A massively parallel reporter assay library to screen short synthetic promoters in mammalian cells.

Cellular responses to stimuli underpin discoveries in drug development, synthetic biology, and general life sciences. We introduce a library comprising 6144 synthetic promoters, each shorter than 250 bp, designed as transcriptional readouts of cellular stimulus responses in massively parallel reporter assay format. This library facilitates precise detection and amplification of transcriptional activity from our promoters, enabling the systematic development of tunable reporters with dynamic ranges of 50-100 fold.

Cryptosporidium PI(4)K inhibitor EDI048 is a gut-restricted parasiticidal agent to treat paediatric enteric cryptosporidiosis.

Diarrhoeal disease caused by Cryptosporidium is a major cause of morbidity and mortality in young and malnourished children from low- and middle-income countries, with no vaccine or effective treatment. Here we describe the discovery of EDI048, a Cryptosporidium PI(4)K inhibitor, designed to be active at the infection site in the gastrointestinal tract and undergo rapid metabolism in the liver. By using mutational analysis and crystal structure, we show that EDI048 binds to highly conserved amino acid residues in the ATP-binding site.

Targeting the muscarinic M1 receptor with a selective, brain-penetrant antagonist to promote remyelination in multiple sclerosis.

Multiple sclerosis (MS) is a chronic and debilitating neurological disease that results in inflammatory demyelination. While endogenous remyelination helps to recover function, this restorative process tends to become less efficient over time. Currently, intense efforts aimed at the mechanisms that promote remyelination are being considered promising therapeutic approaches.

Incidence and Outcomes of Cardiocerebral Infarction: A Cohort Study of 2 National Population-Based Registries.

Background: Cardiocerebral infarction (CCI), which is concomitant with acute myocardial infarction (AMI) and acute ischemic stroke (AIS), is a rare but severe presentation. However, there are few data on CCI, and the treatment options are uncertain. We investigated the characteristics and outcomes of CCI compared with AMI or AIS alone.

Coronary and Systemic Vasodilator Responsiveness of Patients Receiving Conventional Intermittent or Nocturnal Hemodialysis.

Background: Nocturnal hemodialysis (nHD) restores the attenuated brachial artery vasodilator responsiveness of patients receiving conventional intermittent hemodialysis (iHD). Its impact on coronary vasodilatation is unknown.

Methods: We evaluated 25 patients on hemodialysis who fulfilled transplant criteria: 15 on iHD (4-hour sessions, 3 d/wk) and 10 on nHD (≈40 h/wk over 8-10-hour sessions) plus 6 control participants.

Combined Quantitative amyloid-β PET and Structural MRI Features Improve Alzheimer's Disease Classification in Random Forest Model - A Multicenter Study.

Rationale And Objectives: Prior to clinical presentations of Alzheimer's Disease (AD), neuropathological changes, such as amyloid-β and brain atrophy, have accumulated at the earlier stages of the disease. The combination of such biomarkers assessed by multiple modalities commonly improves the likelihood of AD etiology. We aimed to explore the discriminative ability of Aβ PET features and whether combining Aβ PET and structural MRI features can improve the classification performance of the machine learning model in older healthy control (OHC) and mild cognitive impairment (MCI) from AD.

Contributions of Brain Microstructures and Metabolism to Visual Field Loss Patterns in Glaucoma Using Archetypal and Information Gain Analyses.

Purpose: To investigate the contributions of the microstructural and metabolic brain environment to glaucoma and their association with visual field (VF) loss patterns by using advanced diffusion magnetic resonance imaging (dMRI), proton magnetic resonance spectroscopy (MRS), and clinical ophthalmic measures.

Methods: Sixty-nine glaucoma and healthy subjects underwent dMRI and/or MRS at 3 Tesla. Ophthalmic data were collected from VF perimetry and optical coherence tomography.

Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia.

Background: Adrenal insufficiency in patients with classic 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) is treated with glucocorticoid replacement therapy. Control of adrenal-derived androgen excess usually requires supraphysiologic glucocorticoid dosing, which predisposes patients to glucocorticoid-related complications. Crinecerfont, an oral corticotropin-releasing factor type 1 receptor antagonist, lowered androstenedione levels in phase 2 trials involving patients with CAH.

A Sensitive Assay for Unbound Docetaxel Using Ultrafiltration plus HPLC-MS and Its Application to a Clinical Study.

Introduction: Docetaxel, a taxane used in the treatment of solid tumours, exerts pharmacological activity when in its unbound form. We report a sensitive assay to quantify unbound docetaxel after oral administration of docetaxel plus encequidar (oDox+E). Unbound drug quantification is important due to its direct correlation with drug-related toxicity and therapeutic efficacy.

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.

Is Upper Extremity or Lower Extremity Function More Important for Patient Satisfaction? An Analysis of 24-Month Outcomes from the QOD Cervical Spondylotic Myelopathy Cohort.

Study Design: Retrospective analysis of a prospective, multicenter registry.

Objective: To assess whether upper or lower limb mJOA improvement more strongly associates with patient satisfaction after surgery for cervical spondylotic myelopathy (CSM).

Summary Of Background Data: The modified Japanese Orthopaedic Association (mJOA) is commonly used to assess functional status in patients with CSM.

Motive and opportunity: MYC rearrangements in high-grade B-cell lymphoma with MYC and BCL2 rearrangements (an LLMPP study).

Rearrangements that place the oncogenes MYC, BCL2, or BCL6 adjacent to superenhancers are common in mature B-cell lymphomas. Lymphomas with diffuse large B-cell lymphoma (DLBCL) or high-grade morphology with both MYC and BCL2 rearrangements are classified as high-grade B-cell lymphoma with MYC and BCL2 rearrangements ("double hit"; HGBCL-DH-BCL2) and are associated with aggressive disease and poor outcomes. Although it is established that MYC rearrangements involving immunoglobulin (IG) loci are associated with inferior outcomes relative to those involving other non-IG superenhancers, the frequency of and mechanisms driving IG vs non-IG MYC rearrangements have not been elucidated.

BCLA CLEAR Presbyopia: Evaluation and diagnosis.

It is important to be able to measure the range of clear focus in clinical practice to advise on presbyopia correction techniques and to optimise the correction power. Both subjective and objective techniques are necessary: subjective techniques (such as patient reported outcome questionnaires and defocus curves) assess the impact of presbyopia on a patient and how the combination of residual objective accommodation and their natural DoF work for them; objective techniques (such as autorefraction, corneal topography and lens imaging) allow the clinician to understand how well a technique is working optically and whether it is the right choice or how adjustments can be made to optimise performance. Techniques to assess visual performance and adverse effects must be carefully conducted to gain a reliable end-point, considering the target size, contrast and illumination.

Creativity, Connection, and Community: Reimagining the Radiology Society Meeting.

Rationale And Objectives: With the shifting needs of radiologists due to escalating healthcare demands, the impetus for an increased focus on wellness and the benefits of the humanities in medicine inspired a novel approach to curricular planning of the 2023 Association of University Radiologists (AUR) annual meeting. In this manuscript, we describe the creative process behind planning and executing this innovative meeting format.

Materials And Methods: Reimagining the annual meeting was a collaborative effort centered around the development of an innovative Arts and Wellness Program, with the goal of integrating opportunities for artistic expression and experiential wellness throughout the meeting.

Comparing Low- or Standard-Dose Alteplase in Endovascular Thrombectomy: Insights From a Nationwide Registry.

Background: Timely intravenous thrombolysis and endovascular thrombectomy are the standard reperfusion treatments for large vessel occlusion stroke. Currently, it is unknown whether a low-dose thrombolytic agent (0.6 mg/kg alteplase) can offer similar efficacy to the standard dose (0.

Early inner plexiform layer thinning and retinal nerve fiber layer thickening in excitotoxic retinal injury using deep learning-assisted optical coherence tomography.

Excitotoxicity from the impairment of glutamate uptake constitutes an important mechanism in neurodegenerative diseases such as Alzheimer's, multiple sclerosis, and Parkinson's disease. Within the eye, excitotoxicity is thought to play a critical role in retinal ganglion cell death in glaucoma, diabetic retinopathy, retinal ischemia, and optic nerve injury, yet how excitotoxic injury impacts different retinal layers is not well understood. Here, we investigated the longitudinal effects of N-methyl-D-aspartate (NMDA)-induced excitotoxic retinal injury in a rat model using deep learning-assisted retinal layer thickness estimation.

Maximizing wound coverage in full-thickness skin defects: A randomized-controlled trial of autologous skin cell suspension and widely meshed autograft versus standard autografting.

Background: Traumatic insults, infection, and surgical procedures can leave skin defects that are not amenable to primary closure. Split-thickness skin grafting (STSG) is frequently used to achieve closure of these wounds. Although effective, STSG can be associated with donor site morbidity, compounding the burden of illness in patients undergoing soft tissue reconstruction procedures.