Structural Dynamics of the Ubiquitin Specific Protease USP30 in Complex with a Cyanopyrrolidine-Containing Covalent Inhibitor.

Inhibition of the mitochondrial deubiquitinating (DUB) enzyme USP30 is neuroprotective and presents therapeutic opportunities for the treatment of idiopathic Parkinson's disease and mitophagy-related disorders. We integrated structural and quantitative proteomics with biochemical assays to decipher the mode of action of covalent USP30 inhibition by a small-molecule containing a cyanopyrrolidine reactive group, . The inhibitor demonstrated high potency and selectivity for endogenous USP30 in neuroblastoma cells.

A prospective, multicenter analysis of the integrated 31-gene expression profile test for sentinel lymph node biopsy (i31-GEP for SLNB) test demonstrates reduced number of unnecessary SLNBs in patients with cutaneous melanoma.

Background: National Comprehensive Cancer Network guidelines recommend sentinel lymph node biopsy (SLNB) for patients with > 10% risk of positivity, consider SLNB with 5-10% risk, and foregoing with < 5% risk. The integrated 31-gene expression profile (i31-GEP) algorithm combines the 31-GEP with clinicopathologic variables, estimating SLN positivity risk.

Methods: The i31-GEP SLNB risk prediction accuracy was assessed in patients with T1-T2 tumors enrolled in the prospective, multicenter DECIDE study (n = 322).

In-depth analysis of serum antibodies against Epstein-Barr virus lifecycle proteins, and EBNA1, ANO2, GlialCAM and CRYAB peptides in patients with multiple sclerosis.

Background: A strong association between multiple sclerosis (MS) and Epstein-Barr virus (EBV) has been established but the exact role of EBV in MS remains controversial. Recently, molecular mimicry between EBNA1 and specific GlialCAM, CRYAB and ANO2 peptides has been suggested as a possible pathophysiological mechanism. The aim of this study was to analyse anti-EBV antibodies in MS patients against (I) EBV lifecycle proteins, (II) putative cross-reactive peptides, and (III) during treatment.

Efficacy of parenteral bronchodilators on ventilatory outcomes in pediatric critical asthma: a national cohort study.

To evaluate the association of parenteral epinephrine and terbutaline use on ventilatory support in children admitted to the intensive care unit (ICU) with critical asthma in the United States. Data were obtained from the Pediatric Health Information System data base for children ages 2 to 18 years admitted to the ICU with a diagnosis of asthma exacerbation from January 1, 2016, to December 31, 2023. The primary outcomes included noninvasive ventilation (NIV) and/or invasive mechanical ventilation (IMV) use after receipt of terbutaline and/or epinephrine.

Prevalence of human papillomavirus genotypes in women of different ethnicity from rural northwestern Ecuador.

Background: In Ecuador, cervical cancer is the third most common cancer among women and the second most common cause of cancer-related death in women. Although HPV represents a serious public health problem worldwide, the information about its prevalence and genotypes in remote communities of Ecuador is limited. The aim of this study was to determine the distribution of HPV genotypes among ethnic minority women from two remote communities of the northwestern region of Ecuador: Afro-Ecuadorians and Chachis (Amerindian group).

Primary inferior vena cava synovial sarcoma treated with caval replacement during cardiopulmonary bypass and liver perfusion.

Primary inferior vena cava (IVC) tumors are rare. Most are leiomyosarcomas. The prognosis is poor with those involving and superior to the hepatic veins faring worse than those isolated within the retrohepatic cava.

Career pathways into the medical laboratory workforce: Education, exposures, and motivations.

Objectives: The goal of this study was to investigate career pathways into the medical laboratory workforce by examining medical laboratory scientists, medical laboratory technicians, histotechnologists, histotechnicians, cytologists, and phlebotomists.

Methods: We collected data through an anonymous online survey (May-June 2023) from a convenience sample of medical laboratory professionals in the United States (N = 1243). We performed descriptive analyses of demographics, current employment characteristics, educational and training history, career exposures, motivations, movement, and outlook (eg, job satisfaction, future career plans).

Low birthweight rate differences associated with distinct perinatal staffing mixes at federally funded health centers.

Health centers (sometimes referred to as "federally qualified health centers") can play an important role in addressing perinatal inequities. However, there is limited information on how different staffing models in health centers contribute to perinatal outcomes, including the availability of certified nurse midwives (CNMs). Using 2011-2021 Uniform Data System files, we examined 4 staffing models in 1385 health centers: those with no CNMs or obstetricians-gynecologists (OBs) ("non-CNM/OB"), CNM-only, OB-only, and both CNMs and OBs ("CNM/OB").

The cannabinoid CB agonist LY2828360 suppresses neuropathic pain behavior and attenuates morphine tolerance and conditioned place preference in rats.

Cannabinoid CB agonists show promise as analgesics because they lack unwanted side effects associated with direct activation of CB receptors. CB receptor activation suppresses pathological pain in animal models, but the types of pain that best respond to CB agonists are incompletely understood. This gap in knowledge may contribute to failures in clinical translation.

Radio-pathomic estimates of cellular growth kinetics predict survival in recurrent glioblastoma.

A radio-pathomic machine learning (ML) model has been developed to estimate tumor cell density, cytoplasm density (Cyt) and extracellular fluid density (ECF) from multimodal MR images and autopsy pathology. In this multicenter study, we implemented this model to test its ability to predict survival in patients with recurrent glioblastoma (rGBM) treated with chemotherapy. Pre- and post-contrast T-weighted, FLAIR and ADC images were used to generate radio-pathomic maps for 51 patients with longitudinal pre- and post-treatment scans.

No clinically relevant relationship between different quantitative measurement methods of the lateral femoral condyle morphology on lateral radiographs in anterior cruciate ligament-injured patients.

Purpose: To clarify whether different methods of quantifying lateral femoral condyle (LFC) bone morphology as risk factors for anterior cruciate ligament (ACL) injury on lateral radiographs should be considered as individual risk factors and to assess inter- and intraobserver reliability.

Methods: We retrospectively reviewed 487 patients undergoing primary ACL reconstruction at our institution. Routine lateral radiographs of the injured knees were utilized to measure the following parameters: LFC ratio (LFCR), height of LFC to anteroposterior diameter ratio (HAPR), femur tibia size ratio (FTSR), tibia to posterior femoral condyle ratio (TPFCR) and Porto ratios (XY/AB; B/AB; B/XY).

Unexpectedly strong heat stress induction of monoterpene, methylbutenol, and other volatile emissions for conifers in the cypress family (Cupressaceae).

We investigated the biogenic volatile organic compound (BVOC) emission rates and composition of Cupressaceae species and how the emissions change in response to moderate warming and more severe heat stress. A total of 8 species from 7 distinct Cupressaceae genera were targeted in this study and exposed to laboratory-simulated heatwaves. Each plant was enclosed in a temperature-controlled glass chamber and allowed to equilibrate at 30 °C for 24 h.

CACHE Challenge #1: Targeting the WDR Domain of LRRK2, A Parkinson's Disease Associated Protein.

The CACHE challenges are a series of prospective benchmarking exercises to evaluate progress in the field of computational hit-finding. Here we report the results of the inaugural CACHE challenge in which 23 computational teams each selected up to 100 commercially available compounds that they predicted would bind to the WDR domain of the Parkinson's disease target LRRK2, a domain with no known ligand and only an apo structure in the PDB. The lack of known binding data and presumably low druggability of the target is a challenge to computational hit finding methods.

My virtual escape from patient life: a feasibility study on the experiences and benefits of individualized virtual reality for inpatients in palliative cancer care.

Background: Cancer patients benefit from Virtual Reality (VR) in burdensome situations, but evidence is scarce for palliative situations. Based on earlier work in palliative care, individualized VR interventions like seeing the patient's home may address a patient's wish to be at home and thus have a greater effect compared to standard VR content. Yet, some patients and relatives may be concerned about their privacy.

Impact of metadata in multimodal classification of bone tumours.

Unlabelled: The accurate classification of bone tumours is crucial for guiding clinical decisions regarding treatment and follow-up. However, differentiating between various tumour types is challenging due to the rarity of certain entities, high intra-class variability, and limited training data in clinical practice. This study proposes a multimodal deep learning model that integrates clinical metadata and X-ray imaging to improve the classification of primary bone tumours.

Effectiveness and efficiency of immunisation strategies to prevent RSV among infants and older adults in Germany: a modelling study.

Background: Recently, several novel RSV immunisation products that protect infants and older adults against RSV disease have been licensed in Europe. We estimated the effectiveness and efficiency of introducing these RSV immunisation strategies in Germany.

Methods: We used a Bayesian framework to fit a deterministic age-structured dynamic transmission model of RSV to sentinel surveillance and RSV-specific hospitalisation data in Germany from 2015 to 2019.

Single-Stranded Hairpin Loop RNAs (loopmeRNAs) Potently Induce Gene Silencing through the RNA Interference Pathway.

Synthetic small interfering RNAs conjugated to trivalent -acetylgalactosamine (GalNAc) are clinically validated drugs for treatment of liver diseases. Incorporation of phosphorothioate linkages and ribose modifications are necessary for stability, potency, and duration of pharmacology. Although multiple alternative siRNA designs such as Dicer-substrate RNA, shRNA, and circular RNA have been evaluated in vitro and in preclinical studies with some success, clinical applications of these designs are limited as it is difficult to incorporate chemical modifications in these designs.