A Phase III Randomized Controlled Trial of Plitidepsin, a Marine-Derived Compound, in Hospitalized Adults With Moderate COVID-19.

Background: Plitidepsin has shown potent preclinical activity against severe acute respiratory syndrome coronavirus 2 and was generally well tolerated in a phase I trial of hospitalized patients with coronavirus disease 2019 (COVID-19). NEPTUNO, a phase III, multicenter, randomized, controlled trial, was designed to evaluate the efficacy and safety of plitidepsin in the management of moderate COVID-19 in hospitalized adult patients.

Methods: Included patients had documented severe acute respiratory syndrome coronavirus 2 infection, required oxygen therapy, and had adequate organ function.

Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia.

Background: Angiopoietin-like 3 (ANGPTL3) inhibits lipoprotein and endothelial lipases and hepatic uptake of triglyceride-rich lipoprotein remnants. loss-of-function carriers have lower levels of triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and non-HDL cholesterol and a lower risk of atherosclerotic cardiovascular disease than noncarriers. Zodasiran is an RNA interference (RNAi) therapy targeting expression of in the liver.

Autoantibodies Targeting Nephrin in Podocytopathies.

Background: Minimal change disease and primary focal segmental glomerulosclerosis in adults, along with idiopathic nephrotic syndrome in children, are immune-mediated podocytopathies that lead to nephrotic syndrome. Autoantibodies targeting nephrin have been found in patients with minimal change disease, but their clinical and pathophysiological roles are unclear.

Methods: We conducted a multicenter study to analyze antinephrin autoantibodies in adults with glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, antineutrophil cytoplasmic antibody-associated glomerulonephritis, and lupus nephritis, as well as in children with idiopathic nephrotic syndrome and in controls.

Long-term evaluation of clinical success and safety of omadacycline in nontuberculous mycobacteria infections: a retrospective, multicenter cohort of real-world health outcomes.

Infections due to nontuberculous mycobacteria (NTM) continue to increase in prevalence, leading to problematic clinical outcomes. Omadacycline (OMC) is an aminomethylcycline antibiotic with FDA orphan drug and fast-track designations for pulmonary NTM infections, including (MAB). This multicenter retrospective study across 16 U.

Association of Plasma Biomarkers of Alzheimer Disease With Cognition and Medical Comorbidities in a Biracial Cohort.

Background And Objectives: Recent advances in blood-based biomarkers offer the potential to revolutionize the diagnosis and management of Alzheimer disease (AD), but additional research in diverse populations is critical. We assessed the profiles of blood-based AD biomarkers and their relationships to cognition and common medical comorbidities in a biracial cohort.

Methods: Participants were evaluated through the Mayo Clinic Jacksonville Alzheimer Disease Research Center and matched on age, sex, and cognitive status.

Antihypertensives and Antibiotics: Impact on Intestinal Dysfunction and Hypertension.

Gut dysfunction has emerged as a contributor to hypertension, the leading risk factor for disease globally, including stroke, heart failure, and kidney disease. This is underpinned by breakdown of the homeostatic relationship connecting intestinal epithelial function, the microbiota and immune responses. Antihypertensive medications have been shown to reverse intestinal dysfunction and gut dysbiosis.

Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial.

The multimodal activities of farnesoid X receptor (FXR) agonists make this class an attractive option to treat nonalcoholic steatohepatitis. The safety and efficacy of tropifexor, an FXR agonist, in a randomized, multicenter, double-blind, three-part adaptive design, phase 2 study, in patients with nonalcoholic steatohepatitis were therefore assessed. In Parts A + B, 198 patients were randomized to receive tropifexor (10-90 μg) or placebo for 12 weeks.

Perfusion Imaging and Clinical Outcome in Acute Minor Stroke With Large Vessel Occlusion.

Background: Whether bridging therapy (intravenous thrombolysis [IVT] followed by mechanical thrombectomy) is superior to IVT alone in minor stroke with large vessel occlusion is unknown. Perfusion imaging may identify subsets of large vessel occlusion-related minor stroke patients with distinct response to bridging therapy.

Methods: We conducted a multicenter international observational study of consecutive IVT-treated patients with minor stroke (National Institutes of Health Stroke Scale score ≤5) who had an anterior circulation large vessel occlusion and perfusion imaging performed before IVT, with a subset undergoing immediate thrombectomy.

Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation.

COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11.

Hypertensive Disorders of Pregnancy With and Without Prepregnancy Hypertension Are Associated With Incident Maternal Kidney Disease Subsequent to Delivery.

Background: Maternal morbidity and mortality are related to prepregnancy hypertensive disease and hypertensive disorders of pregnancy (HDP) including preeclampsia (41.1% of HDP), eclampsia (1.3% of HDP), and gestational hypertension (39.

Systemic Delivery of mLIGHT-Armed Myxoma Virus Is Therapeutic for Later-Stage Syngeneic Murine Lung Metastatic Osteosarcoma.

Cancers that metastasize to the lungs represent a major challenge in both basic and clinical cancer research. Oncolytic viruses are newly emerging options but successful delivery and choice of appropriate therapeutic armings are two critical issues. Using an immunocompetent murine K7M2-luc lung metastases model, the efficacy of MYXV armed with murine LIGHT (TNFSF14/CD258) expressed under virus-specific early/late promoter was tested in an advanced later-stage disease K7M2-luc model.

Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women.

Background: Safe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preventing HIV infection.

Methods: We conducted a randomized, double-blind, double-dummy, noninferiority trial to compare long-acting injectable cabotegravir (CAB-LA, an integrase strand-transfer inhibitor [INSTI]) at a dose of 600 mg, given intramuscularly every 8 weeks, with daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for the prevention of HIV infection in at-risk cisgender men who have sex with men (MSM) and in at-risk transgender women who have sex with men. Participants were randomly assigned (1:1) to receive one of the two regimens and were followed for 153 weeks.

Role of Human Papillomavirus Infection in Head and Neck Cancer in Italy: The HPV-AHEAD Study.

Literature on the role of human papillomavirus (HPV) in head and neck cancer (HNC) in Italy is limited, especially for non-oropharyngeal tumours. Within the context of the HPV-AHEAD study, we aimed to assess the prognostic value of different tests or test algorithms judging HPV carcinogenicity in HNC and factors related to HPV positivity at the European Institute of Oncology. We conducted a retrospective cohort study (2000-2010) on a total of 696 primary HNC patients.

Dietary Short-Term Fiber Interventions in Arthritis Patients Increase Systemic SCFA Levels and Regulate Inflammation.

Chronic inflammatory diseases are often initiated and guided by the release of proinflammatory mediators. Rheumatoid arthritis (RA) is caused by an imbalance between the pro- and anti-inflammatory mediators in the joints, thereby favoring chronic inflammation and joint damage. Here, we investigate if short-term high-fiber dietary intervention shifts this towards anti-inflammatory mediators.

Impact of Reperfusion for Nonagenarians Treated by Mechanical Thrombectomy: Insights From the ETIS Registry.

Background and Purpose- Nonagenarians represent a growing stroke population characterized by a higher frailty. Although endovascular therapy (ET) is a cornerstone of the management of acute ischemic stroke related to large vessel occlusion, the benefit of reperfusion among nonagenarians is poorly documented. We aimed to assess the impact of ET-related reperfusion on the functional outcome of reperfusion in this elderly population.

HIV, Cocaine Use, and Hepatitis C Virus: A Triad of Nontraditional Risk Factors for Subclinical Cardiovascular Disease.

Objective: We assessed cross-sectional and longitudinal associations of 3 nontraditional cardiovascular disease risk factors-HIV, cocaine use, and chronic hepatitis C virus infection-with 3 validated markers of subclinical cardiovascular disease: carotid artery plaque, albuminuria, and aortic pulse wave velocity in a well-characterized cohort.

Approach And Results: We measured carotid plaque at baseline and after 24 months, urine albumin/creatinine ratio every 6 months, and pulse wave velocity annually for up to 36 months in a predominantly black cohort of 292 participants (100 HIV negative and 192 HIV positive). Thirty-nine percent had chronic hepatitis C virus infection and 20%, 28%, and 52% were never, past, and current cocaine users, respectively.

Medicago truncatula natural resistance-associated macrophage Protein1 is required for iron uptake by rhizobia-infected nodule cells.

Iron is critical for symbiotic nitrogen fixation (SNF) as a key component of multiple ferroproteins involved in this biological process. In the model legume Medicago truncatula, iron is delivered by the vasculature to the infection/maturation zone (zone II) of the nodule, where it is released to the apoplast. From there, plasma membrane iron transporters move it into rhizobia-containing cells, where iron is used as the cofactor of multiple plant and rhizobial proteins (e.

Laminar shear stress inhibits endothelial cell metabolism via KLF2-mediated repression of PFKFB3.

Objective: Cellular metabolism was recently shown to regulate endothelial cell phenotype profoundly. Whether the atheroprotective biomechanical stimulus elicited by laminar shear stress modulates endothelial cell metabolism is not known.

Approach And Results: Here, we show that laminar flow exposure reduced glucose uptake and mitochondrial content in endothelium.

Bcl10 mediates angiotensin II-induced cardiac damage and electrical remodeling.

Angiotensin (Ang) II is a potent mediator of both hypertension and cardiac damage; however, the mechanisms by which this occur remain unclear. B-cell lymphoma/leukemia 10 (Bcl10) is a member of the CBM signalosome, which links Ang II and nuclear factor-κB signaling. We hypothesized that Bcl10 is pivotal in the pathogenesis of Ang II-induced cardiac damage.

A generalized formulation of ion-π electron interactions: role of the nonelectrostatic component and probe of the potential parameter transferability.

The intermolecular potentials for hexafluorobenzene (HFBz) and 1,3,5-trifluorobenzene (TFBz) interacting with alkali (M(+); M = Li, Na, K, Rb, Cs) and halogen (X(-); X = F, Cl, Br, I) ions are provided as a combination of electrostatic and nonelectrostatic terms. The ion-HFBz and ion-TFBz electrostatic components are formulated as a sum of Coulombic potentials associated with the interactions between the ion charge and point charges on the molecular frame, whose distributions are consistent with the permanent quadrupole moment of HFBz and TFBz, respectively. The corresponding nonelectrostatic components are represented as a sum of effective potential functions, each one having a specific physical meaning, related to ion-molecular bond pair interactions.

Trends in electrocatalysis on extended and nanoscale Pt-bimetallic alloy surfaces.

One of the key objectives in fuel-cell technology is to improve and reduce Pt loading as the oxygen-reduction catalyst. Here, we show a fundamental relationship in electrocatalytic trends on Pt(3)M (M=Ni, Co, Fe, Ti, V) surfaces between the experimentally determined surface electronic structure (the d-band centre) and activity for the oxygen-reduction reaction. This relationship exhibits 'volcano-type' behaviour, where the maximum catalytic activity is governed by a balance between adsorption energies of reactive intermediates and surface coverage by spectator (blocking) species.

Chemistry and electrochemistry of the heterodinuclear complex ClPd(dppm)2PtCl: a M-M' bond providing site selectivity.

The heterodinuclear d(9)-d(9) title compound 1, whose crystal structure has been solved, reacts with dppm [bis(diphenylphosphino)methane] in the presence of NaBF4 to generate the salt [ClPd(mu-dppm)2Pt(eta(1)-dppm)][BF4] (2a), which contains a Pt-bound dangling dppm ligand. 2a has been characterized by 1H and 31P NMR, Fourier transform Raman [nu(Pd-Pt) = 138 cm(-1)], and UV-vis spectroscopy [lambda(max)(dsigma-dsigma*) = 366 nm]. In a similar manner, [ClPd(mu-dppm)2Pt(eta(1)-dppm=O)][BF4] (2b), ligated with a dangling phosphine oxide, has been prepared by the addition of dppm=O.

Thermal and electrochemical C-X activation (X = Cl, Br, I) by the strong Lewis acid Pd3(dppm)3(CO)2+ cluster and its catalytic applications.

The stoichiometric and catalytic activations of alkyl halides and acid chlorides by the unsatured Pd(3)(dppm)(3)(CO)(2+) cluster (Pd(3)(2+)) are investigated in detail. A series of alkyl halides (R-X; R = t-Bu, Et, Pr, Bu, allyl; X = Cl, Br, I) react slowly with Pd(3)(2+) to form the corresponding Pd(3)(X)(+) adduct and "R(+)". This activation can proceed much faster if it is electrochemically induced via the formation of the paramagnetic species Pd(3)(+).