FAMIN Is a Multifunctional Purine Enzyme Enabling the Purine Nucleotide Cycle.

Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases the risk for Crohn's disease and leprosy. We developed an unbiased liquid chromatography-mass spectrometry screen for enzymatic activity of this orphan protein. We report that FAMIN phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate. Such activity was considered absent from eukaryotic metabolism. FAMIN and its prokaryotic orthologs additionally have adenosine deaminase, purine nucleoside phosphorylase, and S-methyl-5'-thioadenosine phosphorylase activity, hence, combine activities of the namesake enzymes of central purine metabolism. FAMIN enables in macrophages a purine nucleotide cycle (PNC) between adenosine and inosine monophosphate and adenylosuccinate, which consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity. This macrophage PNC synchronizes mitochondrial activity with glycolysis by balancing electron transfer to mitochondria, thereby supporting glycolytic activity and promoting oxidative phosphorylation and mitochondrial H+ and phosphate recycling.

The cellular composition of the human immune system is shaped by age and cohabitation.

Detailed population-level description of the human immune system has recently become achievable. We used a 'systems-level' approach to establish a resource of cellular immune profiles of 670 healthy individuals. We report a high level of interindividual variation, with low longitudinal variation, at the level of cellular subset composition of the immune system. Despite the profound effects of antigen exposure on individual antigen-specific clones, the cellular subset structure proved highly elastic, with transient vaccination-induced changes followed by a return to the individual's unique baseline. Notably, the largest influence on immunological variation identified was cohabitation, with 50% less immunological variation between individuals who share an environment (as parents) than between people in the wider population. These results identify local environmental conditions as a key factor in shaping the human immune system.

Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway.

The clinical course and eventual outcome, or prognosis, of complex diseases varies enormously between affected individuals. This variability critically determines the impact a disease has on a patient's life but is very poorly understood. Here, we exploit existing genome-wide association study data to gain insight into the role of genetics in prognosis. We identify a noncoding polymorphism in FOXO3A (rs12212067: T > G) at which the minor (G) allele, despite not being associated with disease susceptibility, is associated with a milder course of Crohn's disease and rheumatoid arthritis and with increased risk of severe malaria. Minor allele carriage is shown to limit inflammatory responses in monocytes via a FOXO3-driven pathway, which through TGFß1 reduces production of proinflammatory cytokines, including TNFα, and increases production of anti-inflammatory cytokines, including IL-10. Thus, we uncover a shared genetic contribution to prognosis in distinct diseases that operates via a FOXO3-driven pathway modulating inflammatory responses.

A Differential Analysis of Preferred Feminine Facial Contours for Transfeminine Individuals.

BACKGROUND: Facial feminization surgeries are important gender-affirming procedures for transfeminine individuals. The literature provides guidance on classically feminine facial features but the aesthetic preferences of transgender patients have not been studied. This study aimed to define the preferred feminine facial proportions of transfeminine patients and compare them to a mixed population of US adults. METHODS: An online survey was designed consisting of virtually modified images with progressive degrees of change in 6 facial features: forehead, nasal dorsum, chin projection, nasolabial angle, mandibular angle, and chin height. It was administered to transfeminine patients in a large-scale health system as well as the general population using an online market research instrument. Respondents ranked each image on a 7-point Likert scale from "very unattractive" to "very attractive" for a feminine face. RESULTS: Both groups agreed that a moderately convex forehead without supraorbital ridge prominence, slightly sloped nasal dorsum, ∼105-degree nasolabial angle, and decreased chin height were considered most attractive. In addition, very concave nasal slope and ∼110-degree nasolabial angle were rated significantly higher by transfeminine respondents compared with controls. The most classically masculine versions of each feature were considered significantly more unattractive by transfeminine patients when compared with controls. CONCLUSION: Transfeminine individuals share significant preferences in feminine facial features with control respondents. However, transfeminine patients were more averse to traditionally masculine features on a feminine face and more accepting of the most traditionally feminine versions of nasal contours. Understanding these differences can facilitate surgical planning between surgeons and patients and potentially improve patient satisfaction.

How Do We Predict a Patient's Disease Course and Whether They Will Respond to Specific Treatments?

Gastroenterologists will be all too familiar with the difficult decisions that managing inflammatory bowel disease often presents. How aggressively should I treat this patient? Do I expect them to have a mild or aggressive form of disease? Do they need a biologic? If so, which one? And when should I start it? The reality is that the answers that would be right for one patient might be disastrous for another. The growing therapeutic armamentarium will only make these decisions more difficult, and yet, we have seen how other specialties have begun to use the molecular heterogeneity in their diseases to provide some answers. Here, we review the progress that has been made in predicting the future for any given patient with inflammatory bowel disease-whether that is the course of disease that they will experience or whether or not they will respond to, or indeed tolerate, a particular therapy.

Artificial Intelligence for Pre-operative Diagnosis of Malignant Thyroid Nodules Based on Sonographic Features and Cytology Category.

BACKGROUND: Current diagnosis and classification of thyroid nodules are susceptible to subjective factors. Despite widespread use of ultrasonography (USG) and fine needle aspiration cytology (FNAC) to assess thyroid nodules, the interpretation of results is nuanced and requires specialist endocrine surgery input. Using readily available pre-operative data, the aims of this study were to develop artificial intelligence (AI) models to classify nodules into likely benign or malignant and to compare the diagnostic performance of the models. METHODS: Patients undergoing surgery for thyroid nodules between 2010 and 2020 were recruited from our institution's database into training and testing groups. Demographics, serum TSH level, cytology, ultrasonography features and histopathology data were extracted. The training group USG images were re-reviewed by a study radiologist experienced in thyroid USG, who reported the relevant features and supplemented with data extracted from existing reports to reduce sampling bias. Testing group USG features were extracted solely from existing reports to reflect real-life practice of a non-thyroid specialist. We developed four AI models based on classification algorithms (k-Nearest Neighbour, Support Vector Machine, Decision Tree, Naïve Bayes) and evaluated their diagnostic performance of thyroid malignancy. RESULTS: In the training group (n = 857), 75% were female and 27% of cases were malignant. The testing group (n = 198) consisted of 77% females and 17% malignant cases. Mean age was 54.7 ± 16.2 years for the training group and 50.1 ± 17.4 years for the testing group. Following validation with the testing group, support vector machine classifier was found to perform best in predicting final histopathology with an accuracy of 89%, sensitivity 89%, specificity 83%, F-score 94% and AUROC 0.86. CONCLUSION: We have developed a first of its kind, pilot AI model that can accurately predict malignancy in thyroid nodules using USG features, FNAC, demographics and serum TSH. There is potential for a model like this to be used as a decision support tool in under-resourced areas as well as by non-thyroid specialists.

Differential effects of obesity on visceral versus subcutaneous adipose arteries: role of shear-activated Kir2.1 and alterations to the glycocalyx.

Obesity imposes well-established deficits to endothelial function. We recently showed that obesity-induced endothelial dysfunction was mediated by disruption of the glycocalyx and a loss of Kir channel flow sensitivity. However, obesity-induced endothelial dysfunction is not observed in all vascular beds: visceral adipose arteries (VAAs), but not subcutaneous adipose arteries (SAAs), exhibit endothelial dysfunction. To determine whether differences in SAA versus VAA endothelial function observed in obesity are attributed to differential impairment of Kir channels and alterations to the glycocalyx, mice were fed a normal rodent diet, or a high-fat Western diet to induce obesity. Flow-induced vasodilation (FIV) was measured ex vivo. Functional downregulation of endothelial Kir2.1 was accomplished by transducing adipose arteries from mice and obese humans with adenovirus containing a dominant-negative Kir2.1 construct. Kir function was tested in freshly isolated endothelial cells seeded in a flow chamber for electrophysiological recordings under fluid shear. Atomic force microscopy was used to assess biophysical properties of the glycocalyx. Endothelial dysfunction was observed in VAAs of obese mice and humans. Downregulating Kir2.1 blunted FIV in SAAs, but had no effect on VAAs, from obese mice and humans. Obesity abolished Kir shear sensitivity in VAA endothelial cells and significantly altered the VAA glycocalyx. In contrast, Kir shear sensitivity was observed in SAA endothelial cells from obese mice and effects on SAA glycocalyx were less pronounced. We reveal distinct differences in Kir function and alterations to the glycocalyx that we propose contribute to the dichotomy in SAA versus VAA endothelial function with obesity.NEW & NOTEWORTHY We identified a role for endothelial Kir2.1 in the differences observed in VAA versus SAA endothelial function with obesity. The endothelial glycocalyx, a regulator of Kir activation by shear, is unequally perturbed in VAAs as compared with SAAs, which we propose results in a near complete loss of VAA endothelial Kir shear sensitivity and endothelial dysfunction. We propose that these differences underly the preserved endothelial function of SAA in obese mice and humans.

High-throughput functional analysis of lncRNA core promoters elucidates rules governing tissue specificity.

Transcription initiates at both coding and noncoding genomic elements, including mRNA and long noncoding RNA (lncRNA) core promoters and enhancer RNAs (eRNAs). However, each class has a different expression profile with lncRNAs and eRNAs being the most tissue specific. How these complex differences in expression profiles and tissue specificities are encoded in a single DNA sequence remains unresolved. Here, we address this question using computational approaches and massively parallel reporter assays (MPRA) surveying hundreds of promoters and enhancers. We find that both divergent lncRNA and mRNA core promoters have higher capacities to drive transcription than nondivergent lncRNA and mRNA core promoters, respectively. Conversely, intergenic lncRNAs (lincRNAs) and eRNAs have lower capacities to drive transcription and are more tissue specific than divergent genes. This higher tissue specificity is strongly associated with having less complex transcription factor (TF) motif profiles at the core promoter. We experimentally validated these findings by testing both engineered single-nucleotide deletions and human single-nucleotide polymorphisms (SNPs) in MPRA. In both cases, we observe that single nucleotides associated with many motifs are important drivers of promoter activity. Thus, we suggest that high TF motif density serves as a robust mechanism to increase promoter activity at the expense of tissue specificity. Moreover, we find that 22% of common SNPs in core promoter regions have significant regulatory effects. Collectively, our findings show that high TF motif density provides redundancy and increases promoter activity at the expense of tissue specificity, suggesting that specificity of expression may be regulated by simplicity of motif usage.

Preoperative mineralocorticoid receptor antagonist reduces postoperative hyperkalaemia in patients with Conn syndrome.

BACKGROUND: The preoperative use of mineralocorticoid receptor antagonists (MRA) in patients with unilateral forms of primary aldosteronism (PA) is not standardized. The current Endocrine Society Guidelines do not specifically recommend MRA treatment before surgery. It is unclear whether preoperative MRA can optimize perioperative blood pressure and potassium control, and reduce the incidence of postoperative hyperkalaemia. OBJECTIVE: This study aimed to investigate the effect of MRA on the incidence of postoperative hyperkalaemia in addition to perioperative blood pressure and potassium concentration in patients undergoing unilateral adrenalectomy for the treatment of PA. DESIGN: Retrospective cohort study. SETTING: Tertiary referral centres, Victoria, Australia. PATIENTS: A total of 96 patients who were diagnosed with unilateral forms of PA: 73 patients ('MRA' group) received preoperative MRA while 23 patients ('No-MRA' group) did not. RESULTS: The prevalence of postoperative hyperkalaemia was significantly higher in the 'No-MRA' group at 2-4 weeks after surgery, compared to the 'MRA' group (35% vs. 11%, p = .014). In a logistic regression, the use of MRA significantly predicted a lower incidence of postoperative hyperkalaemia after adjusting for age, sex, baseline aldosterone-to-renin ratio, potassium and preoperative eGFR. Before surgery, patients in the 'MRA' group had normalized blood pressure and potassium concentration requiring fewer antihypertensive medications and no potassium supplements. CONCLUSION: Preoperative MRA use was associated with optimal perioperative blood pressure and normalized serum potassium in addition to a lower incidence of postoperative hyperkalaemia. MRA should be considered standard treatment for patients awaiting surgery for PA.

Unexpected deaths after endocrine surgery: learning from rare events using a national audit of surgical mortality.

BACKGROUND: The mortality rate is low in endocrine surgery, making it a difficult outcome to use for quality improvement in individual units. Lessons from population data sets are of value in improving outcomes. Data from the Australian and New Zealand Audit of Surgical Mortality (ANZASM) were used here to understand and elucidate potential systems issues that may contribute to preventable deaths. METHODS: ANZASM data relating to 30-day mortality after thyroidectomy, parathyroidectomy, and adrenalectomy from 2009 to 2020 were reviewed. Mortality rates were calculated using billing data. Thematic analysis of independent assessor reports was conducted to produce a coding framework. RESULTS: A total of 67 deaths were reported, with an estimated mortality rate of 0.03-0.07 per cent (38 for thyroidectomy (0.03-0.06 per cent), 16 for parathyroidectomy (0.03-0.06 per cent), 13 for adrenalectomy (0.15-0.33 per cent)). Twenty-seven deaths (40 per cent) were precipitated by clinically significant adverse events, and 18 (27 per cent) were judged to be preventable by independent ANZASM assessors. Recurrent themes included inadequate preoperative assessment, lack of anticipation of intraoperative pitfalls, and failure to recognize and effectively address postoperative complications. Several novel themes were reiterated, such as occult ischaemic heart disease associated with death after parathyroid surgery, unexpected intraoperative difficulties from adrenal metastasis, and complications due to anticoagulation therapy after thyroid surgery. CONCLUSION: This study represents a large-scale national report of deaths after endocrine surgery and provides insights into these rare events. Although the overall mortality rate is low, 27 per cent of deaths involved systems issues that were preventable following independent peer review.

Hypotension in Posterior Retroperitoneoscopic Versus Transperitoneal Laparoscopic Adrenalectomy.

INTRODUCTION: Despite preoperative optimization, hemodynamic instability can be a major challenge during adrenalectomy. Even brief episodes of intraoperative hypotension can be associated with ischemia-reperfusion injury. This study aimed to compare intraoperative hemodynamic parameters between posterior retroperitoneoscopic adrenalectomy (PRA) and transperitoneal laparoscopic adrenalectomy (TPA). METHODS: This is a retrospective study of patients undergoing PRA and TPA without conversion or concomitant intraabdominal pathology from 2008 to 2019. The primary outcome was intraoperative hypotension defined by mean arterial pressure <60 mm Hg or the need for ≥1 intravenous vasopressors at least 30 min after anesthetic induction. RESULTS: Overall, 108 patients met the inclusion criteria; 33 (30.6%) had pheochromocytoma, 26 (24.1%) had aldosterone excess, 8 (7.4%) had corticosteroid excess, and 41 (38.0%) had nonfunctioning adrenal tumors. Of these, 68 (63.0%) underwent PRA and 40 (37.0%) underwent TPA. Age, sex, body mass index, preinduction blood pressure, number of preoperative antihypertensives, and histopathological diagnosis were similar in the two groups. Tumor size was greater in the TPA group. The presence of pheochromocytoma was an independent risk factor for hypotension. Multivariate analysis revealed that PRA was associated with a higher risk of experiencing a mean arterial pressure <60 mm Hg (odds ratio 4.44, 95% confidence interval 1.27-15.54, P = 0.02) and the need for ≥1 intravenous vasopressors (odds ratio 9.97, 95% confidence interval 3.34-29.78, P < 0.001) compared with TPA. CONCLUSIONS: Although PRA offers several advantages over TPA, it carries a greater risk of intraoperative hypotension. A prospective trial is required to validate these findings. Nevertheless, institution of risk reduction strategies is encouraged to be considered for individuals undergoing PRA.

Pacemaker following transcatheter aortic valve replacement and tricuspid regurgitation: A single-center experience.

BACKGROUND: As transcatheter aortic valve replacement (TAVR) procedures increase, more data is available on the development of conduction abnormalities requiring permanent pacemaker (PPM) implantation post-TAVR. Mechanistically, new pacemaker implantation and incidence of associated tricuspid regurgitation (TR) post-TAVR is not well understood. Studies have evaluated the predictability of patient anatomy towards risk for needing permanent pacemaker (PPM) post-TAVR; however, little has been reported on new PPM and TR in patients post-TAVR. METHODS: This retrospective study identified patients at our health system who underwent PPM following TAVR from January 2014 to June 2018. Data from both TAVR and PPM procedures as well as patient demographics were collected. Echocardiographic data before TAVR, between TAVR and PPM placement, and the most recent echocardiogram at the time of chart review were analyzed. RESULTS: Of 796 patients who underwent TAVR between January 2014 and June 2018, 89 patients (11%) subsequently required PPM. Out of the 89 patients who required PPM implantation, 82 patients had pre-TAVR and 2-year post-TAVR echocardiographic imaging data. At baseline, 22% (18/82) of patients had at least moderate TR. At 2-year post-TAVR echocardiographic imaging follow-up; 27% (22/82) of patients had at least moderate TR. Subgroup analysis was performed according to the TAVR valve size implanted. In patients who received a TAVR device < 29 mm in diameter in size, 25% (11/44) had worsening TR. In patients who received a TAVR device ≥ 29 mm in diameter, 37% (14/38) had worsening TR. CONCLUSION: We have demonstrated a patient population that may be predisposed to developing worsening TR and right heart function after TAVR and Pacemaker implantation.

Complexity of Online Facial Feminization Surgery Material Exceeds Patient Health Literacy.

The increase in healthcare coverage for transgender populations has made facial feminization surgeries (FFS) more accessible. Majority of patients interested in surgery regularly check online medical information to help understand surgical procedures, risks, and recovery. National health organizations recommend that patient information material should be written at a sixth-grade-reading level, but online material often surpasses patient health literacy. This study evaluates the readability of online FFS resources. An Internet search of the top 100 Web sites was conducted using the keywords "facial feminization surgery." Web sites were analyzed for relevant patient information articles on FFS and categorized into health care and nonhealth care groups. Readability examinations were performed for written text using the Automated Readability Index, Coleman-Liau Index, Flesch-Kincaid Grade Level, Gunning Fog Index, and Simple Measure of Gobbledygook Index. Statistical analysis was performed using 2-tailed z tests, with statistical significance set at P≤0.05. A total of 100 articles from 100 Web sites were examined. The average readability for all online FFS resources was at a 12th-grade-writing level. Articles from health care organizations were at a 13th-grade-reading level and nonhealth care organization articles were at a 12th-grade-reading level (P<0.01). Online patient information for FFS is more complex than nationally recommended writing levels, which may interfere with patient decision making and outcomes. Patient resources for FFS should be written at a lower reading level to promote patient education, satisfaction, and compliance.

Multisite investigation of strategies for the clinical implementation of pre-emptive pharmacogenetic testing.

PURPOSE: The increased availability of clinical pharmacogenetic (PGx) guidelines and decreasing costs for genetic testing have slowly led to increased utilization of PGx testing in clinical practice. Pre-emptive PGx testing, where testing is performed in advance of drug prescribing, is one means to ensure results are available at the time of prescribing decisions. However, the most efficient and effective methods to clinically implement this strategy remain unclear. METHODS: In this report, we compare and contrast implementation strategies for pre-emptive PGx testing by 15 early-adopter institutions. We surveyed these groups, collecting data on testing approaches, team composition, and workflow dynamics, in addition to estimated third-party reimbursement rates. RESULTS: We found that while pre-emptive PGx testing models varied across sites, institutions shared several commonalities, including methods to identify patients eligible for testing, involvement of a precision medicine clinical team in program leadership, and the implementation of pharmacogenes with Clinical Pharmacogenetics Implementation Consortium guidelines available. Finally, while reimbursement rate data were difficult to obtain, the data available suggested that reimbursement rates for pre-emptive PGx testing remain low. CONCLUSION: These findings should inform the establishment of future implementation efforts at institutions considering a pre-emptive PGx testing program.

Measurement of Spin Dynamics in a Layered Nickelate Using X-Ray Photon Correlation Spectroscopy: Evidence for Intrinsic Destabilization of Incommensurate Stripes at Low Temperatures.

We study the temporal stability of stripe-type spin order in a layered nickelate with x-ray photon correlation spectroscopy and observe fluctuations on timescales of tens of minutes over a wide temperature range. These fluctuations show an anomalous temperature dependence: they slow down at intermediate temperatures and speed up on both heating and cooling. This behavior appears to be directly connected with spatial correlations: stripes fluctuate slowly when stripe correlation lengths are large and become faster when spatial correlations decrease. A low-temperature decay of nickelate stripe correlations, reminiscent of what occurs in cuprates as a result of a competition between stripes and superconductivity, hence occurs via loss of both spatial and temporal correlations.

Short- and mid-term outcomes in percutaneous mitral valve replacement using balloon expandable valves.

BACKGROUND: Due to elevated surgical risk, transcatheter mitral valve replacement (TMVR) is used as an alternative for treating failed bioprosthetic valves, annuloplasty repairs and mitral annular calcification (MAC). We report the procedural and longitudinal outcomes for each subtype: Mitral valve-in-valve (MVIV), mitral valve-in-ring (MViR), and valve-in-MAC (ViMAC). METHODS: Consecutive patients undergoing TMVR from October 2013 to December 2019 were assessed. Patients at high risk for left ventricular outflow tract obstruction had either alcohol septal ablation or intentional laceration of the anterior leaflet (LAMPOON). RESULTS: Eight-eight patients underwent TMVR; 38 MViV, 31 MViR, and 19 ViMAC procedures were performed. The median Society of Thoracic Surgery 30-day predicted risk of mortality was 8.2% (IQR 5.2, 19.9) for all. Sapien 3 (78%) and transseptal access (98%) were utilized in most cases. All-cause in-hospital mortality, technical, and procedural success were 8%, 83%, and 66% respectively. Median follow up was 1.4 years (IQR 0.5-2.9 years) and overall survival was 40% at 4 years. Differential survival rates were observed with MViV doing the best, followed by MViR and ViMAC having a <20% survival at 4 years. After adjusting for co-variates, MViV procedure was the strongest predictor of survival (HR 0.24 [95% CI 0.079-0.7]). CONCLUSION: TMVR is performed in at high-risk patients with attenuated long-term survival. MViV has the best success and survival rate, but long-term survival in MViR and ViMAC is guarded.

Patient Reported Experience on Consenting for Surgery - Elective Versus Emergency Patients.

INTRODUCTION: Informed consent for surgery is a medical and legal requirement, but completing these does not necessarily translate to high patient satisfaction. This patient-reported experience study aimed to examine the surgical consent process, comparing the patients' experience in elective and emergency settings. METHODS: Over a 6-mo period, postoperative patients at The Alfred Hospital Breast and Endocrine Surgical Unit were invited to participate in a survey on the surgical consent process - including perceived priorities, information provided and overall experience. Standard statistical techniques were used, with a significant P-value of < 0.05. RESULTS: A total of 412 patients were invited, with 130 (32%) responses. More patients underwent elective surgery (N= 90, 69%) than emergency surgery (N = 40, 31%). Emergency patients were more likely to sign the consent form regardless of its contents (93% versus 39%, P < 0.001) and more likely to be influenced by external pressures (63% versus 1%, P < 0.001). Elective patients were more likely to want to discuss their surgery with a senior surgeon (74% versus 23%, P < 0.001) and more likely to seek advice from external sources (83% versus 10%, P < 0.001). Both groups highly valued the opportunity to ask questions (67% versus 63%, P = 0.65). CONCLUSION: This study shows patients have a range of different priorities in preparation for surgery. Therefore, each consent process should be patient-specific, and focus on providing the patient with quality resources that inform decision-making.

Impairment of Flow-Sensitive Inwardly Rectifying K+ Channels via Disruption of Glycocalyx Mediates Obesity-Induced Endothelial Dysfunction.

OBJECTIVE: To determine if endothelial dysfunction in a mouse model of diet-induced obesity and in obese humans is mediated by the suppression of endothelial Kir (inwardly rectifying K+) channels. Approach and Results: Endothelial dysfunction, observed as reduced dilations to flow, occurred after feeding mice a high-fat, Western diet for 8 weeks. The functional downregulation of endothelial Kir2.1 using dominant-negative Kir2.1 construct resulted in substantial reductions in the response to flow in mesenteric arteries of lean mice, whereas no effect was observed in arteries of obese mice. Overexpressing wild-type-Kir2.1 in endothelium of arteries from obese mice resulted in full recovery of the flow response. Exposing freshly isolated endothelial cells to fluid shear during patch-clamp electrophysiology revealed that the flow-sensitivity of Kir was virtually abolished in cells from obese mice. Atomic force microscopy revealed that the endothelial glycocalyx was stiffer and the thickness of the glycocalyx layer reduced in arteries from obese mice. We also identified that the length of the glycocalyx is critical to the flow-activation of Kir. Overexpressing Kir2.1 in endothelium of arteries from obese mice restored flow- and heparanase-sensitivity, indicating an important role for heparan sulfates in the flow-activation of Kir. Furthermore, the Kir2.1-dependent component of flow-induced vasodilation was lost in the endothelium of resistance arteries of obese humans obtained from biopsies collected during bariatric surgery. CONCLUSIONS: We conclude that obesity-induced impairment of flow-induced vasodilation is attributed to the loss of flow-sensitivity of endothelial Kir channels and propose that the latter is mediated by the biophysical alterations of the glycocalyx.