Biosynthetic Incorporation of Non-native Aryl Acid Building Blocks into Peptide Products Using Engineered Adenylation Domains.

Nonribosomal peptides (NRPs), one of the most widespread secondary metabolites in nature, with therapeutically significant activities, are biosynthesized by modular nonribosomal peptide synthetases (NRPSs). Aryl acids contribute to the structural diversity of NRPs as well as nonproteinogenic amino acids and keto acids. We previously confirmed that a single Asn-to-Gly substitution in the 2,3-dihydroxybenzoic acid-activating adenylation (A) domain EntE involved in enterobactin biosynthesis accepts monosubstituted benzoic acid derivatives with nitro, cyano, bromo, and iodo functionalities at the 2 or 3 positions.

Quantitative prediction of CYP3A induction-mediated drug-drug interactions in clinical practice.

There have been no reports on the quantitative prediction of CYP3A induction-mediated decreases in AUC and C for drug candidates identified as a "victims" of CYP3A induction. Our previous study separately evaluated the fold-induction of hepatic and intestinal CYP3A by known inducers using clinical induction data and revealed that we were able to quantitatively predict the AUC ratio (AUCR) of a few CYP3A substrates in the presence and absence of CYP3A inducers. In the present study, we investigate the predictability of AUCR and also C ratio (CR) in additional 54 clinical studies.

Structure-activity relationships of middle-size cyclic peptides, KRAS inhibitors derived from an mRNA display.

Cyclic peptides are attracting attention as therapeutic agents due to their potential for oral absorption and easy access to tough intracellular targets. LUNA18, a clinical KRAS inhibitor, was transformed-without scaffold hopping-from the initial hit by using an mRNA display library that met our criteria for drug-likeness. In drug discovery using mRNA display libraries, hit compounds always possess a site linked to an mRNA tag.

Inverse kinetic isotope effect of ammonia decomposition over Ru/CeO using deuterated ammonia.

This study investigated the ammonia decomposition mechanism over Ru/CeO. Isotopic tests using ND revealed that the rate-determining step involves adsorbed nitrogen atoms on Ru. Moreover, an inverse kinetic isotope effect where ND decomposition was faster than NH was clearly observed.

Impact of the COVID-19 pandemic on routine childhood vaccination in 9 U.S. jurisdictions.

Importance: Routine vaccinations are key to prevent outbreaks of vaccine-preventable diseases. However, there have been documented declines in routine childhood vaccinations in the U.S.

The effectiveness of palliative middle meningeal artery embolization prior to craniotomy for large acute epidural hematoma: A case report.

Introduction And Importance: Acute epidural hematoma is typically managed with craniotomy. However, there are a few reports on transcatheter arterial embolization (TAE) as an adjunctive therapy.

Case Presentation: A 70-year-old female with no obvious history of trauma was transported to our hospital.

Tri-State Evaluation of the Effects of the COVID-19 Pandemic on Routine Vaccine Uptake in Iowa, Minnesota, and North Dakota, 2017-2021.

The objective of this analysis was to evaluate and compare the effects of the COVID-19 pandemic on routine and annual influenza vaccination in Iowa, Minnesota, and North Dakota. Routine and annual influenza vaccination uptake and coverage between 2017 and 2021 was collected from each state's immunization information system (IIS) by age group and stratified by provider and vaccine type. Data from 2017 to 2019 were averaged to obtain a pre-pandemic baseline and compared to 2020 and 2021 data.

Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets.

Establishing a technological platform for creating clinical compounds inhibiting intracellular protein-protein interactions (PPIs) can open the door to many valuable drugs. Although small molecules and antibodies are mainstream modalities, they are not suitable for a target protein that lacks a deep cavity for a small molecule to bind or a protein found in intracellular space out of an antibody's reach. One possible approach to access these targets is to utilize so-called middle-size cyclic peptides (defined here as those with a molecular weight of 1000-2000 g/mol).

Effective use of the hybrid emergency Department system in the treatment of non-traumatic critical care diseases.

Background: The hybrid emergency room (ER) system can provide resuscitation, computed tomography imaging, endovascular treatment, and emergency surgery, without transferring the patient. However, although several reports have demonstrated the effectiveness of the hybrid ER for trauma conditions, only a few case reports have demonstrated its usefulness for non-traumatic critical diseases. In this observational cohort study, we aimed to identify endogenous diseases that may benefit from treatment in the hybrid ER.

Optimal tentative abdominal closure for open abdomen: a multicenter retrospective observational study (OPTITAC study).

Background: Primary fascia closure is often difficult following an open abdomen (OA). While negative-pressure wound therapy (NPWT) is recommended to enhance successful primary fascia closure, the optimal methods and degree of negative pressure remain unclear. This study aimed to elucidate optimal methods of NPWT as a tentative abdominal closure for OA to achieve primary abdominal fascia closure.

Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor.

Cyclic peptides as a therapeutic modality are attracting a lot of attention due to their potential for oral absorption and accessibility to intracellular tough targets. Here, starting with a drug-like hit discovered using an mRNA display library, we describe a chemical optimization that led to the orally available clinical compound known as LUNA18, an 11-mer cyclic peptide inhibitor for the intracellular tough target RAS. The key findings are as follows: (i) two peptide side chains were identified that each increase RAS affinity over 10-fold; (ii) physico-chemical properties (PCP) including log can be adjusted by side-chain modification to increase membrane permeability; (iii) restriction of cyclic peptide conformation works effectively to adjust PCP and improve bio-activity; (iv) cellular efficacy was observed in peptides with a permeability of around 0.

Discovery of CH7057288 as an Orally Bioavailable, Selective, and Potent pan-TRK Inhibitor.

Kinase fusions involving tropomyosin receptor kinases (TRKs) have been proven to act as strong oncogenic drivers and are therefore recognized as attractive therapeutic targets. We screened an in-house kinase-focused library and identified a promising hit compound with a unique tetracyclic scaffold. Compound showed high TRK selectivity but moderate cell growth inhibitory activity as well as a potential risk of inducing CYP3A4.

Neutralizing-antibody response to SARS-CoV-2 for 12 months after the COVID-19 workplace outbreaks in Japan.

This study aimed to elucidate the 12-month durability of neutralizing antibodies (NAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients infected during the 2020 workplace outbreaks of coronavirus disease 2019 (COVID-19) in Japan. We followed 33 Japanese patients infected with SARS-CoV-2 in April 2020 for 12 months (12M). Patients were tested for NAbs and for antibodies against the SARS-CoV-2 nucleocapsid (anti-NC-Ab) and antibodies against the spike receptor-binding domain (anti-RBD-Ab).

Successful endovascular treatment of a ruptured bihemispheric posterior inferior cerebellar artery aneurysm: illustrative case.

Background: Normal posterior inferior cerebellar artery (PICA) anatomy is highly variable, but bihemispheric PICA crossing the midline to supply the vascular territory of bilateral cerebellar hemisphere is rare. Herein, the authors reported a rare case of ruptured aneurysm that was associated with bihemispheric PICA and successfully treated endovascularly.

Observations: A 46-year-old woman presented with sudden headache and loss of consciousness because of an intraventricular hemorrhage due to a ruptured aneurysm that was associated with the bihemispheric PICA.

Rapid molecular diagnosis of Parechovirus infection using the reverse transcription loop-mediated isothermal amplification technique.

Objectives: Human parechovirus (HPeV), especially HPeV A3 (HPeV3), causes sepsis-like diseases and sudden infant death syndrome in neonates and young infants. Development of rapid and easier diagnostic laboratory tests for HPeVs is desired.

Methods: Original inner primers, outer primers, and loop-primers were designed on the 5' untranslated region of HPeV3.

Influenza Vaccinations During the COVID-19 Pandemic - 11 U.S. Jurisdictions, September-December 2020.

Influenza causes considerable morbidity and mortality in the United States. Between 2010 and 2020, an estimated 9-41 million cases resulted in 140,000-710,000 hospitalizations and 12,000-52,000 deaths annually (1). As the United States enters the 2021-22 influenza season, the potential impact of influenza illnesses is of concern given that influenza season will again coincide with the ongoing COVID-19 pandemic, which could further strain overburdened health care systems.

Missed Opportunities for Human Papillomavirus Vaccination by Parental Nativity, Minnesota, 2015-2018.

Objectives: Human papillomavirus (HPV) vaccination coverage in the United States is far below coverage for other routine adolescent vaccines. We examined whether missed opportunities for HPV vaccination among adolescents differ by parental nativity (country of origin) in Minnesota.

Methods: We retrospectively analyzed birth record and immunization information data for adolescents in Minnesota born during 2004-2007 using data from January 1, 2015, through December 31, 2018.

Hybrid emergency rooms reduce the requirement of blood transfusion in patients with severe trauma.

Background: A hybrid emergency room (ER) is defined as an emergency unit with four functions-performing resuscitation, computed tomography (CT), surgery, and angiography. However, the safety and efficacy of performing CT in a hybrid ER are unclear in primary surveys. Therefore, this study aimed to evaluate the safety and clinical effects of hybrid ERs.

Impact of the COVID-19 Pandemic on Administration of Selected Routine Childhood and Adolescent Vaccinations - 10 U.S. Jurisdictions, March-September 2020.

After the March 2020 declaration of the COVID-19 pandemic in the United States, an analysis of provider ordering data from the federally funded Vaccines for Children program found a substantial decrease in routine pediatric vaccine ordering (1), and data from New York City and Michigan indicated sharp declines in routine childhood vaccine administration in these areas (2,3). In November 2020, CDC interim guidance stated that routine vaccination of children and adolescents should remain an essential preventive service during the COVID-19 pandemic (4,5). To further understand the impact of the pandemic on routine childhood and adolescent vaccination, vaccine administration data during March-September 2020 from 10 U.

Damage control surgery for spontaneous perforation of pyometra with septic shock: a case report.

Background: Although spontaneous perforation of pyometra is very rare, it sometimes causes severe peritonitis, leading to lethal conditions. Damage control surgery reportedly improves the survival of critically ill patients; however, there has been no report describing damage control surgery for ruptured pyometra.

Case Presentation: An 83-year-old postmenopausal woman with generalized peritonitis and septic shock was admitted and underwent emergency laparotomy.

Evaluation of Methods to Assess CYP3A Induction Risk in Clinical Practice Using in Vitro Induction Parameters.

Established guidelines have recommended a number of methods based on in vitro data to assess the CYP3A induction risk of new chemical entities in clinical practice. In this study, we evaluated the predictability of various assessment methods. We collected in vitro parameters from a variety of literature that includes data on 19 batches of hepatocytes.

Delayed massive hemothorax due to diaphragm injury with rib fracture: A case report.

Introduction: Delayed massive hemothorax after blunt trauma is rare, although associated with significant morbidity and mortality. In most cases, the intercostal artery is the main bleeding source. We report a rare case of delayed massive hemothorax due to a diaphragm injury with a lower rib fractures.