Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial.

Patients with obesity-related heart failure with preserved ejection fraction (HFpEF) display circulatory volume expansion and pressure overload contributing to cardiovascular-kidney end-organ damage. In the SUMMIT trial, patients with HFpEF and obesity were randomized to the long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist tirzepatide (n = 364, 200 women) or placebo (n = 367, 193 women). As reported separately, tirzepatide decreased cardiovascular death or worsening heart failure.

Comorbid neuropathology and atypical presentation of Alzheimer's disease.

Introduction: Alzheimer's disease (AD) neuropathological changes present with amnestic and nonamnestic (atypical) syndromes. The contribution of comorbid neuropathology as a substratum of atypical expression of AD remains under investigated.

Methods: We examined whether atypical AD exhibited increased comorbid neuropathology compared to typical AD and if such neuropathologies contributed to the accelerated clinical decline in atypical AD.

A multicenter randomized controlled feasibility trial of a digital self-management intervention for adults with epilepsy.

Objective: Self-management interventions may enhance health-related quality of life (HRQoL) in epilepsy. However, several barriers often impair their implementation in the real world. Digital interventions may help to overcome some of these barriers.

New onset lymphopenia in patients with relapsing multiple sclerosis switching from long-standing dimethyl fumarate treatment to diroximel fumarate: A case series.

Lymphopenia is a known adverse effect in patients with relapsing multiple sclerosis (RMS) treated with fumaric acids. We present a case series of four patients diagnosed with RMS with prolonged lymphocyte stability on dimethyl fumarate for over 1 year who developed significant lymphopenia after transitioning to diroximel fumarate. This case series highlights the need for further research to elucidate the risk of lymphopenia in patients switching between fumaric acids.

Longitudinal Spin Fluctuations Driving Field-Reinforced Superconductivity in UTe_{2}.

Our measurements of ^{125}Te NMR relaxations reveal an enhancement of electronic spin fluctuations above μ_{0}H^{*}∼15  T, leading to their divergence in the vicinity of the metamagnetic transition at μ_{0}H_{m}≈35  T, below which field-reinforced superconductivity appears when a magnetic field (H) is applied along the crystallographic b axis. The NMR data evidence that these fluctuations are dominantly longitudinal, providing a key to understanding the peculiar superconducting phase diagram in H∥b, where such fluctuations enhance the pairing interactions.

Neurophysiological trajectories in Alzheimer's disease progression.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid- and misfolded tau proteins causing synaptic dysfunction, and progressive neurodegeneration and cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, the trajectories of abnormal neural oscillations in AD progression and their relationship to neurodegeneration and cognitive decline are unknown.

Pharmacological Modulation of the Crosstalk between Aberrant Janus Kinase Signaling and Epigenetic Modifiers of the Histone Deacetylase Family to Treat Cancer.

Hyperactivated Janus kinase (JAK) signaling is an appreciated drug target in human cancers. Numerous mutant JAK molecules as well as inherent and acquired drug resistance mechanisms limit the efficacy of JAK inhibitors (JAKi). There is accumulating evidence that epigenetic mechanisms control JAK-dependent signaling cascades.

Angiopoietin-like 3-derivative LNA043 for cartilage regeneration in osteoarthritis: a randomized phase 1 trial.

Osteoarthritis (OA) is a common, debilitating, chronic disease with no disease-modifying drug approved to date. We discovered LNA043-a derivative of angiopoietin-like 3 (ANGPTL3)-as a potent chondrogenesis inducer using a phenotypic screen with human mesenchymal stem cells. We show that LNA043 promotes chondrogenesis and cartilage matrix synthesis in vitro and regenerates hyaline articular cartilage in preclinical OA and cartilage injury models in vivo.

Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Identifies Abnormal Calf Muscle-Specific Energetics in Peripheral Artery Disease.

Background: Peripheral artery disease (PAD) results in exercise-induced ischemia in leg muscles. Phosphorus (P) magnetic resonance spectroscopy demonstrates prolonged phosphocreatine recovery time constant after exercise in PAD but has low signal to noise, low spatial resolution, and requires multinuclear hardware. Chemical exchange saturation transfer (CEST) is a quantitative magnetic resonance imaging method for imaging substrate (CEST asymmetry [CEST]) concentration by muscle group.

Rapid Campimetry-A Novel Screening Method for Glaucoma Diagnosis.

One of the most important functions of the retina-the enabling of perception of fast movements-is largely suppressed in standard automated perimetry (SAP) and kinetic perimetry (Goldmann) due to slow motion and low contrast between test points and environment. Rapid campimetry integrates fast motion (=10°/4.7 s at 40 cm patient-monitor distance) and high contrast into the visual field (VF) examination in order to facilitate the detection of absolute scotomas.

Allergen Content of Therapeutic Preparations for Allergen-Specific Immunotherapy of European Paper Wasp Venom Allergy.

Allergy to (European paper wasp) venom is of particular relevance in Southern Europe, potentially becoming a threat in other regions in the near future, and can be effectively cured by venom immunotherapy (VIT). As allergen content in extracts may vary and have an impact on diagnostic and therapeutic approaches, the aim was to compare five therapeutic preparations for VIT of venom allergy available in Spain. Products from five different suppliers were analyzed by SDS-PAGE and LC-MS/MS and compared with a reference venom sample.

Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress.

The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells.

Interferon Gamma Secretion of Adaptive and Innate Immune Cells as a Parameter to Describe Leukaemia-Derived Dendritic-Cell-Mediated Immune Responses in Acute Myeloid Leukaemia in vitro.

Introduction: Myeloid leukaemic blasts can be converted into leukaemia-derived dendritic cells (DC), characterised by the simultaneous expression of dendritic- and leukaemia-associated antigens, which have the competence to prime and enhance (leukaemia-specific) immune responses with the whole leukaemic antigen repertoire. To display and further specify dendritic cell (DC)- and DC-mediated immune responses, we analysed the interferon gamma (IFNy) secretion of innate and adaptive immune cells.

Methods: DC/DC were generated from leukaemic whole blood (WB) with (blast)modulatory Kit-I (granulocyte-macrophage colony-stimulating factor [GM-CSF] + Picibanil [OK-432]) and Kit-M (GM-CSF + prostaglandin E1) and were used to stimulate T cell-enriched immunoreactive cells.

Delayed mortality among solid organ transplant recipients hospitalized for COVID-19.

Introduction: Most studies of solid organ transplant (SOT) recipients with COVID-19 focus on outcomes within one month of illness onset. Delayed mortality in SOT recipients hospitalized for COVID-19 has not been fully examined.

Methods: We used data from a multicenter registry to calculate mortality by 90 days following initial SARS-CoV-2 detection in SOT recipients hospitalized for COVID-19 and developed multivariable Cox proportional-hazards models to compare risk factors for death by days 28 and 90.

From Screening to Therapy: Anti-HCV Screening and Linkage to Care in a Network of General Practitioners and a Private Gastroenterology Practice.

(1) Background: Low rates of hepatitis C virus (HCV) diagnosis and sub-optimal linkage to care constitute barriers toward eliminating the infection. In 2012/2013, we showed that HCV screening in primary care detects unknown cases. However, hepatitis C patients may not receive further diagnostics and therapy because they drop out during the referral pathway to secondary care.

A human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade.

Immune checkpoint inhibitors demonstrate clinical activity in many tumor types, however, only a fraction of patients benefit. Combining CD137 agonists with these inhibitors increases anti-tumor activity preclinically, but attempts to translate these observations to the clinic have been hampered by systemic toxicity. Here we describe a human CD137xPD-L1 bispecific antibody, MCLA-145, identified through functional screening of agonist- and immune checkpoint inhibitor arm combinations.

APOSTEL 2.0 Recommendations for Reporting Quantitative Optical Coherence Tomography Studies.

Objective: To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations.

Methods: To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method.

The prognostic value of serum MMP-7 levels in prostate cancer patients who received docetaxel, abiraterone, or enzalutamide therapy.

Objectives: The rapidly changing treatment landscape in metastatic castration-resistant prostate cancer (mCRPC) calls for biomarkers to guide treatment decisions. We recently identified MMP-7 as a potential serum marker for the prediction of response and survival in mCRPC patients who received docetaxel (DOC) chemotherapy. Here, we aimed to test this finding in an independent patient cohort and in addition to explore the prognostic potential of serum MMP-7 in abiraterone (ABI) or enzalutamide (ENZA) treated patients.

Beyond the biopsy: predictors of decision regret and anxiety following preimplantation genetic testing for aneuploidy.

Study Question: What factors are associated with decision regret and anxiety following preimplantation genetic testing for aneuploidy (PGT-A)?

Summary Answer: The majority of patients viewed PGT-A favourably regardless of their outcome; although patients with negative outcomes expressed greater decision regret and anxiety.

What Is Known Already: PGT-A is increasingly utilized in in vitro fertilization (IVF) cycles to aid in embryo selection. Despite the increasing use of PGT-A technology, little is known about patients' experiences and the possible unintended consequences of decision regret and anxiety related to PGT-A outcome.

Effects of Chronic Carbamazepine Treatment on the ECG in Patients with Focal Seizures.

Background And Objectives: Several mechanisms have been proposed for the sudden unexpected death in epilepsy patients, such as cardiac arrhythmias, a decrease in heart rate variability and the use of anti-epileptic drugs (AEDs). Although carbamazepine is commonly used as an AED, the exact working mechanism of this drug as well as its effect on the heart are not completely understood. The aim of this study was to determine whether chronic carbamazepine therapy in patients with focal seizures and impaired awareness has an effect on the electrocardiogram (ECG).

Microcrystalline Tyrosine (MCT): A Depot Adjuvant in Licensed Allergy Immunotherapy Offers New Opportunities in Malaria.

Microcrystalline Tyrosine (MCT) is a widely used proprietary depot excipient in specific immunotherapy for allergy. In the current study we assessed the potential of MCT to serve as an adjuvant in the development of a vaccine against malaria. To this end, we formulated the circumsporozoite protein (CSP) of in MCT and compared the induced immune responses to CSP formulated in PBS or Alum.

Isolation, Co-Crystallization and Structure-Based Characterization of Anabaenopeptins as Highly Potent Inhibitors of Activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa).

Mature thrombin activatable fibrinolysis inhibitor (TAFIa) is a carboxypeptidase that stabilizes fibrin clots by removing C-terminal arginines and lysines from partially degraded fibrin. Inhibition of TAFIa stimulates the degradation of fibrin clots and may help to prevent thrombosis. Applying a lead finding approach based on literature-mining, we discovered that anabaenopeptins, cyclic peptides produced by cyanobacteria, were potent inhibitors of TAFIa with IC50 values as low as 1.

Frequent Dilatation of the Descending Aorta in Children With Hypoplastic Left Heart Syndrome Relates to Decreased Aortic Arch Elasticity.

Background: Patients with hypoplastic left heart syndrome after a Norwood operation show dilatation and reduced distensibility of the reconstructed proximal aorta. Cardiac magnetic resonance imaging (CMR) and angiographic examinations indicate that the native descending aorta (DAo) is also dilated, but this has not been studied in detail.

Methods And Results: Seventy-nine children with hypoplastic left heart syndrome in Fontan circulation (aged 6.