Citations

Renal artery stenosis (RAS) is a common public health problem, affecting up to 7% of individuals over 65 years of age. Optimal therapy for patients with RAS is controversial, as recent studies have indicated that revascularization via stenting fails to improve renal function or patient survival. Medical therapy is associated with high morbidity and mortality, primarily due to cardiovascular disease. However, morphologic correlates for reversibility following restoration of blood flow have not been adequately defined. The purpose of this study was to standardize an experimental model for the restoration of blood flow, employing a well characterized murine RAS model. Total N=10 C57B/6J male mice were used. RAS was induced on the right renal artery by putting a polytetrafluoroethylene cuff (N=6) and sham surgery was performed without cuff placement (N=4). To determine the feasibly of restoring the blood flow to the stenotic kidney, cuff was taken off at day 7 following the RAS surgery. Blood pressure measurements were done using tail cuff method at baseline, before taking cuff off and then every week until harvest. MRI images were captured using an Avance DRX 700WB spectrometer with a vertical 16.4 T wide bore magnet connected with the imaging tools at baseline, 3 days after putting the cuff on or sham surgery, and at 3 weeks after cuff off. The animals were harvested at day 28 following surgery and kidney weights are obtained. Baseline renal perfusion (1018±41.6 ml/100g/min) was significantly reduced (634.7±141.3 ml/100g/min, p=0.01) following cuff placement. Perfusion was restored to normal (955±59.8 ml/100g/min) at 28 days following cuff removal at 7 days after RAS. Similarly, volume of the stenotic kidney was significantly reduced (at day 3 after RAS 172±8.6 mm 3 ) compared to baseline (206.3±4.4 mm 3 , p=0.0007). There was no significant difference in perfusion and volume after cuff off compared to baseline and sham groups. There was no significant difference in kidney weight between cuff‐off (167± 4.7 mg) and sham groups (163±9.95 mg). Also, there was no difference in heart weight between cuff off (150±3.7mg) and sham groups (148±6.7mg). We conclude that this model will provide the basis for determining the latest time point associated with recovery of renal structure and potential histopathologic markers that predict preservation of renal structure following cuff removal. Also, this model would provide the basis for determining efficacy of additional therapies to target inflammation, etc. to widen the “therapeutic window” during which restoration of renal blood flow is beneficial. Support or Funding Information This project is funded by National Institutes of health, NIAID R01 AI100911.

CX3CR1 is a chemokine receptor widely expressed on inflammatory cells which recognizes CX3CL1 (fractalkine) a membrane bound chemokine that can function as an adhesion receptor. Blockade of CX3CR1 has been shown to reduce inflammation and chronic renal injury in a variety of models. We sought to determine whether CX3CR1 deficient mice are protected from chronic renal injury in experimental renal artery stenosis (RAS). RAS was established in CX3CR1 knockout (KO) and wild‐type C57BLK/6 mice (WT) through placement of a cuff on the right renal artery. Sham mice underwent manipulation of the right renal artery without placement of a cuff. As assessed by MRI, mean flow reduction was 65.3% in the WT mice and 66.5% in the KO mice (p=ns) subjected to RAS. Both KO and WT mice developed hypertension, which persisted throughout the 4 week study. KO and WT mice developed a similar degree of cardiac hypertrophy (166 mg WT, 172 mg KO, p=ns; 117 mg sham). Stenotic kidney weights were reduced to a similar extent in KO and WT mice (sham 148 mg, WT 83 mg, KO 53 mg) with compensatory hypertrophy of the contralateral kidney (sham 136 mg, WT 170 mg, KO 206 mg, p=0.0016 KO vs WT). The stenotic kidney of both KO and WT mice developed severe atrophy, characterized by flattening and simplification of tubular epithelium and influx of interstitial T cells and macrophages (32.8 % cortical surface area for WT and 76.4% cortical surface area for KO, p=0.01). The contralateral kidney was without significant histopathologic abnormality. We conclude that development of severe atrophy is not prevented in CX3CR1 KO mice, indicating that alternative pathways contribute to chronic renal damage in this model. Support or Funding Information This work is supported by NIH Grant R01 AI100911.

Abstract Introduction: First pass effect (FPE), achievement of complete recanalization (mTICI 2c/3) with a single pass, is a significant predictor of favorable outcomes for endovascular treatment (EVT) in large vessel occlusion stroke (LVO). However, data concerning the impact on functional outcomes and predictors of FPE in medium vessel occlusions (MeVO) are scarce. Patients and Methods: We conducted an international retrospective study on MeVO cases. Multivariable logistic modeling was used to establish independent predictors of FPE. Clinical and safety outcomes were compared between the two study groups (FPE vs non-FPE) using logistic regression models. Good outcome was defined as modified Rankin Scale 0–2 at 3 months. Results: Eight hundred thirty-six patients with a final mTICI ⩾ 2b were included in this analysis. FPE was observed in 302 patients (36.1%). In multivariable analysis, hypertension (aOR 1.55, 95% CI 1.10–2.20) and lower baseline NIHSS score (aOR 0.95, 95% CI 0.93–0.97) were independently associated with an FPE. Good outcomes were more common in the FPE versus non-FPE group (72.8% vs 52.8%), and FPE was independently associated with favorable outcome (aOR 2.20, 95% CI 1.59–3.05). 90-day mortality and intracranial hemorrhage (ICH) were significantly lower in the FPE group, 0.43 (95% CI, 0.25–0.72) and 0.55 (95% CI, 0.39–0.77), respectively. Conclusion: Over 2/3 of patients with MeVOs and FPE in our cohort had a favorable outcome at 90 days. FPE is independently associated with favorable outcomes, it may reduce the risk of any intracranial hemorrhage, and 3-month mortality.

OBJECTIVE The Woven EndoBridge (WEB) device is an intrasaccular flow disruptor designed for wide-necked bifurcation aneurysms. These aneurysms may require the use of a concomitant stent. The objective of this study was to determine the clinical and radiological outcomes of patients undergoing stent-assisted WEB treatment. In addition, the authors also sought to determine the predictors of a concomitant stent in aneurysms treated with the WEB device. METHODS The data for this study were taken from the WorldWideWEB Consortium, an international multicenter cohort including patients treated with the WEB device. Aneurysms were classified into two groups based on treatment: stent-assisted WEB and WEB device alone. The authors compared clinical and radiological outcomes of both groups. Univariable and multivariable binary logistic regression analyses were performed to determine factors that predispose to stent use. RESULTS The study included 691 intracranial aneurysms (31 with stents and 660 without stents) treated with the WEB device. The adequate occlusion status did not differ between the two groups at the latest follow-up (83.3% vs 85.6%, p = 0.915). Patients who underwent stenting had more thromboembolic (32.3% vs 6.5%, p < 0.001) and procedural (16.1% vs 3.0%, p < 0.001) complications. Aneurysms treated with a concomitant stent had wider necks, greater heights, and lower dome-to-neck ratios. Increasing neck size was the only significant predictor for stent use. CONCLUSIONS This study demonstrates that there is no difference in the degree of aneurysm occlusion between the two groups; however, complications were more frequent in the stent group. In addition, a wider aneurysm neck predisposes to stent assistance in WEB-treated aneurysms.

Abstract Purpose Clinical practice guidelines recommend altering neurotoxic chemotherapy treatment in patients experiencing intolerable chemotherapy-induced peripheral neuropathy (CIPN). The primary objective of this survey was to understand patient’s perspectives on altering neurotoxic chemotherapy treatment, including their perceptions of the benefits of preventing irreversible CIPN and the risks of reducing treatment efficacy.Methods A cross-sectional online survey was distributed via social networks to patients who were currently receiving or had previously received neurotoxic chemotherapy for cancer. Survey results were analyzed using descriptive statistics and qualitative analysis.Results Following data cleaning, 447 participants were included in the analysis. The median age was 57 years, 93% were white, and most were from the United Kingdom (53%) or United States of America (38%). Most participants who were currently or recently treated expected some CIPN symptom resolution (86%), but 45% of those who had completed treatment more than a year ago reported experiencing no symptom resolution. Participants reported that they would discontinue chemotherapy treatment for less severe CIPN if they knew their symptoms would be permanent than if symptoms would disappear after treatment. Most patients stated that the decision to alter chemotherapy or not was usually made collaboratively between the patient and their treating clinician (61%). The most common reason participants were reluctant to talk with their clinician about CIPN was fear that treatment would be altered. Participants noted a need for improved understanding of CIPN symptoms and their permanence, better patient education relating to CIPN prior to and after treatment, and greater clinician understanding and empathy around CIPN.Conclusions This survey highlights the importance of shared decision-making, including a consideration of both the long-term benefits and risks of altering neurotoxic chemotherapy treatment due to CIPN. Additional work is needed to develop decision aids and other communication tools that can be used to improve shared decision making and help patients with cancer achieve their treatment goals.

AbstractThe phosphatidylinositol glycan anchor biosynthesis class O protein (PIGO) enzyme is an important step in the biosynthesis of glycosylphosphatidylinositol (GPI), which is essential for the membrane anchoring of several proteins. Bi‐allelic pathogenic variants in PIGO lead to a congenital disorder of glycosylation (CDG) characterized by global developmental delay, an increase in serum alkaline phosphatase levels, congenital anomalies including anorectal, genitourinary, and limb malformations in most patients; this phenotype has been alternately called “Mabry syndrome” or “hyperphosphatasia with impaired intellectual development syndrome 2.” We report a 22‐month‐old female with PIGO deficiency caused by novel PIGO variants. In addition to the Mabry syndrome phenotype, our patient's clinical picture was complicated by intermittent hypoglycemia with signs of functional hyperinsulinism, severe secretory diarrhea, and osteopenia with a pathological fracture, thus, potentially expanding the known phenotype of this disorder, although more studies are necessary to confirm these associations. We also provide an updated review of the literature, and propose unifying the nomenclature of PIGO deficiency as “PIGO‐CDG,” which reflects its pathophysiology and position in the broad scope of metabolic disorders and congenital disorders of glycosylation.

ImportanceLip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning.ObjectiveTo analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates.Evidence ReviewThe incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019.FindingsIn 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia.Conclusions and RelevanceIn this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts.

ObjectiveApproximately one third of individuals worldwide have not received a COVID‐19 vaccine. Although studies have investigated risk factors linked to severe COVID‐19 among unvaccinated people with rheumatic diseases (RDs), we know less about whether these factors changed as the pandemic progressed. We aimed to identify risk factors associated with severe COVID‐19 in unvaccinated individuals in different pandemic epochs corresponding to major variants of concern.MethodsPatients with RDs and COVID‐19 were entered into the COVID‐19 Global Rheumatology Alliance Registry between March 2020 and June 2022. An ordinal logistic regression model (not hospitalized, hospitalized, and death) was used with date of COVID‐19 diagnosis, age, sex, race and/or ethnicity, comorbidities, RD activity, medications, and the human development index (HDI) as covariates. The main analysis included all unvaccinated patients across COVID‐19 pandemic epochs; subanalyses stratified patients according to RD types.ResultsAmong 19,256 unvaccinated people with RDs and COVID‐19, those who were older, male, had more comorbidities, used glucocorticoids, had higher disease activity, or lived in lower HDI regions had worse outcomes across epochs. For those with rheumatoid arthritis, sulfasalazine and B‐cell–depleting therapy were associated with worse outcomes, and tumor necrosis factor inhibitors were associated with improved outcomes. In those with connective tissue disease or vasculitis, B‐cell–depleting therapy was associated with worse outcomes.ConclusionRisk factors for severe COVID‐19 outcomes were similar throughout pandemic epochs in unvaccinated people with RDs. Ongoing efforts, including vaccination, are needed to reduce COVID‐19 severity in this population, particularly in those with medical and social vulnerabilities identified in this study.