Understanding recent advances in non-amyloid/non-tau (NANT) biomarkers and therapeutic targets in Alzheimer's disease.

Unlabelled: The Alzheimer's disease (AD) research community continues to make great strides in expanding approaches for early detection and treatment of the disease, including recent advances in our understanding of fundamental AD pathophysiology beyond the classical targets: beta-amyloid and tau. Recent clinical trial readouts implicate a variety of non-amyloid/non-tau (NANT) approaches that show promise in slowing cognitive decline for people with AD. The Alzheimer's Association Research Roundtable (AARR) meeting held on December 13-14, 2022, reviewed the current state of NANT targets on underlying AD pathophysiology and their contribution to cognitive decline, the current data on a diverse range of NANT biomarkers and therapeutic targets, and the integration of NANT concepts in clinical trial designs.

Application of the revised criteria for diagnosis and staging of Alzheimer's disease: Drug development and clinical practice.

Unlabelled: The newly proposed revised criteria for diagnosis and staging of Alzheimer's disease (AD) by the Alzheimer's Association (AA) Workgroup represent a significant milestone in the field. These criteria offer objective measures for diagnosing and staging biological AD, bridging the gap between research and clinical care. Although implementation feasibility may vary across regions and settings, improving the availability and accuracy of biomarkers, especially plasma biomarkers, is expected to enhance the applicability of these criteria in clinical practice.

A safety and feasibility randomized placebo controlled trial exploring electroencephalographic effective connectivity neurofeedback treatment for fibromyalgia.

Fibromyalgia is a chronic pain condition contributing to significant disability worldwide. Neuroimaging studies identify abnormal effective connectivity between cortical areas responsible for descending pain modulation (pregenual anterior cingulate cortex, pgACC) and sensory components of pain experience (primary somatosensory cortex, S1). Neurofeedback, a brain-computer interface technique, can normalise dysfunctional brain activity, thereby improving pain and function.

Dengue virus IgG and neutralizing antibody titers measured with standard and mature viruses are protective.

The standard dengue virus (DENV) neutralization assay inconsistently predicts dengue protection. We compare how IgG ELISA, envelope domain III (EDIII), or non-structural protein 1 (NS1) binding antibodies, and titers from plaque reduction neutralization tests (PRNTs) using standard and mature viruses are associated with dengue. The ELISA measures IgG antibodies that bind to inactivated DENV1-4.

The global impact of the COVID-19 pandemic on delays and disruptions in cancer care services: a systematic review and meta-analysis.

The coronavirus disease 2019 pandemic substantially impacted the delivery of cancer services and programs. Here we reviewed and synthesized the global scale and impact of pandemic-related delays and disruptions on cancer services, including diagnosis, diagnostic procedures, screening, treatment and supportive and palliative care. Based on data from 245 articles in 46 countries, we observed declines in the number of cancer screening participation (39.

Targeting chromosomally unstable tumors with a selective KIF18A inhibitor.

Chromosome instability is a prevalent vulnerability of cancer cells that has yet to be fully exploited therapeutically. To identify genes uniquely essential to chromosomally unstable cells, we mined the Cancer Dependency Map for genes essential in tumor cells with high levels of copy number aberrations. We identify and validate KIF18A, a mitotic kinesin, as a vulnerability of chromosomally unstable cancer cells.

Hemophilia B Leyden: characteristics and natural history in the International Pediatric Network of Hemophilia Management Registry.

Background: A unique form of hemophilia B (HB) is HB Leyden. We evaluated the international Pediatric Network on Hemophilia Management Registry (PedNet) database to explore the natural history of HB Leyden, investigate genotype-phenotype associations, and guide clinical decision-making.

Objectives: To assess the association between genetic variants, endogenous factor (F)IX levels over time, treatment, and bleeding phenotype in children with HB Leyden.

Co-essentiality analysis identifies PRR12 as a cohesin interacting protein and contributor to genomic integrity.

The cohesin complex is critical for genome organization and regulation, relying on specialized co-factors to mediate its diverse functional activities. Here, by analyzing patterns of similar gene requirements across cell lines, we identify PRR12 as a mediator of cohesin and genome integrity. We show that PRR12 interacts with NIPBL/MAU2 and the cohesin complex, and that the loss of PRR12 results in reduced cohesin localization and a substantial increase in DNA double-strand breaks in mouse NIH-3T3 cells.

The promise of cyclic AMP modulation to restore cognitive function in neurodevelopmental disorders.

Cyclic AMP (cAMP) is a key regulator of synaptic function and is dysregulated in both neurodevelopmental (NDD) and neurodegenerative disorders. Due to the ease of diffusion and promiscuity of downstream effectors, cAMP signaling is restricted within spatiotemporal domains to localize activation. Among the best-studied mechanisms is the feedback inhibition of cAMP-dependent protein kinase (PKA) activity by phosphodiesterases 4 (PDE4s) at synapses controlling neuronal plasticity, which is largely regulated by PDE4D.

More Than the Sum of Its Parts: Disrupted Core Periphery of Multiplex Brain Networks in Multiple Sclerosis.

Disruptions to brain networks, measured using structural (sMRI), diffusion (dMRI), or functional (fMRI) MRI, have been shown in people with multiple sclerosis (PwMS), highlighting the relevance of regions in the core of the connectome but yielding mixed results depending on the studied connectivity domain. Using a multilayer network approach, we integrated these three modalities to portray an enriched representation of the brain's core-periphery organization and explore its alterations in PwMS. In this retrospective cross-sectional study, we selected PwMS and healthy controls with complete multimodal brain MRI acquisitions from 13 European centers within the MAGNIMS network.

Rapid identification and phenotyping of nonalcoholic fatty liver disease patients using a machine-based approach in diverse healthcare systems.

Nonalcoholic fatty liver disease (NAFLD) is the most common global cause of chronic liver disease and remains under-recognized within healthcare systems. Therapeutic interventions are rapidly advancing for its inflammatory phenotype, nonalcoholic steatohepatitis (NASH) at all stages of disease. Diagnosis codes alone fail to recognize and stratify at-risk patients accurately.

AI allows pre-screening of FGFR3 mutational status using routine histology slides of muscle-invasive bladder cancer.

Pathogenic activating mutations in the fibroblast growth factor receptor 3 (FGFR3) drive disease maintenance and progression in urothelial cancer. 10-15% of muscle-invasive and metastatic urothelial cancer (MIBC/mUC) are FGFR3-mutant. Selective targeting of FGFR3 hotspot mutations with tyrosine kinase inhibitors (e.

Human respiratory organoids sustained reproducible propagation of human rhinovirus C and elucidation of virus-host interaction.

The lack of a robust system to reproducibly propagate HRV-C, a family of viruses refractory to cultivation in standard cell lines, has substantially hindered our understanding of this common respiratory pathogen. We sought to develop an organoid-based system to reproducibly propagate HRV-C, and characterize virus-host interaction using respiratory organoids. We demonstrate that airway organoids sustain serial virus passage with the aid of CYT387-mediated immunosuppression, whereas nasal organoids that more closely simulate the upper airway achieve this without any intervention.

PSCA-targeted BPX-601 CAR T cells with pharmacological activation by rimiducid in metastatic pancreatic and prostate cancer: a phase 1 dose escalation trial.

Here we report results of a phase 1 multi-institutional, open-label, dose-escalation trial (NCT02744287) of BPX-601, an investigational autologous PSCA-directed GoCAR-T® cell product containing an inducible MyD88/CD40 ON-switch responsive to the activating dimerizer rimiducid, in patients with metastatic pancreatic (mPDAC) or castration-resistant prostate cancer (mCRPC). Primary objectives were to evaluate safety and tolerability and determine the recommended phase 2 dose/schedule (RP2D). Secondary objectives included the assessment of efficacy and characterization of the pharmacokinetics of rimiducid.

Association of SARS-CoV-2 Infection during pregnancy with placental weight and histopathologic lesions.

Introduction: The reported gross and histopathologic changes in the placenta associated with SARS-CoV-2 infection are heterogeneous. We sought to summarize placental histopathologic findings from pregnancies affected by SARS-CoV-2 infection according to timing of infection and symptom severity.

Methods: We conducted a retrospective cohort study of patients with SARS-CoV-2 infection during pregnancy who had deliveries at Mayo Clinic, Rochester, Minnesota, from April 2020 through June 2021.

Carbon Fiber Reinforced Hybrid Polyaryl-Ether-Ether-Ketone (PEEK) Spinal Fixation System: Technical Features and Preliminary Clinical Trial.

Objective: To present the clinical result of spinal fixation system made entirely of Carbon-Fiber-Reinforced (CFR)-Hybrid Polyaryl-Ether-Ether-Ketone (PEEK).

Summary Of Background Data: Fusion surgery has been used to treat chronic low back pain caused by degenerative disk disease (DDD). The traditional pedicle screw system made of titanium, though biocompatible, can lead to complications, such as stress shielding and implant failure.

Phase 1b/2 study of orally administered pexidartinib in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma.

Background: Glioblastoma (GBM) has a median survival of <2 years. Pexidartinib (PLX3397) is a small-molecule inhibitor of CSF1R, KIT, and oncogenic FTL3, which are implicated in GBM treatment resistance. Results from glioma models indicate that combining radiation therapy (RT) and pexidartinib reduces radiation resistance.

Correction method of Mohr-Coulomb strength criterion for rock based on freeze-thaw and residual effects.

Under confining pressure, rocks transition from brittle failure to plastic failure, and residual strength exists after complete failure. However, in the process of establishing rock damage constitutive models, the strength criteria used usually do not consider residual stress. In cold region engineering, the freeze-thaw effect caused by temperature changes should be considered in the constitutive model, and strength criteria should also be introduced.

Identifying predictors of nosocomial pneumonia in trauma patients admitted to a level-1 trauma center.

Background: Nosocomial pneumonia is common in trauma patients and associated with an adverse prognosis. We recently externally validated and recalibrated an existing formula to predict nosocomial pneumonia risk. Identifying more potential predictors could aid in a more accurate prediction of nosocomial pneumonia risk in level-1 trauma patients.

Degradation of Cylindrospermopsin Spiked in Natural Water (Paranoá Lake, Brasília, Brazil) by Fenton Process: A Bench-Scale Study.

The frequency and intensity of harmful cyanobacterial blooms have increased in the last decades, posing a risk to public health since conventional water treatments do not effectively remove extracellular cyanotoxins. Consequently, advanced technologies such as the Fenton process are required to ensure water safety. The cyanotoxin cylindrospermopsin (CYN) demands special attention, as it is abundant in the extracellular fraction and has a high toxicological potential.

Is a No-Restraint Policy Associated with Increased Aggression Towards Healthcare Professionals Among Inpatient Psychiatric Units? A 16-Year Retrospective Observational Study Conducted in Italy.

The aim of this study was to investigate aggression-related work accidents in an inpatient psychiatric unit before and after implementing a no-restraint policy in Italy. Results revealed that, over the study period (2007-2022), 113 accidents occurred, mostly related to physical aggression (81.4%), with healthcare assistants and psychiatric nurses being the most affected and more accidents occurring during the morning shift (49.

Giant Primary Cutaneous Nodular Melanoma of the Forehead: A Case Report.

The incidence of melanoma is increasing globally. The estimated worldwide incidence is projected to increase from 324,635 cases in 2020 to 510,000 in 2040. In the UK, melanoma accounts for 4% of all new cases of cancer.

Venous Endothelial Cell Transcriptomic Profiling Implicates METAP1 in Preeclampsia.

Background: Preeclampsia is a hypertensive disorder of pregnancy characterized by systemic endothelial dysfunction. The pathophysiology of preeclampsia remains incompletely understood. This study used human venous endothelial cell (EC) transcriptional profiling to investigate potential novel mechanisms underlying EC dysfunction in preeclampsia.

Update on inborn errors of immunity.

Ever since the first description of an inherited immunodeficiency in 1952 in a boy with gammaglobulin deficiency, new insights have progressed rapidly in disorders that are now referred to as inborn errors of immunity. In a field where fundamental molecular biology, genetics, immune signaling, and clinical care are tightly intertwined, 2022-24 saw a multitude of advances. Here we report a selection of research updates with a main focus on (1) diagnosis and screening, (2) new genetic defects, (3) susceptibility to severe coronavirus disease 2019 infection and impact of vaccination, and (4) treatment.

Gadopiclenol: A q = 2 Gadolinium-Based MRI Contrast Agent Combining High Stability and Efficacy.

Objectives: Gadopiclenol is a q = 2 pyclen gadolinium-based contrast agent (GBCA) recently approved by the Food and Drug Administration, European Medicines Agency, and other European countries. The aim of this report is to demonstrate its stability in multiple stressed in vitro conditions and in vivo, in rat kidney, while maintaining its higher relaxivity compared with conventional GBCAs on the market.

Materials And Methods: Both gadopiclenol and its chemical precursor Pi828-Gd were characterized and compared with q = 1 gadolinium (Gd) complexes.