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Background Male sex and old age are risk factors for severe coronavirus disease 2019, but the intersection of sex and aging on antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines has not been characterized. Methods Plasma samples were collected from older adults (aged 75–98 years) before and after 3 doses of SARS-CoV-2 mRNA vaccination, and from younger adults (aged 18–74 years) post-dose 2, for comparison. Antibody binding to SARS-CoV-2 antigens (spike protein [S], S receptor-binding domain, and nucleocapsid), functional activity against S, and live-virus neutralization were measured against the vaccine virus and the Alpha, Delta, and Omicron variants of concern (VOCs). Results Vaccination induced greater antibody titers in older females than in older males, with both age and frailty associated with reduced antibody responses in males but not females. Responses declined significantly in the 6 months after the second dose. The third dose restored functional antibody responses and eliminated disparities caused by sex, age, and frailty in older adults. Responses to the VOCs, particularly the Omicron variant, were significantly reduced relative to the vaccine virus, with older males having lower titers to the VOCs than older females. Older adults had lower responses to the vaccine and VOC viruses than younger adults, with greater disparities in males than in females. Conclusions Older and frail males may be more vulnerable to breakthrough infections owing to low antibody responses before receipt of a third vaccine dose. Promoting third dose coverage in older adults, especially males, is crucial to protecting this vulnerable population.

Despite the prominence of rare-earth complexes to act as Lewis acid catalysts in organic synthesis, the comprehensive measure of the Lewis acid strength of such compounds has yet to be performed due to incompatibilities with existing methods. We report our results in measurement of a sequence of lanthanide triflates via our recently established fluorescent Lewis adduct (FLA) method. The persistence in solution of these Lewis acids as solvated coordination complexes is accurately measurable by the FLA method. However, several of the rare-earth species exhibit fluorescence quenching, which may potentially inhibit the measurement. Nevertheless, meaningful FLA measurements were still possible, and the results correspond to both periodic trends and were even consistent with previous correlated reported data.

BackgroundMale sex and old age are risk factors for severe COVID-19, but the intersection of sex and aging on antibody responses to SARS-CoV-2 vaccines has not been characterized.MethodsPlasma samples were collected from older adults (75-98 years) before and after three doses of SARS-CoV-2 mRNA vaccination, and from younger adults (18-74 years) post-dose two, for comparison. Antibody binding to SARS-CoV-2 antigens (spike protein [S], S-receptor binding domain [S-RBD], and nucleocapsid [N]) and functional activity against S were measured against the vaccine virus and variants of concern (VOC).ResultsVaccination induced greater antibody titers in older females than males, with both age and frailty associated with reduced antibody responses to vaccine antigens in males, but not females. ACE2 binding inhibition declined more than anti-S or anti-S-RBD IgG in the six months following the second dose (28-fold vs. 12- and 11-fold decreases in titer). The third dose restored functional antibody responses and eliminated disparities caused by sex, age, and frailty in older adults. Responses to the VOC were significantly reduced relative to the vaccine virus, with older males having lower titers to the VOC than females. Older adults had lower responses to the vaccine and VOC viruses than younger adults, with disparities being greater in males than females.ConclusionOlder and frail males may be more vulnerable to breakthrough infections due to low antibody responses before receipt of a third vaccine dose. Promoting third dose coverage in older adults, especially males, is crucial to protecting this vulnerable population.Brief summarySARS-CoV-2 mRNA vaccination induces greater antibody response in older females than males, and age and frailty reduce responses in males only. These effects are eliminated by a third vaccine dose, highlighting the need for third dose coverage, especially in older males.

BACKGROUNDWhile most children who contract COVID-19 experience mild disease, high-risk children with underlying conditions may develop severe disease, requiring interventions. Kinetics of antibodies transferred via COVID-19 convalescent plasma early in disease have not been characterized.METHODSIn this study, high-risk children were prospectively enrolled to receive high-titer COVID-19 convalescent plasma (1:320 anti-spike IgG; Euroimmun). Passive transfer of antibodies and endogenous antibody production were serially evaluated for up to 2 months after transfusion. Commercial and research ELISA assays, virus neutralization assays, high-throughput phage-display assay utilizing a coronavirus epitope library, and pharmacokinetic analyses were performed.RESULTSFourteen high-risk children (median age, 7.5 years) received high-titer COVID-19 convalescent plasma, 9 children within 5 days (range, 2-7 days) of symptom onset and 5 children within 4 days (range, 3-5 days) after exposure to SARS-CoV-2. There were no serious adverse events related to transfusion. Antibodies against SARS-CoV-2 were transferred from the donor to the recipient, but antibody titers declined by 14-21 days, with a 15.1-day half-life for spike protein IgG. Donor plasma had significant neutralization capacity, which was transferred to the recipient. However, as early as 30 minutes after transfusion, recipient plasma neutralization titers were 6.2% (range, 5.9%-6.7%) of donor titers.CONCLUSIONConvalescent plasma transfused to high-risk children appears to be safe, with expected antibody kinetics, regardless of weight or age. However, current use of convalescent plasma in high-risk children achieves neutralizing capacity, which may protect against severe disease but is unlikely to provide lasting protection.Trial registrationClinicalTrials.gov NCT04377672.FundingThe state of Maryland, Bloomberg Philanthropies, and the NIH (grants R01-AI153349, R01-AI145435-A1, K08-AI139371-A1, and T32-AI052071).

PROMUS Element (PE) Plus post-approval study was a large prospective, observational, all-comers study designed to evaluate the safety and performance of a thin-strut platinum chromium everolimus-eluting PE Plus stent in everyday clinical practice. A total of 2,683 "real-world" patients with limited clinical or anatomic exclusion criteria were enrolled at 52 clinical sites in the United States. The study met its primary end point of 12-month cardiac death or myocardial infarction (CD/MI) compared with a prespecified performance goal (p

We describe the synthesis of alkynyl phosphanes of the type R2P-C≡C-C(OCH3)Ph2, (R = Ph, Cy) and investigate their transformation to geminally substituted phosphonium borato-allene zwitterions upon their reaction with B(C6F5)3. The mechanism for this transformation was studied experimentally and by density functional theory computations (DFT), suggesting the intermediacy of an unsaturated 3-coordinate phosphonium electrophile akin to a methylene phosphonium cation.

DNA methylation is a reversible process catalyzed by the ten-eleven translocation (TET) family of enzymes (TET1, TET2, TET3) that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Altered patterns of 5hmC and 5mC are widely reported in human cancers and loss of 5hmC correlates with poor prognosis. Understanding the mechanisms leading to 5hmC loss and its role in oncogenesis will advance the development of epigenetic-based therapeutics. We show that TET2 loss associates with GBM stem cells and correlates with poor survival of GBM patients. We further identify a SOX2:miR-10b-5p:TET2 axis that represses TET2 expression, represses 5hmC, increases 5mC levels and induces GBM cell stemness and tumor-propagating potential. In vivo delivery of a miR-10b-5p inhibitor that normalizes TET2 expression and 5hmC levels inhibits tumor growth and prolongs survival of animals bearing pre-established orthotopic GBM xenografts. These findings highlight the importance of TET2 and 5hmC loss in Sox2-driven oncogenesis and their potential for therapeutic targeting.

Adult female mice generate greater vaccine-induced immunity and protection than their male counterparts, but this female advantage is lost with age. We hypothesized that treatment of aged female mice with exogenous estradiol would improve vaccine-induced antibody responses and protection from both pulmonary infection and disease after live influenza virus challenge. To investigate this, adult (2–3 months old) and aged (17–18 months old) female C57BL/6 mice were implanted with either empty (placebo) capsules or capsules loaded with 17β-estradiol (E2) hormone, and then vaccinated with mouse-adapted A/California/04/09 (ma2009 H1N1) vaccine. Total IgG and neutralizing antibody titers (nAb) were quantified using blood samples collected post vaccination. >1 month post vaccination, mice were challenged intranasally with ma2009 H1N1 drift variant virus. A subset of mice was euthanized at 3 days post challenge to collect lungs and measure infectious virus titer. Another subset was followed for 14 days to measure changes in body mass as a measure of disease severity. We found that aged female mice treated with E2 produced significantly greater IgG and nAb responses compared to placebo-treated aged females, and the responses of E2-treated aged females were comparable to the antibody responses generated in adult females. Treatment with E2 also reduced morbidity, but not pulmonary virus titers, following live virus challenge. Our data suggest that estrogen replacement in aged female mice improves their humoral immune response to influenza vaccination and protects them from severe disease. Supported by U54AG062333

Objectives This study sought to compare outcomes of patients enrolled in the NCSI (National Cardiogenic Shock Initiative) trial who were treated using a revascularization strategy of percutaneous coronary intervention (PCI) of multivessel PCI (MV-PCI) versus culprit-vessel PCI (CV-PCI). Background In patients with multivessel disease who present with acute myocardial infarction and cardiogenic shock (AMICS), intervening on the nonculprit vessel is controversial. There are conflicting published reports and lack of evidence, particularly in patients treated with early mechanical circulatory support (MCS). Methods From July 2016 to December 2019, patients who presented with AMICS to 57 participating hospitals were included in this analysis. All patients were treated using a standard shock protocol emphasizing early MCS, revascularization, and invasive hemodynamic monitoring. Patients with multivessel coronary artery disease (MVCAD) were analyzed according to whether CV-PCI or MV-PCI was undertaken during the index procedure. Results Of 198 patients with MVCAD, 126 underwent MV-PCI (64%) and 72 underwent CV-PCI (36%). Demographics between the cohorts were similar with respect to age, sex, history of diabetes, prior PCI or coronary artery bypass grafting, and prior history of myocardial infarction. Patients who underwent MV-PCI had a trend toward more severe impairment of cardiac output and worse lactate clearance on presentation, and cardiac performance was significantly worse at 12 h. However, 24 h from PCI, the hemometabolic derangements were similar. Survival and rates of acute kidney injury were not significantly different between groups (69.8% MV-PCI vs. 65.3% CV-PCI; p = 0.51; and 29.9% vs. 34.2%; p = 0.64, respectively). Conclusions In patients with MVCAD presenting with AMICS treated with early MCS, revascularization of nonculprit lesions was associated with similar hospital survival and acute kidney injury when compared with culprit-only PCI. Selective nonculprit PCI can be safety performed in AMICS in patients supported with mechanical circulatory support.

We sought to explore the relationship between obesity and overactive bladder (OAB) and to review the available literature that supports weight loss as a means to alter OAB severity and bother. Over the past 15 years, several population-based human studies and animal models have identified obesity as a risk factor for the development of OAB. The bariatric surgery literature demonstrates that substantial weight loss following some form of gastric bypass can lead to at least subjective improvement in OAB symptoms. Ongoing research seeks to further elucidate the role of anti-inflammatory agents, anti-oxidants, and β3-receptor agonists in obesity-associated OAB. The currently available literature has identified obesity as a risk factor for the development OAB. Data taken from the bariatric surgery literature indicates that surgical weight loss can lead to a significant improvement in OAB severity and bother. Future studies will determine if less dramatic weight changes can lead to significant and sustained changes in OAB parameters. Based on the available literature, clinicians should start to counsel their obese patients with OAB that weight loss can help improve their OAB severity and bother.

Multi-potent stem-like cells (i.e. cancer stem cells, CSCs) are critical determinants of tumor propagation, therapeutic resistance, and recurrence in glioblastoma (GBM). Modifications in chromatin architecture play a fundamental role in the tumor cell phenotype of GBM. The polycomb repressor complex 2 (PRC2) is a key histone modifier that supports multi-potency and oncogenesis via H3K27 trimethylation (H3K27me3). Understanding how these epigenetic modifications cooperatively drive cancer cell stemness should unveil new targets for therapeutic development in GBM. Using a combination of next-generation sequencing, bioinformatics, and molecular approaches we identified EZH2, the catalytic domain of the PRC2 complex, as a critical mediator of reprograming events in GBM cells. We found that EZH2 is highly induced in response to transgenic Oct4/Sox2 with global increases in H3K27me3. Pharmacological inhibition of EZH2 diminishes self-renewal capacity of GBM neurospheres concurrent with a reduction in gene expression levels of markers and drivers of stemness. Furthermore, we identified and validated a set of 6 putative tumor suppressor genes repressed by Oct4 and Sox2 in a PRC2-dependent manner. We identified miR-217 as an EZH2 regulator in GBM cells and miR-217 reconstitution using advanced nanoparticle formulations re-activates the PRC2-repressed tumor suppressors, inhibited tumor growth and enhanced the effects of ionizing radiation in an orthotopic model of GBM. Taken together, these data show that PRC2-mediated chromatin changes in H3K27me3 help regulate the stem-cell phenotype induced by Oct4 and Sox2 in GBM cells and predict that targeting EZH2 could have therapeutic benefit in GBM.

The National Cardiogenic Shock Initiative is a single-arm, prospective, multicenter study to assess outcomes associated with early mechanical circulatory support (MCS) in patients presenting with acute myocardial infarction and cardiogenic shock (AMICS) treated with percutaneous coronary intervention (PCI).Between July 2016 and February 2019, 35 sites participated and enrolled into the study. All centers agreed to treat patients with AMICS using a standard protocol emphasizing invasive hemodynamic monitoring and rapid initiation of MCS. Inclusion and exclusion criteria mimicked those of the "SHOCK" trial with an additional exclusion criteria of intra-aortic balloon pump counter-pulsation prior to MCS.A total of 171 consecutive patients were enrolled. Patients had an average age of 63 years, 77% were male, and 68% were admitted with AMICS. About 83% of patients were on vasopressors or inotropes, 20% had a witnessed out of hospital cardiac arrest, 29% had in-hospital cardiac arrest, and 10% were under active cardiopulmonary resuscitation during MCS implantation. In accordance with the protocol, 74% of patients had MCS implanted prior to PCI. Right heart catheterization was performed in 92%. About 78% of patients presented with ST-elevation myocardial infarction with average door to support times of 85 ± 63 min and door to balloon times of 87 ± 58 min. Survival to discharge was 72%. Creatinine ≥2, lactate4, cardiac power output (CPO)0.6 W, and age ≥ 70 years were predictors of mortality. Lactate and CPO measurements at 12-24 hr reliably predicted overall mortality postindex procedure.In contemporary practice, use of a shock protocol emphasizing best practices is associated with improved outcomes.

The PROMUS Element Plus US Post-Approval Study (PE-Plus PAS) was a prospective, open-label, multicenter, observational study designed to examine outcomes in everyday clinical practice in patients treated with everolimus-eluting, platinum-chromium PROMUS Element Plus stents at 52 centers in the United States. This is the first report of results from this large study. The primary end point of the PE-Plus PAS was 12-month cardiac death or myocardial infarction in the more restricted population of "PLATINUM-like" patients pooled from the PE-Plus PAS, PE-PROVE (PROMUS Element European post-approval study), and PLATINUM Workhorse/Small Vessel trials. Additional clinical end points were tested in the overall PE-Plus PAS patient population. Of the 2,683 patients enrolled in PE-Plus PAS, 70% were men, mean age was 64 years, 33% had diabetes, and 29% were "PLATINUM-like." Among the PLATINUM-like patients, 12-month cardiac death or myocardial infarction was 1.8% (33 of 1,855) with an upper 1-sided 95% confidence interval of 2.3%, which was significantly less than the prespecified performance goal of 3.2% (pnoninferiority

A randomized controlled trial of N-acetylcysteine to prevent contrast nephropathy in cardiac angiography. Background Contrast nephropathy (CN) is a common cause of renal dysfunction after cardiac angiography. Recently, N-acetylcysteine (NAC) has been found to reduce the risk of CN after CT imaging with contrast enhancement. The purpose of the current study was to evaluate the efficacy of NAC for the prevention of CN in the setting of cardiac angiography. Methods Eligible patients were those undergoing cardiac angiography with serum creatinine>1.7 mg/dL. Patients were randomized to one of two groups: Group 1, IV hydration and NAC, 1200 mg one hour before angiography, and a second dose 3 hours after; Group 2, IV hydration and placebo. CN was defined as an increase of 0.5 mg/dL in serum creatinine. Results Seventy-nine patients completed the study. There were no significant differences between the groups in baseline characteristics, duration of angiography, mean volume of dye infused or mean IV hydration. Contrast nephropathy developed in 24.0% of subjects, 26.3% NAC, and 22.0% placebo ( P = NS). Among subjects with diabetes mellitus, there was no significant difference in the rate of CN between the groups (42.1% NAC, 27.8% placebo; P = 0.09). The independent predictors of CN risk were diabetes mellitus and preexisting chronic renal insufficiency. Conclusions NAC was not effective for the prevention of CN after cardiac angiography.

Background and objectives: Lupus nephritis is a classic immune complex glomerulonephritis. In contrast, antineutrophil cytoplasmic antibodies are associated with necrotizing and crescentic glomerulonephritis, in the absence of significant immune deposits. Antineutrophil cytoplasmic antibodies are detected by indirect immunofluorescence in 20% of patients with systemic lupus erythematosus. We report 10 cases of necrotizing and crescentic lupus nephritis with antineutrophil cytoplasmic antibody seropositivity. Design, setting, participants, & measurements: Ten patients with systemic lupus erythematosus, antineutrophil cytoplasmic antibody positivity, and renal biopsy findings of lupus nephritis and antineutrophil cytoplasmic antibody–associated glomerulonephritis were identified. The clinical features, pathologic findings, and outcomes are described. Results: The cohort consisted of eight women and two men with a mean age of 48.4 yr. Perinuclear antineutrophil cytoplasmic antibody was detected by indirect immunofluorescence in nine patients. Four of the nine patients and the single remaining patient were found to have myeloperoxidase–antineutrophil cytoplasmic antibodies by enzyme-linked immunosorbent assay. Clinical presentation included proteinuria, hematuria, and acute renal insufficiency, with mean creatinine of 7.1 mg/dl. All biopsies exhibited prominent necrosis and crescents with absent or rare subendothelial deposits and were interpreted as lupus nephritis and antineutrophil cytoplasmic antibody–associated glomerulonephritis. All patients received cyclophosphamide and prednisone. Three patients died of infectious complications. Among the remaining seven patients, five achieved a complete or near-complete remission, one had a remission with subsequent relapse, and one had no response to therapy. Conclusion: Antineutrophil cytoplasmic antibody–associated necrotizing and crescentic glomerulonephritis may occur superimposed on lupus nephritis. In patients with lupus nephritis and biopsy findings of prominent necrosis and crescent formation in the absence of significant endocapillary proliferation or subendothelial deposits, antineutrophil cytoplasmic antibody testing by enzyme-linked immunosorbent assay is recommended.

A patient with pyelonephritis developed multiorgan failure resulting in death. Clinical findings were consistent with multiple endocrine neoplasia type II, with bilateral pheochromocytomas identified by computed tomography scan. We hypothesize that either the infection or the administration of radiocontrast media led to a massive release of catecholamines from the pheochromocytomas. As a result, tissue perfusion was severely compromised, and multiorgan failure developed. This exceedingly rare complication of pheochromocytoma has been termed pheochromocytoma multisystem crisis.