Phase 1 dose expansion and biomarker study assessing first-in-class tumor microenvironment modulator VT1021 in patients with advanced solid tumors.

Background: Preclinical studies have demonstrated that VT1021, a first-in-class therapeutic agent, inhibits tumor growth via stimulation of thrombospondin-1 (TSP-1) and reprograms the tumor microenvironment. We recently reported data from the dose escalation part of a phase I study of VT1021 in solid tumors. Here, we report findings from the dose expansion phase of the same study.

Retinal Dystrophies Associated With Peripherin-2: Genetic Spectrum and Novel Clinical Observations in 241 Patients.

Purpose: To describe the clinical, electrophysiological and genetic spectrum of inherited retinal diseases associated with variants in the PRPH2 gene.

Methods: A total of 241 patients from 168 families across 15 sites in 9 countries with pathogenic or likely pathogenic variants in PRPH2 were included. Records were reviewed for age at symptom onset, visual acuity, full-field ERG, fundus colour photography, fundus autofluorescence (FAF), and SD-OCT.

Postfracture survival in a population-based study of adults aged ≥66 yr: a call to action at hospital discharge.

Postfracture survival rates provide prognostic information but are rarely reported along with other mortality outcomes in adults aged ≥50 yr. The timing of survival change following a fracture also needs to be further elucidated. This population-based, matched-cohort, retrospective database study examined 98 474 patients (73% women) aged ≥66 yr with an index fracture occurring at an osteoporotic site (hip, clinical vertebral, proximal non-hip non-vertebral [pNHNV], and distal non-hip non-vertebral [dNHNV]) from 2011 to 2015, who were matched (1:1) to nonfracture individuals based on sex, age, and comorbidities.

Kappa Free Light Chain Biomarkers Are Efficient for the Diagnosis of Multiple Sclerosis: A Large Multicenter Cohort Study.

Background And Objectives: Kappa free light chains (KFLC) seem to efficiently diagnose MS. However, extensive cohort studies are lacking to establish consensus cut-offs, notably to rule out non-MS autoimmune CNS disorders. Our objectives were to (1) determine diagnostic performances of CSF KFLC, KFLC index, and KFLC intrathecal fraction (IF) threshold values that allow us to separate MS from different CNS disorder control populations and compare them with oligoclonal bands' (OCB) performances and (2) to identify independent factors associated with KFLC quantification in MS.

Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome.

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome.

Evidence for a New Structure in the J/ψp and J/ψp[over ¯] Systems in B_{s}^{0}→J/ψpp[over ¯] Decays.

An amplitude analysis of flavor-untagged B_{s}^{0}→J/ψpp[over ¯] decays is performed using a sample of 797±31 decays reconstructed with the LHCb detector. The data, collected in proton-proton collisions between 2011 and 2018, correspond to an integrated luminosity of 9  fb^{-1}. Evidence for a new structure in the J/ψp and J/ψp[over ¯] systems with a mass of 4337_{-4}^{+7} _{-2}^{+2}  MeV and a width of 29_{-12}^{+26} _{-14}^{+14}  MeV is found, where the first uncertainty is statistical and the second systematic, with a significance in the range of 3.

Long-Term Outcomes After Melody Transcatheter Pulmonary Valve Replacement in the US Investigational Device Exemption Trial.

Background: The Melody valve was developed to extend the useful life of previously implanted right ventricular outflow tract (RVOT) conduits or bioprosthetic pulmonary valves, while preserving RV function and reducing the lifetime burden of surgery for patients with complex congenital heart disease.

Methods: Enrollment for the US Investigational Device Exemption study of the Melody valve began in 2007. Extended follow-up was completed in 2020.

Ultrasound- Versus Fluoroscopy-Guided Strategy for Transfemoral Transcatheter Aortic Valve Replacement Access: A Systematic Review and Meta-Analysis.

[Figure: see text].

Observation of New Resonances Decaying to J/ψK^{+} and J/ψϕ.

The first observation of exotic states with a new quark content cc[over ¯]us[over ¯] decaying to the J/ψK^{+} final state is reported with high significance from an amplitude analysis of the B^{+}→J/ψϕK^{+} decay. The analysis is carried out using proton-proton collision data corresponding to a total integrated luminosity of 9  fb^{-1} collected by the LHCb experiment at center-of-mass energies of 7, 8, and 13 TeV. The most significant state, Z_{cs}(4000)^{+}, has a mass of 4003±6_{-14}^{+4}  MeV, a width of 131±15±26  MeV, and spin parity J^{P}=1^{+}, where the quoted uncertainties are statistical and systematic, respectively.

Retinal alterations in patients with Lafora disease.

Purpose: Lafora disease is a genetic neurodegenerative metabolic disorder caused by insoluble polyglucosan aggregate accumulation throughout the central nervous system and body. The retina is an accessible neural tissue, which may offer alternative methods to assess neurological diseases quickly and noninvasively. In this way, noninvasive imaging may provide a means to characterize neurodegenerative disease, which enables earlier identification and diagnosis of disease and the ability to monitor disease progression.

Impact of Insulin Treatment on the Effect of Eplerenone: Insights From the EMPHASIS-HF Trial.

Background: Patients with heart failure with reduced ejection fraction (HFrEF) and insulin-treated diabetes have a high risk of cardiovascular complications. Mineralocorticoid receptor antagonists may mitigate this risk. We aim to explore the effect of eplerenone on cardiovascular outcomes and all-cause mortality in HFrEF patients with diabetes, including those treated with insulin in the EMPHASIS-HF trial (Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms).

Observation of a New Excited D_{s}^{+} Meson in B^{0}→D^{-}D^{+}K^{+}π^{-} Decays.

Using pp collision data corresponding to an integrated luminosity of 5.4  fb^{-1} collected with the LHCb detector at a center-of-mass energy of 13 TeV, the B^{0}→D^{-}D^{+}K^{+}π^{-} decay is studied. A new excited D_{s}^{+} meson is observed decaying into the D^{+}K^{+}π^{-} final state with large statistical significance.

Vascular Endothelial Damage in the Pathogenesis of Organ Injury in Severe COVID-19.

[Figure: see text].

Arrhythmias in Cardiac Sarcoidosis Bench to Bedside: A Case-Based Review.

Cardiac sarcoidosis is a component of an often multiorgan granulomatous disease of still uncertain cause. It is being recognized with increasing frequency, mainly as the result of heightened awareness and new diagnostic tests, specifically cardiac magnetic resonance imaging and F-fluorodeoxyglucose positron emission tomography scans. The purpose of this case-based review is to highlight the potentially life-saving importance of making the early diagnosis of cardiac sarcoidosis using these new tools and to provide a framework for the optimal care of patients with this disease.

Impacts of Australian Firefighters' On-Call Work Arrangements on the Sleep of Partners.

On-call work arrangements are commonly utilised in the emergency services sector and are consistency associated with inadequate sleep. Despite sleep being a common shared behaviour, studies are yet to assess the impact of on-call work on the sleep of co-sleeping partners. This study aimed to investigate whether frequent 24/7 on-call work impacted the sleep and relationship happiness of firefighters' partners.

fastMRI: A Publicly Available Raw k-Space and DICOM Dataset of Knee Images for Accelerated MR Image Reconstruction Using Machine Learning.

A publicly available dataset containing k-space data as well as Digital Imaging and Communications in Medicine image data of knee images for accelerated MR image reconstruction using machine learning is presented.

Balloon-Expandable Versus Self-Expanding Transcatheter Aortic Valve Replacement: A Propensity-Matched Comparison From the FRANCE-TAVI Registry.

Background: No randomized study powered to compare balloon expandable (BE) with self expanding (SE) transcatheter heart valves (THVs) on individual end points after transcatheter aortic valve replacement has been conducted to date.

Methods: From January 2013 to December 2015, the FRANCE-TAVI nationwide registry (Registry of Aortic Valve Bioprostheses Established by Catheter) included 12 141 patients undergoing BE-THV (Edwards, n=8038) or SE-THV (Medtronic, n=4103) for treatment of native aortic stenosis. Long term mortality status was available in all patients (median 20 months; interquartile range, 14 to 30).

B Cells and T Follicular Helper Cells Mediate Response to Checkpoint Inhibitors in High Mutation Burden Mouse Models of Breast Cancer.

This study identifies mechanisms mediating responses to immune checkpoint inhibitors using mouse models of triple-negative breast cancer. By creating new mammary tumor models, we find that tumor mutation burden and specific immune cells are associated with response. Further, we developed a rich resource of single-cell RNA-seq and bulk mRNA-seq data of immunotherapy-treated and non-treated tumors from sensitive and resistant murine models.

TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence.

Liver injury results in rapid regeneration through hepatocyte proliferation and hypertrophy. However, after acute severe injury, such as acetaminophen poisoning, effective regeneration may fail. We investigated how senescence may underlie this regenerative failure.

Data-Driven Approach to Identify Subgroups of Heart Failure With Reduced Ejection Fraction Patients With Different Prognoses and Aldosterone Antagonist Response Patterns.

Background: Patients with heart failure with reduced ejection fraction have a poor prognosis. The identification of subgroups with different outcomes and treatment response patterns may help to tailor strategies to each individual patient. We present an exploratory study of patients enrolled in the EMPHASIS-HF trial (Eplerenone in Patients With Systolic Heart Failure and Mild Symptoms) using latent class analysis with validation using the EPHESUS trial (Eplerenone, a Selective Aldosterone Blocker, in Patients With Left Ventricular Dysfunction After Myocardial Infarction) to identify subgroups of patients with different prognosis and response to eplerenone therapy.

In vivo [F]-AV-1451 tau-PET imaging in sporadic Creutzfeldt-Jakob disease.

Objective: To determine whether specific patterns of [F]-AV-1451 tau-PET retention are observed in patients with autopsy-proven sporadic Creutzfeldt-Jakob disease (CJD).

Methods: In vivo [F]-AV-1451 PET neuroimaging was performed in 5 patients with sporadic CJD (median age, 66 years [63-74]), and results were compared to cognitively normal (CN) persons (n = 44; median age, 68 years [63-74]) and to participants with very mild Alzheimer disease (AD) dementia (n = 8; median age, 77 years [63-90]). Autopsy was completed in all patients with CJD, confirming the clinical diagnosis and permitting characterization of AD neuropathologic change (ADNC).

Gene-environment interaction and psychiatric disorders: Review and future directions.

Empirical studies suggest that psychiatric disorders result from a complex interplay between genetic and environmental factors. Most evidence for such gene-environment interaction (GxE) is based on single candidate gene studies conducted from a Diathesis-Stress perspective. Recognizing the short-comings of candidate gene studies, GxE research has begun to focus on genome-wide and polygenic approaches as well as drawing on different theoretical concepts underlying GxE, such as Differential Susceptibility.

Modeling Major Adverse Outcomes of Pediatric and Adult Patients With Congenital Heart Disease Undergoing Cardiac Catheterization: Observations From the NCDR IMPACT Registry (National Cardiovascular Data Registry Improving Pediatric and Adult Congenital Treatment).

Background: Risk standardization for adverse events after congenital cardiac catheterization is needed to equitably compare patient outcomes among different hospitals as a foundation for quality improvement. The goal of this project was to develop a risk-standardization methodology to adjust for patient characteristics when comparing major adverse outcomes in the NCDR's (National Cardiovascular Data Registry) IMPACT Registry (Improving Pediatric and Adult Congenital Treatment).

Methods: Between January 2011 and March 2014, 39 725 consecutive patients within IMPACT undergoing cardiac catheterization were identified.

Impact of Routine Fractional Flow Reserve on Management Decision and 1-Year Clinical Outcome of Patients With Acute Coronary Syndromes: PRIME-FFR (Insights From the POST-IT [Portuguese Study on the Evaluation of FFR-Guided Treatment of Coronary Disease] and R3F [French FFR Registry] Integrated Multicenter Registries - Implementation of FFR [Fractional Flow Reserve] in Routine Practice).

Background: Fractional flow reserve (FFR) is not firmly established as a guide to treatment in patients with acute coronary syndromes (ACS). Primary goals were to evaluate the impact of integrating FFR on management decisions and on clinical outcome of patients with ACS undergoing coronary angiography, as compared with patients with stable coronary artery disease.

Methods And Results: R3F (French FFR Registry) and POST-IT (Portuguese Study on the Evaluation of FFR-Guided Treatment of Coronary Disease), sharing a common design, were pooled as PRIME-FFR (Insights From the POST-IT and R3F Integrated Multicenter Registries - Implementation of FFR in Routine Practice).