Deriving a point of departure for assessing the skin sensitization risk of wearable device constituents with in vitro methods.

Wearable devices are in contact with the skin for extended periods. As such, the device constituents should be evaluated for their skin sensitization potential, and a Point of Departure (PoD) should be derived to conduct a proper risk assessment. Without historical in vivo data, the PoD must be derived with New Approach Methods (NAMs).

Longitudinal Analysis of Mpox Virus DNA Detectability From Multiple Specimen Types During Acute Illness: A Cohort Study.

Background: Longitudinal data on the detectability of monkeypox virus (MPXV) genetic material in different specimen types are scarce.

Methods: We describe MPXV-specific polymerase chain reaction (PCR) results from adults with confirmed mpox infection from Toronto, Canada, including a cohort undergoing weekly collection of specimens from multiple anatomic sites until 1 week after skin lesions had fully healed. We quantified the time from symptom onset to resolution of detectable viral DNA (computed tomography [Ct] ≥ 35) by modeling exponential decay in Ct value as a function of illness day for each site, censoring at the time of tecovirimat initiation.

Investigating the anti-cancer potential of pyrimethamine analogues through a modern chemical biology lens.

Pharmacological inhibition of dihydrofolate reductase (DHFR) is an established approach for treating a variety of human diseases, including foreign infections and cancer. However, treatment with classic DHFR inhibitors, such as methotrexate (MTX), are associated with negative side-effects and resistance mechanisms that have prompted the search for alternatives. The DHFR inhibitor pyrimethamine (Pyr) has compelling anti-cancer activity in in vivo models, but lacks potency compared to MTX, thereby requiring higher concentrations to induce therapeutic responses.

Integrating Clinical Decision Support Into Electronic Health Record Systems Using a Novel Platform (EvidencePoint): Developmental Study.

Background: Through our work, we have demonstrated how clinical decision support (CDS) tools integrated into the electronic health record (EHR) assist providers in adopting evidence-based practices. This requires confronting technical challenges that result from relying on the EHR as the foundation for tool development; for example, the individual CDS tools need to be built independently for each different EHR.

Objective: The objective of our research was to build and implement an EHR-agnostic platform for integrating CDS tools, which would remove the technical constraints inherent in relying on the EHR as the foundation and enable a single set of CDS tools that can work with any EHR.

Arenes participate in 1,3-dipolar cycloaddition with in situ-generated diazoalkenes.

The venerable 1,3-dipolar cycloaddition has been widely used in organic synthesis for the construction of various heterocycles. However, in its century-long history, the simple and omnipresent aromatic phenyl ring has remained a stubbornly unreactive dipolarophile. Here we report 1,3-dipolar cycloaddition between aromatic groups and diazoalkenes, generated in situ from lithium acetylides and N-sulfonyl azides.

Vi polysaccharide and conjugated vaccines afford similar early, IgM or IgG-independent control of infection but boosting with conjugated Vi vaccines sustains the efficacy of immune responses.

Introduction: Vaccination with Vi capsular polysaccharide (Vi-PS) or protein-Vi typhoid conjugate vaccine (TCV) can protect adults against Typhi infections. TCVs offer better protection than Vi-PS in infants and may offer better protection in adults. Potential reasons for why TCV may be superior in adults are not fully understood.

infection induces the reorganization of follicular dendritic cell networks concomitant with the failure to generate germinal centers.

Germinal centers (GCs) are sites where plasma and memory B cells form to generate high-affinity, Ig class-switched antibodies. Specialized stromal cells called follicular dendritic cells (FDCs) are essential for GC formation. During systemic Typhimurium (STm) infection GCs are absent, whereas extensive extrafollicular and switched antibody responses are maintained.

Cycloguanil and Analogues Potently Target DHFR in Cancer Cells to Elicit Anti-Cancer Activity.

Dihydrofolate reductase (DHFR) is an established anti-cancer drug target whose inhibition disrupts folate metabolism and STAT3-dependent gene expression. Cycloguanil was proposed as a DHFR inhibitor in the 1950s and is the active metabolite of clinically approved DHFR inhibitor Proguanil. The Cycloguanil scaffold was explored to generate potential cancer therapies in the 1970s.

Differential effects of exposure to toxic or nontoxic mold spores on brain inflammation and Morris water maze performance.

People who live or work in moldy buildings often complain of "brain fog" that interferes with cognitive performance. Until recently, there was no published research on the effects of controlled exposure to mold stimuli on cognitive function or an obvious mechanism of action, fueling controversy over these claims. The constellation of health problems reported by mold-exposed individuals (respiratory issues, fatigue, pain, anxiety, depression, and cognitive deficits) correspond to those caused by innate immune activation following exposure to bacterial or viral stimuli.

Mimicking Native Display of CD0873 on Liposomes Augments Its Potency as an Oral Vaccine against .

Mucosal vaccination aims to prevent infection mainly by inducing secretory IgA (sIgA) antibody, which neutralises pathogens and enterotoxins by blocking their attachment to epithelial cells. We previously demonstrated that encapsulated protein antigen CD0873 given orally to hamsters induces neutralising antibodies locally as well as systemically, affording partial protection against infection. The aim of this study was to determine whether displaying CD0873 on liposomes, mimicking native presentation, would drive a stronger antibody response.

The antimicrobial drug pyrimethamine inhibits STAT3 transcriptional activity by targeting the enzyme dihydrofolate reductase.

Cancer is often characterized by aberrant gene expression patterns caused by the inappropriate activation of transcription factors. Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional regulator of many protumorigenic processes and is persistently activated in many types of human cancer. However, like many transcription factors, STAT3 has proven difficult to target clinically.

Structure, Function, and Thermodynamics of Lactate Dehydrogenases from Humans and the Malaria Parasite .

Temperature adaptation is ubiquitous among all living organisms, yet the molecular basis for this process remains poorly understood. It can be assumed that for parasite-host systems, the same enzymes found in both organisms respond to the same selection factor (human body temperature) with similar structural changes. Herein, we report the existence of a reversible temperature-dependent structural transition for the glycolytic enzyme lactate dehydrogenase (LDH) from the malaria parasite (pfLDH) and human heart (hhLDH) occurring in the temperature range of human fever.

Reining in Unnecessary Admission EKGs: A Successful Interdepartmental High-Value Care Initiative.

Introduction Unnecessary "admission electrocardiograms (EKGs)" on admitted patients waiting ("boarding") in the emergency department (ED) are often ordered. We introduced evidence-based EKG ordering guidelines and determined changes in the percent of patients with "preadmission" and "admission" EKGs ordered before vs. after guideline introduction and which patient characteristics predicted EKG ordering.

Clionamines stimulate autophagy, inhibit Mycobacterium tuberculosis survival in macrophages, and target Pik1.

The pathogen Mycobacterium tuberculosis (Mtb) evades the innate immune system by interfering with autophagy and phagosomal maturation in macrophages, and, as a result, small molecule stimulation of autophagy represents a host-directed therapeutics (HDTs) approach for treatment of tuberculosis (TB). Here we show the marine natural product clionamines activate autophagy and inhibit Mtb survival in macrophages. A yeast chemical-genetics approach identified Pik1 as target protein of the clionamines.

Computational Study of Triphosphine-Ligated Cu(I) Catalysts for Hydrogenation of CO to Formate.

The catalyzed hydrogenation of CO to formate via a triphosphine-ligated Cu(I) was studied computationally at the density functional theory level in the presence of a self-consistent reaction field. Of the four functionals benchmarked, M06 was generally in the best agreement with the available experimentally estimated values. Two bases, DBU and TBD, were studied in the context of two proposed mechanisms in the MeCN solvent.

Binding and stability of MgO monomers on anatase TiO(101).

In catalysis, MgO is often used to modify the acid-base properties of support oxides and to stabilize supported metal atoms and particles on oxides. In this study, we show how the sublimation of MgO powder can be used to deposit MgO monomers, hither on anatase TiO(101). A combination of x-ray electron spectroscopy, high-resolution scanning tunneling microscopy, and density functional theory is employed to gain insight into the MgO monomer binding, electronic and vibrational properties, and thermal stability.

Benefits of Digital Health Resources for Substance Use Concerns in Women: Scoping Review.

Background: Digital health resources are being increasingly used to support women with substance use concerns. Although empirical research has demonstrated that these resources have promise, the available evidence for their benefit in women requires further investigation. Evidence supports the capacity of interventions that are sex-, gender-, and trauma-informed to improve treatment access and outcomes and to reduce health system challenges and disparities.

Cerebral cortical autonomic connectivity in low-risk term newborns.

Purpose: The mature central autonomic network includes connectivity between autonomic nervous system brainstem centers and the cerebral cortex. The study objective was to evaluate the regional connectivity between the cerebral cortex and brainstem autonomic centers in term newborns by measuring coherence between high-density electroencephalography and heart rate variability as measured by electrocardiography.

Methods: Low-risk term newborns with birth gestational age of 39-40 weeks were prospectively enrolled and studied using time-synced electroencephalography and electrocardiography for up to 60 min before discharge from the birth hospital.

Selfing is the safest sex for .

Mating systems have profound effects on genetic diversity and compatibility. The convergent evolution of self-fertilization in three species provides a powerful lens to examine causes and consequences of mating system transitions. Among the selfers, is the least genetically diverse and most afflicted by outbreeding depression.

Gel Rounds: Integrating Bedside Ultrasound Training for Third-Year Medical Students Into the Internal Medicine Clerkship.

Despite formal ultrasound training becoming prevalent in preclinical medical student education, significant barriers remain to the continuation of this training during clinical years. We sought to develop a program for third-year medical students to continue ultrasound training after an already robust preclinical ultrasound curriculum and evaluate their scanning confidence after participation. We developed a program to facilitate bedside ultrasound scanning of patients being cared for by third-year students.

The effect of delayed cord clamping on blood sugar levels on 34-36 week neonates exposed to late preterm antenatal steroids.

Objective: Neonatal hypoglycemia is a known side effect of antenatal betamethasone (BMZ) given for fetal maturation. We sought to investigate if delayed cord clamping (DCC) has an impact on neonatal hypoglycemia induced by antenatal late preterm BMZ administration.

Material And Methods: Retrospective cohort study (January 2019-May 2019) of pregnancies undergoing delivery at 34-0/7 to 36-6/7 weeks at a single center included in two groups: DCC + BMZ and BMZ-only (no DCC).

Acellular Pertussis Vaccines Induce Anti-pertactin Bactericidal Antibodies Which Drives the Emergence of Pertactin-Negative Strains.

Despite high vaccination coverage, the causative agent of whooping cough is still a health concern worldwide. A resurgence of pertussis cases has been reported, particularly in countries using acellular vaccines with waning immunity and pathogen adaptation thought to be responsible. A better understanding of protective immune responses is needed for the development of improved vaccines.

Mice Deficient in T-bet Form Inducible NO Synthase-Positive Granulomas That Fail to Constrain .

Clearance of intracellular infections caused by Typhimurium (STm) requires IFN-γ and the Th1-associated transcription factor T-bet. Nevertheless, whereas IFN-γ mice succumb rapidly to STm infections, T-bet mice do not. In this study, we assess the anatomy of immune responses and the relationship with bacterial localization in the spleens and livers of STm-infected IFN-γ and T-bet mice.

Different Carbonate Isomers Formed by the Addition of CO to MO for M = Ti, Zr, and Hf.

The chemisorption addition of CO to MO and MO for M = Ti, Zr, and Hf was examined using couple cluster CCSD(T) theory using density functional theory B3LYP geometries. For neutral MOCO, a bridge chemisorbed tridentate carbonate cluster is the lowest energy for Ti and Zr, and a terminal chemisorbed bidentate carbonate is the lowest energy for Hf. For anionic MOCO, the lowest energy structure is a terminal chemisorbed bidentate carbonate for all three metals.