Citations

Introduction: Fibromuscular dysplasia (FMD) is a non-atherosclerotic arteriopathy of unknown etiology, afflicting mostly middle-aged women. It is characterized by stenotic lesions of the vascular wall in middle-size arteries, sometimes associated with dissection, aneurysm or tortuosity. Renovascular hypertension is a major presentation of FMD and 50–85% of FMD patients are hypertensive. Methods & Results: We report results from the first genome-wide association meta-analysis of six studies including 1556 FMD cases and 7100 controls. We identified four robustly associated loci (PHACTR1, LRP1, ATP2B1, and LIMA1). Using colocalization and transcriptome-wide association analysis with arterial expression datasets, we found PHACTR1, LRP1 and ATP2B1 as target genes at FMD loci and identified one additional locus (SLC24A3). We analysed chromatin accessibility in artery-derived primary cells and found that FMD associated variants were located in arterial specific regulatory elements active in smooth muscle cells. Target genes were broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. All FMD loci were also associated to at least one blood pressure trait. Colocalization analysis supported the same genetic variants to cause association to FMD and systolic blood pressure at PHACTR1, ATP2B1 and LIMA1 loci, and for FMD and pulse pressure at PHACTR1, LRP1 and ATP2B1 loci. Using genome-wide genetic correlation, we found a significant association between FMD and blood pressure. Mendelian Randomization analysis supported genetically determined systolic blood pressure to significantly increase the risk of FMD. However, we confirmed using adjusted and stratified analyses that hypertension status alone was not driving the association with FMD at top loci. We also report an important genetic overlap of FMD with migraine, intracranial aneurysm, coronary artery disease and myocardial infarction. Conclusion: Our study confirms FMD as a polygenic disease following a complex genetic mode of inheritance. We find that FMD shares an important part of its genetic basis with blood pressure regulation, involving in particular several genes related to intracellular calcium homeostasis and vascular smooth muscle contraction. These results are consistent with previous studies showing systemic alterations in vascular contraction in FMD patients, even outside of affected arterial beds. While the mechanisms through which FMD may cause renovascular hypertension are well known, further studies will be required to determine how alterations in vascular contraction may lead to the arterial remodeling observed in FMD.

Abstract Treatment options for glioblastoma remain limited, particularly for those who are not eligible for traditional resection, whether due to lesion location or inability to tolerate open craniotomy. Maximal-safe resection followed by radiation with concurrent and adjuvant temozolomide offers the best outcomes for patients. Unfortunately, not all tumors are amenable to conventional surgical resection at the time of diagnosis with only about 1/3 of patients able to receive a gross-total resection and 15-25% of patients receiving biopsy only, thus reducing their projected overall survival to 9 months. Laser interstitial thermal therapy (LITT) is a minimally invasive, cytoreductive tool, that has demonstrated safety as a surgical approach to treat primary brain tumors. METHODS Data from LAANTERN prospective multicenter registry (NCT02392078) was analyzed to determine clinical outcomes for patients with new and recurrent IDH wild-type glioblastoma (N=89). Demographics, intraprocedural data, adverse events, KPS, health-economics, and survival data were prospectively collected then analyzed separately for newly diagnosed GBM (N=29) and recurrent GBM (N=60). RESULTS Median overall-survival was 9.73 months (95% CI: 5.16, 15.91) for newly diagnosed patients and median post-procedure survival was 8.97 (6.94, 12.36) months for recurrent patients. Median overall-survival for newly diagnosed patients receiving post-LITT chemoradiotherapy was 16.14 months (6.11, not reached). The median length of hospital stay was 50 hours and 80% of patients were discharged to home. CONCLUSIONS LITT offers an effective cytoreductive approach for patients with newly diagnosed and recurrent IDH wild-type glioblastoma. Importantly, its use in newly diagnosed patients who receive post-LITT chemoradiotherapy leads to a median OS similar to that of patients treated with conventional surgical resection. LITT remains an important alternative for patients with inoperable tumors or those not amenable to resection. Enrollment in LAANTERN is ongoing and these cohorts will be revisited as data continues to mature. Benefits beyond cytoreduction are also being actively explored.

AbstractObjectivesDysfunction in smell or taste is well recognized phenomenon in patients infected with SARS‐CoV‐2. This study aimed to quantify the incidence and associated co‐morbidities of reported olfactory or gustatory dysfunction in patients who tested positive for SARS‐CoV‐2.MethodsFrom March 23, 2020 through July 31, 2020, 192,683 patients were tested for SARS‐CoV‐2 at Mayo Clinic. These patients with a positive test were contacted via telephone by physicians at Mayo Clinic and information gathered on patient demographics, comorbidities, symptoms and clinical risk stratification based on these factors.ResultsTwo thousand two hundred and fifty patients tested positive for SARS‐CoV‐2 (1.2%). Six hundred and sixty‐seven (29.6%) of these patients reported loss of smell or taste. Factors found to be correlated with reporting loss of smell or taste on multivariate analysis were: younger age, female sex, or symptoms of chest pain or tightness, cough, or headache and lower clinical risk category. Coronary artery disease (CAD) was associated with not reporting loss of taste or smell.ConclusionOf 2250 patients testing positive for SARS‐CoV‐2 at Mayo Clinic, 667 reported loss of taste and smell. Patients who reported loss of smell or taste were younger, female and more likely to report cough, chest pain, headache, or history of chronic obstructive pulmonary disease (COPD), but overall had fewer high‐risk comorbidities. Those who were older, male, and a reported history of CAD were less likely to report chemosensory dysfunction. Our data are the largest single institution data reporting COVID‐19 associated loss of smell or taste, and the first to associate COPD and CAD as factors that affect rates of reported chemosensory dysfunction.Level of evidenceIIB.

Abstract Background Antispike monoclonal antibodies are recommended for early treatment of high-risk persons with mild to moderate coronavirus disease 2019 (COVID-19). However, clinical outcomes of their use during the severe acute respiratory syndrome coronavirus 2 Omicron wave are limited. Methods This is a descriptive retrospective study of high-risk adult patients who received treatment with sotrovimab (January 1–March 20, 2022) or bebtelovimab (March 21–April 30, 2022). The primary outcome was the proportion of patients who progressed to severe outcome within 30 days after receiving antispike-neutralizing monoclonal antibody infusion. Results A total of 3872 high-risk patients (median age, 62.7 years; 41.1% male) with mild to moderate COVID-19 received sotrovimab (n = 2182) or bebtelovimab (n = 1690). Among sotrovimab-treated patients, the most common comorbidities were an immunosuppressed condition (46.7%), hypertension (38.2%), and diabetes (21.2%). The rates of severe outcome, intensive care unit (ICU) admission, and mortality were 2.2%, 1.0%, and 0.4%, respectively, after sotrovimab infusion. Among bebtelovimab-treated patients, the most common comorbidities were hypertension (42.7%), diabetes (17.1%), and an immunosuppressed condition (17.0%). The rates of severe disease, ICU admission, and mortality were 1.3%, 0.5%, and 0.2%, respectively, after bebtelovimab infusion. Older age, immunosuppressed status, and several comorbidities were associated with severe disease progression, while COVID-19 vaccination was associated with lower risk. No anaphylaxis was reported during monoclonal antibody infusion. Conclusions This real-world analysis of a large cohort of high-risk patients demonstrates low rates of severe disease after treatment with sotrovimab during the era dominated by Omicron B.1.1.529 and after treatment with bebtelovimab during the era dominated by BA.2 and Omicron subvariants.

Abstract Objectives To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). Methods A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification. Results Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration. Conclusions Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT.

Abstract The effectiveness of bebtelovimab in real-world settings has not been assessed. In this retrospective cohort study of 3607 high-risk patients, bebtelovimab was used more commonly than nirmatrelvir-ritonavir for treatment of coronavirus disease 2019 (COVID-19) among older patients, immunosuppressed patients, and those with multiple comorbid conditions. Despite its use in patients with multiple comorbid conditions, the rate of progression to severe disease after bebtelovimab (1.4% [95% confidence interval, 1.2%–1.7%]) was not significantly different from that for nirmatrelvir-ritonavir treatment (1.2% [.8%–1.5%]). Our findings support the emergency use authorization of bebtelovimab for treatment of COVID-19 during the Omicron epoch dominated by BA.2 and subvariants.

Abstract Background Solid organ transplant recipients (SOTRs) are at high‐risk for severe infection from severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Anti‐spike monoclonal antibodies are currently utilized under emergency use authorization to prevent hospitalization in high‐risk individuals with coronavirus disease 2019 (COVID‐19), including SOTRs. However, clinical data for bebtelovimab, the sole currently available anti‐spike monoclonal antibody for COVID‐19, is limited. Methods We conducted a retrospective cohort study of adult SOTRs diagnosed with mild‐to‐moderate COVID‐19 from January 2022 through May 2022 who received either bebtelovimab or sotrovimab. The primary outcome was COVID‐19‐related hospitalization within 30 days of COVID‐19 diagnosis. Data were analyzed with Fisher's exact test. Results Among 361 SOTRs, 92 (25.5%) received bebtelovimab and 269 (74.5%) received sotrovimab. The most common organ transplant was a kidney (42.4%). SOTRs who received bebtelovimab had a higher proportion who had received a booster SARS‐CoV‐2 vaccine dose and had received their last vaccination dose more recently. Eleven (3.0%) SOTRs were hospitalized, and rates of hospitalization were similar between monoclonal antibody groups (3.3% versus 3.0%; p > .99). Three patients required admission to an intensive care unit, all of who received sotrovimab. Four (1.1%) patients died within 30 days of COVID‐19 diagnosis, two from each group. Conclusions SOTRs with mild‐to‐moderate COVID‐19 who received bebtelovimab had similar rates of COVID‐19‐related hospitalization as those who received sotrovimab. While differences in vaccination rates and viral subvariants could act as confounders, bebtelovimab appears to be of similar effectiveness as sotrovimab. image

Background: Lytic or malpositioned tunnels may require bone grafting during revision anterior cruciate ligament reconstruction (rACLR) surgery. Patient characteristics and effects of grafting on outcomes after rACLR are not well described. Purpose: To describe preoperative characteristics, intraoperative findings, and 2-year outcomes for patients with rACLR undergoing bone grafting procedures compared with patients with rACLR without grafting. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 1234 patients who underwent rACLR were prospectively enrolled between 2006 and 2011. Baseline revision and 2-year characteristics, surgical technique, pathology, treatment, and patient-reported outcome instruments (International Knee Documentation Committee [IKDC], Knee injury and Osteoarthritis Outcome Score [KOOS], Western Ontario and McMaster Universities Osteoarthritis Index, and Marx Activity Rating Scale [Marx]) were collected, as well as subsequent surgery information, if applicable. The chi-square and analysis of variance tests were used to compare group characteristics. Results: A total of 159 patients (13%) underwent tunnel grafting—64 (5%) patients underwent 1-stage and 95 (8%) underwent 2-stage grafting. Grafting was isolated to the femur in 31 (2.5%) patients, the tibia in 40 (3%) patients, and combined in 88 patients (7%). Baseline KOOS Quality of Life (QoL) and Marx activity scores were significantly lower in the 2-stage group compared with the no bone grafting group ( P≤ .001). Patients who required 2-stage grafting had more previous ACLRs ( P < .001) and were less likely to have received a bone–patellar tendon–bone or a soft tissue autograft at primary ACLR procedure ( P≤ .021) compared with the no bone grafting group. For current rACLR, patients undergoing either 1-stage or 2-stage bone grafting were more likely to receive a bone–patellar tendon–bone allograft ( P≤ .008) and less likely to receive a soft tissue autograft ( P≤ .003) compared with the no bone grafting group. At 2-year follow-up of 1052 (85%) patients, we found inferior outcomes in the 2-stage bone grafting group (IKDC score = 68; KOOS QoL score = 44; KOOS Sport/Recreation score = 65; and Marx activity score = 3) compared with the no bone grafting group (IKDC score = 77; KOOS QoL score = 63; KOOS Sport/Recreation score = 75; and Marx activity score = 7) ( P≤ .01). The 1-stage bone graft group did not significantly differ compared with the no bone grafting group. Conclusion: Tunnel bone grafting was performed in 13% of our rACLR cohort, with 8% undergoing 2-stage surgery. Patients treated with 2-stage grafting had inferior baseline and 2-year patient-reported outcomes and activity levels compared with patients not undergoing bone grafting. Patients treated with 1-stage grafting had similar baseline and 2-year patient-reported outcomes and activity levels compared with patients not undergoing bone grafting.