forms of neuropsychiatric disease. more...

The article discusses a case of a 78-year-old male with resistant hypertension due to renal artery stenosis. Despite medication, his blood pressure remained uncontrolled, leading to worsening renal function. Imaging tests revealed a significant stenosis in the right renal artery, which was successfully treated with stent placement. Following the procedure, the patient's blood pressure improved, and his renal function stabilized. The article highlights the importance of considering renovascular hypertension in patients with appropriate clinical features and the potential benefits of revascularization in selected cases. [Extracted from the article] more...

Purpose of Review: This review provides a practical, evidence-based summary of the physiology, major trial data and clinical role of renal denervation in the treatment of hypertension. Recent Findings: The cornerstone of hypertension therapy remains anti-hypertensive medications although this strategy has significant limitations with poor rates of blood pressure control for most patients. Renal denervation was designed to bypass concerns about medication adherence and provide an "always-on" treatment. Recent trial data and meta-analyses are presented demonstrating a modest, although heterogeneous, response to renal denervation which led to the treatment's recent FDA approval. Improvements in catheter design and renal artery treatment strategy may underlie the improved clinical response to denervation in more recent trials. Summary: Hypertension centers involving multi-disciplinary care teams are equipped to provide patients with advanced diagnostic testing for secondary hypertension, comprehensive non-invasive management strategies and invasive renal denervation to address hypertension. Early referral for patients with uncontrolled hypertension can provide patients with nuanced conservative and interventional options which have the potential to improve hypertension related morbidity and mortality. Future studies are needed to identify which patients are most likely to respond to renal denervation. [ABSTRACT FROM AUTHOR] more...

Key Points: Question: What are the contemporary practice patterns and clinical outcomes of inferior vena cava filter (IVCF) insertion and retrieval in the US? Findings: In this nationwide observational analysis of more than 270 000 Medicare beneficiaries, IVCF insertion volume declined from 2013 to 2021, but retrieval frequency remained low (~15%). IVCF insertion and retrieval procedures were generally safe (<1% filter-related complications at 30 days). For filters that were not retrieved during the study period (ie, indwelling filters), risk of complications, such as filter thrombosis, accumulated over time. Meaning: Only a minority of patients undergo IVCF retrieval, even though risks of safety events following filter procedures are low and the risks of filter complications accumulate over time. Steps need to be taken to increase timely IVCF retrieval. Importance: Inferior vena cava filters (IVCFs) are commonly used to prevent pulmonary embolism in selected clinical scenarios, despite limited evidence to support their use. Current recommendations from professional societies and the US Food and Drug Administration endorse timely IVCF retrieval when clinically feasible. Current IVCF treatment patterns and outcomes remain poorly described. Objectives: To evaluate temporal trends and practice patterns in IVCF insertion and retrieval among older US patients and report the incidence of periprocedural and long-term safety events of indwelling and retrieved IVCFs. Design, Setting, and Participants: Prespecified, retrospective, observational cohort of Medicare Fee-for-Service (FFS) beneficiaries, leveraging 100% of samples of inpatient and outpatient claims data from January 1, 2013, to December 31, 2021. Exposure: First-time IVCF insertion while insured by Medicare FFS. Main Outcomes and Measures: The primary safety outcome was the composite of all-cause death, filter-related complications (eg, fracture, embolization), operating room visits following filter-related procedures, or new diagnosis of deep vein thrombosis (DVT). Events were considered periprocedural if they occurred within 30 days of IVCF insertion or retrieval and long-term if they occurred more than 30 days after. Results: Among 270 866 patients with IVCFs placed during the study period (mean age, 75.1 years; 52.8% female), 64.9% were inserted for first-time venous thromboembolism (VTE), 26.3% for recurrent VTE, and 8.8% for VTE prophylaxis. Of these patients, 63.3% had major bleeds or trauma within 30 days of IVCF insertion. The volume of insertions decreased from 44 680 per year in 2013 to 19 501 per year in 2021. The cumulative incidence of retrieval was 15.3% at a median of 1.2 years and 16.8% at maximum follow-up of 9.0 years. Older age, more comorbidities, and Black race were associated with a decreased likelihood of retrieval, whereas placement at a large teaching hospital was associated with an increased likelihood of retrieval. The incidence of caval thrombosis and DVT among patients with nonretrieved IVCFs was 2.2% (95% CI, 2.1%-2.3%) and 9.2% (95% CI, 9.0%-9.3%), respectively. The majority (93.5%) of retrieval attempts were successful, with low incidence of 30-day complications (mortality, 0.7% [95% CI, 0.6%-0.8%]; filter-related complications, 1.4% [95% CI, 1.2%-1.5%]). Conclusions and Relevance: In this large, US real-world analysis, IVCF insertion declined, yet retrievals remained low. Strategies to increase timely retrieval are needed, as nonretrieved IVCFs may have long-term complications. This prespecified, retrospective observational cohort study examines the trends in inferior vena cava filter insertion and retrieval for the prevention of venous thromboembolism among US Medicare beneficiaries. [ABSTRACT FROM AUTHOR] more...

Thymic epithelial cells in the medulla (mTECs) play a critical role in enforcing central tolerance through expression and presentation of tissue-specific antigens (TSAs) and deletion of autoreactive thymocytes. TSA expression requires autoimmune regulator (Aire), a transcriptional activator present in a subset of mTECs characterized by high CD80 and major histocompatibility complex II expression and a lack of potential for differentiation or proliferation. Here, using an Aire-DTR transgenic line, we show that short-term ablation specifically targets Aire(+) mTECs, which quickly undergo RANK-dependent recovery. Repeated ablation also affects Aire(-) mTECs, and using an inducible Aire-Cre fate-mapping system, we find that this results from the loss of a subset of mTECs that showed prior expression of Aire, maintains intermediate TSA expression, and preferentially migrates toward the center of the medulla. These results clearly identify a distinct stage of mTEC development and underscore the diversity of mTECs that play a key role in maintaining tolerance. more...

The autoimmune regulator (Aire) is essential for prevention of autoimmunity; its role is best understood in the thymus, where it promotes self-tolerance through tissue-specific antigen (TSA) expression. Recently, extrathymic Aire-expressing cells (eTACs) have been described in murine secondary lymphoid organs, but the identity of such cells and their role in immune tolerance remains unclear. Here we have shown that eTACs are a discrete major histocompatibility complex class II (MHC II)(hi), CD80(lo), CD86(lo), epithelial cell adhesion molecule (EpCAM)(hi), CD45(lo) bone marrow-derived peripheral antigen-presenting cell (APC) population. We also have demonstrated that eTACs can functionally inactivate CD4⁺ T cells through a mechanism that does not require regulatory T cells (Treg) and is resistant to innate inflammatory stimuli. Together, these findings further define eTACs as a distinct tolerogenic cell population in secondary lymphoid organs. more...

This article discusses the underutilization of supervised exercise therapy (SET) for symptomatic peripheral artery disease (PAD) among Medicare beneficiaries. Despite being recommended as a Class IA treatment for claudication from PAD, SET is not widely used, even though it gained coverage approval from the Centers for Medicare & Medicaid Services (CMS) in 2017. The study found that only 1.8% of patients with claudication were enrolled in SET during the study period, and there were disparities in enrollment based on race, sex, socioeconomic status, and geographic region. The study suggests that barriers to accessing SET remain, and efforts are needed to improve awareness, access, and adherence to this recommended intervention. [Extracted from the article] more...

Background: The use of atherectomy during peripheral endovascular interventions (PVI) has increased dramatically, but data regarding its safety and effectiveness are lacking.  Aims: This study sought to determine the long-term safety of atherectomy in contemporary practice.  Methods: Medicare fee-for-service beneficiaries who underwent femoropopliteal artery PVI from 2015-2018 were identified in a 100% sample of inpatient, outpatient, and carrier file data using procedural claims codes. The primary exposure was the use of atherectomy. Inverse probability of treatment weighting was used to adjust for measured differences in patient populations. Kaplan-Meier methods and multivariable Cox proportional hazards regression were used to compare outcomes.  Results: Among 168,553 patients who underwent PVI, 59,142 (35.1%) underwent atherectomy. The mean patient age was 77.0±7.6 years, 44.9% were female, 81.9% were white, and 46.7% had chronic limb-threatening ischaemia. Over a median follow-up time of 993 days (interquartile range 319-1,377 days), atherectomy use was associated with no difference in the risk of either the composite endpoint of death and amputation (adjusted hazard ratio [aHR] 0.99, 95% confidence interval [CI]: 0.97-1.01; p=0.19) or of major adverse limb events (aHR 1.02, 95% CI: 0.99-1.05; p=0.26). Patients who underwent atherectomy had a modest reduction in the risk of subsequently undergoing amputation or surgical revascularisation (aHR 0.92, 95% CI: 0.90-0.94; p<0.01) but an increase in the risk of undergoing a subsequent PVI (aHR 1.19, 95% CI: 1.16-1.21; p<0.01)., Conclusions: The use of atherectomy during femoropopliteal artery PVI was not associated with an increase in the risk of long-term adverse safety outcomes among patients with peripheral artery disease. more...