Identification and In Vitro and In Vivo Characterization of KAC-50.1 as a Potential α-Synuclein PET Radioligand.

The accumulation of aggregated α-synuclein (α-syn) is a pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Here within, we report the in vitro characterization targeting site 2 of α-syn fibrils and in vivo evaluation of NHPs of KAC-50.1 as a potential α-syn positron emission tomography (PET) radioligand.

Selective Deuteration and Tritiation of Pharmaceutically Relevant Sulfoximines.

Pharmaceutical-aligned research endeavors continue to diversify, including via the installation of new chemical functionality and non-classical bioisosteres within drug design. With this, an equally high demand emerges for the direct installation of isotopic substituents into these scaffolds within drug discovery programmes, as isotopologues are essential for the elucidation of the biological efficacy and metabolic fate of the active pharmaceutical ingredient (API). The sulfoximine functional group has recently become established as a high-value unit in this context; however, general and effective methods for the synthesis of deuterium (H, D) and tritium (H, T) labelled analogues have remained elusive.

Assessing Patient Readiness for Hospital Discharge, Discharge Communication, and Transitional Care Management.

Background: Discharge communication between hospitalists and primary care clinicians is essential to improve care coordination, minimize adverse events, and decrease unplanned health services use. Health-related social needs are key drivers of health, and hospitalists and primary care clinicians value communicating social needs at discharge.

Objective: To 1) characterize the current state of discharge communications between an academic medical center hospital and primary care clinicians at associated clinics; 2) seek feedback about the potential usefulness of discharge readiness information to primary care clinicians.

Discovery of F Labeled AZD5213 Derivatives as Novel Positron Emission Tomography (PET) Radioligands Targeting Histamine Subtype-3 Receptor.

The histamine subtype 3 (H) receptor is an important drug target in the central nervous system (CNS), and PET imaging offers a promising technique for the noninvasive evaluation of CNS disease related to the H receptor. In this study, we synthesized and evaluated the binding effects of [F]H3-2404 and [F]H3-2405 by modifying the structure of AZD5213, a selective H antagonist. These two radioligands were prepared in high radiochemical yields and displayed stability in serum.

Impact of Social Risk Screening on Discharge Care Processes and Postdischarge Outcomes: A Pragmatic Mixed-Methods Clinical Trial During the COVID-19 Pandemic.

Background: Social risk screening during inpatient care is required in new CMS regulations, yet its impact on inpatient care and patient outcomes is unknown.

Objectives: To evaluate whether implementing a social risk screening protocol improves discharge processes, patient-reported outcomes, and 30-day service use.

Research Design: Pragmatic mixed-methods clinical trial.

Nickel Catalyzed Carbonylative Cross Coupling for Direct Access to Isotopically Labeled Alkyl Aryl Ketones.

Here we present an effective nickel-catalyzed carbonylative cross-coupling for direct access to alkyl aryl ketones from readily accessible redox-activated tetrachlorophthalimide esters and aryl boronic acids. The methodology, which is run employing only 2.5 equivalents of CO and simple Ni(II) salts as the metal source, exhibits a broad substrate scope under mild conditions.

Radiosynthesis and Evaluation of 11C-Labeled Isoindolone-Based Positive Allosteric Modulators for Positron Emission Tomography Imaging of Metabotropic Glutamate Receptor 2.

The metabotropic glutamate receptor 2 (mGluR) has emerged as a potential therapeutic target for the treatment of various neurological diseases, prompting substantial interest in the development of mGluR-targeted drug candidates. As part of our medicinal chemistry program, we synthesized a series of isoindolone derivatives and assessed their potential as mGluR positive allosteric modulators (PAMs). Notably, AZ12559322 exhibited high affinity ( mGluR = 1.

Synthesis of Stable Isotope, Tritiated, and Carbon-14 Labeled Balcinrenone.

As part of a medicinal chemistry program aimed at discovering a mineralocorticoid receptor modulator for treatment of kidney and cardiovascular indications, multiple labeled versions of the lead compound, balcinrenone (AZD9977), were prepared. Four stable isotope labeled versions of the compound were prepared for clinical bioanalysis and biological investigations. Three of these stable isotope labeled compounds were tritiated as well as the parent for biology applications and DMPK investigations.

Synthesis and preclinical evaluation of [C]EAI045 as a PET tracer for imaging tumors expressing mutated epidermal growth factor receptor.

Background: Mutations in the epidermal growth factor receptor (EGFR) kinase domain are common in non-small cell lung cancer. Conventional tyrosine kinase inhibitors target the mutation site in the ATP binding pocket, thereby inhibiting the receptor's function. However, subsequent treatment resistance mutations in the ATP binding site are common.

Impact of COVID-19 visitation policies and hospital capacity on discharge readiness in medicine patients.

Background: COVID-19 impacted the experience of being hospitalized with the widespread adoption of strict visitation policies to ensure healthcare worker safety. One result was decreased time of caregivers at the bedside of hospitalized patients.

Objective: To understand the impact of pandemic-related system effects on patient-reported discharge preparation.

Co-constructing collaboration: An evidence-based approach to advance and evaluate equitable global public health research partnerships.

Equitable global health partnerships are essential to promote innovative research and strengthen research capacity to address critical public health challenges, but how to optimally evaluate such collaborations is unclear. This was a sequential, multi-method study that utilized an electronic survey informed by the literature followed by semi-structured interviews to comprehensively evaluate the experience of participating in a global research-capacity building collaboration between Nepal and U.S.

The Future of (Radio)-Labeled Compounds in Research and Development within the Life Science Industry.

In this review the applications of isotopically labeled compounds are discussed and put into the context of their future impact in the life sciences. Especially discussing their use in the pharma and crop science industries to follow their fate in the environment, in vivo or in complex matrices to understand the potential harm of new chemical structures and to increase the safety of human society.

Rapid Access to Carbon-Isotope-Labeled Alkyl and Aryl Carboxylates Applying Palladacarboxylates.

Herein, we report a strategy for the formation of isotopically labeled carboxylic esters from boronic esters/acids using a readily accessible palladium carboxylate complex as an organometallic source of isotopically labeled functional groups. The reaction allows access to either unlabeled or full C- or C-isotopically labeled carboxylic esters, and the method is characterized by its operational simplicity, mild conditions, and general substrate scope. Our protocol is further extended to a carbon isotope replacement strategy, involving an initial decarbonylative borylation procedure.

Exploring the trajectory and correlates of social isolation for veterans across a 6-month period during COVID-19.

Social isolation is a relevant problem for veterans who are at risk for disengaging from others as a function of transition stress from military life to civilian life, and given high rates of exposure to trauma and psychological distress. Few researchers have examined social isolation in veterans over time, particularly during COVID-19 that led to significant barriers and restrictions on social interactions. The purpose of this longitudinal study was to assess veterans' experience of social isolation and its mental health and social functioning correlates during a 6-month period of the COVID-19 pandemic.

Pharmacokinetic Evaluation of New Drugs Using a Multi-Labelling Approach and PET Imaging: Application to a Drug Candidate with Potential Application in Neuromuscular Disorders.

Background And Objective: The determination of pharmacokinetic properties of new chemical entities is a key step in the process of drug development. Positron emission tomography (PET) is an ideal technique to obtain both biodistribution and pharmacokinetic parameters of new compounds over a wide range of chemical modalities. Here, we use a multi-radionuclide/multi-position labelling approach to investigate distribution, elimination, and metabolism of a triazole-based FKBP12 ligand (AHK2) with potential application in neuromuscular disorders.

Isotopic Radiolabeling of Crizotinib with Fluorine-18 for In Vivo Pet Imaging.

Crizotinib is a tyrosine kinase inhibitor approved for the treatment of non-small-cell lung cancer, but it is inefficient on brain metastases. Crizotinib is a substrate of the P-glycoprotein, and non-invasive nuclear imaging can be used to assess the brain penetration of crizotinib. Positron emission tomography (PET) imaging using fluorine-18-labeled crizotinib would be a powerful tool for investigating new strategies to enhance the brain distribution of crizotinib.

Advancing COVID-19 Vaccination Equity Among the Refugee Community: An Innovative Multi-Sector Collaborative Outreach Program.

Introduction: Multi-sector outreach collaborations have the potential to improve COVID-19 vaccine access among underserved populations, including refugees.

Methods: Using a four-pronged strategy, we offered the local refugee community COVID-19 vaccine appointments within the next week.

Results: Over a thousand (1,327) individuals from more than 20 countries were identified; mean age 36.

Building a 'Virtual Library': continuing a global collaboration to strengthen research capacity within Nepal and other low- and middle-income countries.

To fill the gap in health research capacity-building efforts, we created the 'Virtual Library' (VL) - a web-based repository of context-relevant resources for health researchers in low- and middle-income countries (LMICs). This paper describes the participatory process used to systematically develop the VL, and describes how our interprofessional team - representing both an LMIC (Nepal) and a high-income country (HIC) (USA, US) - engaged in shared meaning-making. A team of researchers and clinicians representing a range of subdisciplines from Nepal and the US created a replicable search strategy and standardized Resource Screening Guide (RSG) to systematically assess resources to be included within the VL.

Mixed-methods study examining family carers' perceptions of the relationship between intrahospital transitions and patient readiness for discharge.

Introduction: Intrahospital transitions (IHTs) represent movements of patients during hospitalisation. While transitions are often clinically necessary, such as a transfer from the emergency department to an intensive care unit, transitions may disrupt care coordination, such as discharge planning. Family carers often serve as liaisons between the patient and healthcare professionals.

Predictors of cervical cancer screening for refugee women attending an international family medicine clinic in the United States.

Purpose: Cervical cancer screening (CCS) rates are lower for foreign-born women in the United States (U.S.) compared with the overall population.

Differential In Vitro Effects of SGLT2 Inhibitors on Mitochondrial Oxidative Phosphorylation, Glucose Uptake and Cell Metabolism.

(1) The cardio-reno-metabolic benefits of the SGLT2 inhibitors canagliflozin (cana), dapagliflozin (dapa), ertugliflozin (ertu), and empagliflozin (empa) have been demonstrated, but it remains unclear whether they exert different off-target effects influencing clinical profiles. (2) We aimed to investigate the effects of SGLT2 inhibitors on mitochondrial function, cellular glucose-uptake (GU), and metabolic pathways in human-umbilical-vein endothelial cells (HUVECs). (3) At 100 µM (supra-pharmacological concentration), cana decreased ECAR by 45% and inhibited GU (IC5o: 14 µM).

Synthesis and Preclinical Evaluation of [C]AZ11895530 for PET Imaging of the Serotonin 1A Receptor.

The serotonin 1A (5-HT) receptor is a G-protein-coupled receptor implicated in the pathophysiology of several neuropsychiatric and neurodegenerative disorders. We here report the preparation of two candidate 5-HT radioligands, [C]AZ11132132 ([C]) and [C]AZ11895530 ([C]), and their subsequent evaluation using autoradiography and using positron emission tomography (PET). Compounds and were radiolabeled at high radiochemical purity (>99%) and high molar activity (>38 GBq/μmol) by heteroatom methylation with [C]methyl iodide.

Screening, Treatment, and Monitoring of Iron Deficiency Anemia in Pregnancy and Postpartum.

Iron deficiency anemia is the most prevalent form of anemia worldwide. In the United States, clinicians routinely screen for iron deficiency anemia upon initiation of prenatal care, at the start of the third trimester, and prior to birth. Treatment of iron deficiency anemia generally begins with oral supplementation of elemental iron, which is associated with adverse gastrointestinal effects.