Photooxidation-Initiated Aqueous-Phase Formation of Organic Peroxides: Delving into Formation Mechanisms.

Formation of highly oxygenated molecules (HOMs) such as organic peroxides (ROOR, ROOH, and H2O2) is known to degrade food and organic matter. Gas-phase unimolecular autoxidation and bimolecular RO2 + HO2/RO2 reactions are prominently renowned mechanisms associated with the formation of peroxides. However, the reaction pathways and conditions favoring the generation of peroxides in the aqueous phase need to be evaluated. Here, we identified bulk aqueous-phase ROOHs in varying organic precursors, including a laboratory model compound and monoterpene oxidation products. Our results show that formation of ROOHs is suppressed at enhanced oxidant concentrations but exhibits complex trends at elevated precursor concentrations. Furthermore, we observed an exponential increase in the yield of ROOHs when UV light with longer wavelengths was used in the experiment, comparing UVA, UVB, and UVC. Water-soluble organic compounds represent a significant fraction of ambient cloud-water components (up to 500 µM). Thus, the reaction pathways facilitating the formation of HOMs (i.e., ROOHs) during the aqueous-phase oxidation of water-soluble species add to the climate and health burden of atmospheric particulate matter.

Comprehensive mutational scanning of EGFR reveals TKI sensitivities of extracellular domain mutants.

The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different mutation spectra in these diseases are reflected in divergent responses to EGFR inhibition: significant patient benefit in lung cancer, but limited in glioblastoma. Here, we report a comprehensive mutational analysis of EGFR function. We perform saturation mutagenesis of EGFR and assess function of ~22,500 variants in a human EGFR-dependent lung cancer cell line. This approach reveals enrichment of erlotinib-insensitive variants of known and unknown significance in the dimerization, transmembrane, and kinase domains. Multiple EGFR extracellular domain variants, not associated with approved targeted therapies, are sensitive to afatinib and dacomitinib in vitro. Two glioblastoma patients with somatic EGFR G598V dimerization domain mutations show responses to dacomitinib treatment followed by within-pathway resistance mutation in one case. In summary, this comprehensive screen expands the landscape of functional EGFR variants and suggests broader clinical investigation of EGFR inhibition for cancers harboring extracellular domain mutations.

Acetal Formation of Flavoring Agents with Propylene Glycol in E-Cigarettes: Impacts on Indoor Partitioning and Thirdhand Exposure.

The widespread use of flavored e-cigarettes has led to a significant rise in teenage nicotine use. In e-liquids, the flavor carbonyls can form acetals with unknown chemical and toxicological properties. These acetals can cause adverse health effects on both smokers and nonsmokers through thirdhand exposure. This study aims to explore the impacts of these acetals formed in e-cigarettes on indoor partitioning and thirdhand exposure. Specifically, the acetalization reactions of commonly used flavor carbonyls in laboratory-made e-liquids were monitored using proton nuclear magnetic resonance (1H NMR) spectroscopy. EAS-E Suite and polyparameter linear free energy relationships (PP-LFERs) were employed to estimate the partitioning coefficients for species. Further, a chemical two-dimensional partitioning model was applied to visualize the indoor equilibrium partitioning and estimate the distribution of flavor carbonyls and their acetals in the gas phase, aerosol phase, and surface reservoirs. Our results demonstrate that a substantial fraction of carbonyls were converted into acetals in e-liquids and their chemical partitioning was significantly influenced. This study shows that acetalization is a determinant factor in the exposure and toxicology of harmful carbonyl flavorings, with its impact extending to both direct exposure to smokers and involuntary exposure to nonsmokers.

Unexpected electrophiles in the atmosphere - anhydride nucleophile reactions and uptake to biomass burning emissions.

Biomass burning is a significant contributor to atmospheric pollution, its emissions have been found to have adverse impacts on climate and human health. Largely, these impacts are dictated by how the composition of the emissions changes once emitted into the atmosphere. Recently, anhydrides have been identified as a significant fraction of biomass burning emissions, however, little is known about their atmospheric evolution, or their interactions within the burn plume. Without this understanding, it is challenging to predict the impact of anhydrides on biomass burning emissions, and by extension, their influence on climate and health. In this study, we investigate anhydrides as potentially unrecognized electrophiles in the atmosphere. Firstly, by exploring their reactivity towards important biomass burning emitted nucleophiles, and secondly, by measuring their uptake on the emissions themselves. Our results show that phthalic and maleic anhydride can react with a wide range of nucleophiles, including hydroxy and amino-containing compounds, such as levoglucosan or aniline. Additionally, using a coated-wall flow tube setup, we demonstrate that anhydrides reactively uptake to biomass burning films and influence their composition. The anhydride nucleophile reaction was found to be irreversible, proceeding without sunlight or free radicals and indicating it may occur during the day or nighttime. Furthermore, the reaction products were found to be water-stable and contain functional groups which enhance their mass and likely contribute to the formation of secondary organic aerosol, with knock-on climate effects. Overall, our study sheds light on the fundamental chemistry of anhydrides and their potential impacts in the atmosphere.

The c-Abl inhibitor IkT-148009 suppresses neurodegeneration in mouse models of heritable and sporadic Parkinson's disease.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease of the central nervous system, with an estimated 5,000,000 cases worldwide. PD pathology is characterized by the accumulation of misfolded α-synuclein, which is thought to play a critical role in the pathogenesis of the disease. Animal models of PD suggest that activation of Abelson tyrosine kinase (c-Abl) plays an essential role in the initiation and progression of α-synuclein pathology and initiates processes leading to degeneration of dopaminergic and nondopaminergic neurons. Given the potential role of c-Abl in PD, a c-Abl inhibitor library was developed to identify orally bioavailable c-Abl inhibitors capable of crossing the blood-brain barrier based on predefined characteristics, leading to the discovery of IkT-148009. IkT-148009, a brain-penetrant c-Abl inhibitor with a favorable toxicology profile, was analyzed for therapeutic potential in animal models of slowly progressive, α-synuclein-dependent PD. In mouse models of both inherited and sporadic PD, IkT-148009 suppressed c-Abl activation to baseline and substantially protected dopaminergic neurons from degeneration when administered therapeutically by once daily oral gavage beginning 4 weeks after disease initiation. Recovery of motor function in PD mice occurred within 8 weeks of initiating treatment concomitantly with a reduction in α-synuclein pathology in the mouse brain. These findings suggest that IkT-148009 may have potential as a disease-modifying therapy in PD.

Single-institution experience of extracorporeal membrane oxygenation for near-fatal asthma.

Near-fatal asthma (NFA) is the most severe presentation of asthma. It is characterized by hypoxemic and hypercapnic respiratory failure requiring ventilatory assistance, including non-invasive ventilation and mechanical ventilation. However, NFA has a high mortality rate despite conventional therapy. Extracorporeal membrane oxygenation (ECMO) is a treatment modality that is increasingly being utilized as rescue therapy in patients with NFA that is refractory to mechanical ventilation. Prior analyses of the international Extracorporeal Life Support Organization (ELSO) registry data showed a survival rate of over 83% in patients placed on venovenous (VV) ECMO for NFA, but with notable rate of hemorrhagic complications. We report seven cases of adults with NFA requiring ECMO support at our large quaternary care institution between the years 2019 and 2022. All seven patients presented with respiratory failure in the setting of asthma exacerbation that progressed despite standard pharmacotherapy and mechanical ventilation. All patients survived to hospital discharge after ECMO support without hemorrhagic complications, highlighting the effectiveness and safety of ECMO when appropriately used in this population.

Indoor partitioning and potential thirdhand exposure to carbonyl flavoring agents added in e-cigarettes and hookah tobacco.

Flavoring agents added to the e-cigarettes and hookah tobacco have increased the attractiveness of novel nicotine products. Many widely used flavorings are carbonyls, which are toxic to humans. In an indoor environment, residents can be exposed to such harmful flavorings previously emitted to the surrounding environment, through a process termed thirdhand exposure. The recent discovery of a large volume of indoor reservoirs emphasizes the importance of indoor partitioning, which is responsible for thirdhand exposure. Indoor partitioning can be expressed with partitioning coefficients, such as Henry's law solubility constant (H). However, reliable H values for many key flavorings are currently lacking. To better understand their environmental behavior, this study experimentally determined the effective Henry's law constant (Hcps,eff) using the inert gas stripping (IGS) method. Further, the influence of the hydration process for target flavorings was quantified using proton nuclear magnetic resonance (1H NMR) spectroscopy. We found that hydration of α-dicarbonyls (diacetyl and 2,3-pentanedione) enhanced their Hcps,eff from their intrinsic Henry's law constant (Hcps) by a factor of 3.52 and 2.88, respectively. The two-dimensional partitioning plots were employed to simulate the indoor phase distribution and evaluate the pathways of human exposure. Our findings show that the indoor partitioning of many harmful flavorings is highly sensitive to temperature and the size of indoor reservoirs, indicating that residents are likely to experience third-hand exposure.

A Case of Ophthalmoplegia, Hypotonia, and Developmental Delay in the Setting of Corpus Callosum Hypoplasia.

Anomalies of the corpus callosum, including complete agenesis, partial agenesis, and hypoplasia, are some of the most common brain malformations. Corpus callosum abnormalities are potentially syndromic, many of which have identifiable genetic etiologies. Patients affected with either syndromic or non-syndromic corpus callosum anomalies may also have associated ophthalmologic abnormalities. Some of the syndromes with corpus callosum malformations that also involve ophthalmologic findings include Aicardi syndrome, Mowat-Wilson syndrome, and Xia-Gibbs syndrome. This case report describes a patient with hypoplasia and possible dysgenesis of the corpus callosum noted on magnetic resonance imaging (MRI) who had several ophthalmologic findings, including ophthalmoplegia, strabismus, and nystagmus, associated with microcephaly, dysmorphic facial features, global developmental delay, hypotonia, and cryptorchidism. While several previously identified syndromes share similar clinical features with this patient, these findings may also represent an unidentified genetic syndrome, and the patient remains under evaluation for a genetic diagnosis. This report explores the differential for ophthalmologic abnormalities in the setting of corpus callosum hypoplasia.

Delayed Diagnosis of Osteogenesis Imperfecta: A Differential Diagnosis Guided by Competing Ocular Findings and a Lack of Family History.

Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with variable clinical manifestations involving many structures and organ systems, leading to characteristic presentations such as low bone mineral density (BMD), vertebral compression fractures, hearing loss, and blue sclerae. Even within the same family, individuals with the same inherited genotype may have differential presentations due to variable expressivity. Early diagnosis of OI in the pediatric population may allow for earlier treatment and interprofessional interventions. This case describes a minority female infant who initially presented with bilateral complexion-associated melanosis (CAM) inclusions in her eyes. The appearance of her inclusions was reminiscent of the blue sclera seen in OI; however, there was no clinical suspicion for OI on birth, developmental, and family histories. Her growth and development were unremarkable at all well-child checks until her three-year well-child check. It was then discovered that she suffered multiple long bone fractures due to low trauma, vertebral compression fractures, and kyphoscoliosis. Due to the occurrence of these fragility fractures, she was given a clinical diagnosis of osteoporosis with pending genetic testing for osteogenesis imperfecta. It was later discovered that there was, in fact, an extensive history of recurrent childhood fractures in the patient's brother, mother, and numerous maternal relatives. Our case demonstrates the greater need for certified medical interpretation services to obtain clear past medical and family history, especially in the face of language barriers and low health literacy, in conjunction with clinical findings, i.e., CAM, to guide the differential diagnosis and subsequent management appropriately.

Case of Treatment-Resistant Aggression in the Context of a Medically Underserved Community.

Aggression tends to decrease as a child matures and develops conflict resolution skills. However, aggression can persist if children are exposed to consistent negative stimuli, such as poor parenting and adverse childhood experiences (ACEs). Furthermore, aggression is commonplace in numerous psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder. These negative stimuli and comorbid conditions could ultimately stunt a child's development during pivotal moments, leading to worsening aggressive behaviors, such as criminal activity. Behavioral interventions are imperative for individuals with these comorbid conditions and experiences. Our patient is an 11-year-old male with a pertinent past medical history of ADHD and disruptive mood dysregulation disorder (DMDD) on multiple psychotropic medications, who presented to the emergency department for the evaluation of homicidal ideation and suicidality. This also occurred with worsening aggressive behavior, demonstrated by his killing of family pets and subsequent threats to kill his family. The patient has had multiple emergency department visits for similar threats and has been admitted to numerous inpatient psychiatric facilities. Currently, the patient is being treated at an out-of-state inpatient psychiatric facility. Our patient's aggression most likely stems from his comorbid ADHD and DMDD, complicated by other factors, such as low socioeconomic status, limited access to mental health services, and living in a medically underserved community. Factors such as increasing primary care provider comfort in managing these conditions, especially in underserved communities where there are already shortages of mental health providers, could help address this issue. Furthermore, it is imperative to screen for other contributing factors, such as ACEs. This case also highlights the need for genetic testing as a part of the medical workup in psychiatric cases that display psychotropic medication resistance. However, genetic testing is something that is not readily available in our state and is not covered by Medicaid. Early treatment of mental health conditions can prevent social difficulties later in life. With aggression, providing appropriate interventions is key to preventing an individual from engaging in harmful activities. It is important to screen for ACEs in order to address well-known aggravating factors. Underserved populations also face a myriad of challenges that prevent them from accessing healthcare services. There are numerous problems contributing to this disparity, ranging from lack of adequate mental health services to lack of access. Accordingly, it is imperative that primary care physicians and providers practicing in underserved areas receive the training necessary to recognize and treat mental health conditions. Furthermore, physicians should be able to focus on psychosocial stressors that contribute to these mental health conditions and provide the resources necessary to address these factors.

A Delayed Diagnosis of Autism Spectrum Disorder in the Setting of Complex Attention Deficit Hyperactivity Disorder.

Autism spectrum disorder (ASD) presents a diagnostic challenge due to its highly heterogeneous nature. The most common clinical manifestations include difficulty with social interaction and the presence of repetitive sensory-motor behaviors. Females are more likely to be misdiagnosed or have a delayed diagnosis compared to males. Other factors that contribute to delayed diagnosis include low socioeconomic status and belonging to an ethnic minority. In pediatrics, the goal of ASD screening is to diagnose ASD earlier, with timely referral to early intervention services, so that better long-term neurodevelopmental outcomes can be achieved. Moreover, attention deficit hyperactivity disorder (ADHD) is the most common comorbidity in patients with ASD. While the Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-4) prohibited a co-diagnosis of autism and ADHD, the DSM-5 has modified exclusion criteria to allow such. This case describes a minority adolescent male patient who presented initially with complex ADHD, who upon extensive evaluation, was ultimately diagnosed with co-existing autism. This patient's diagnosis of ASD at the age of 14 in the setting of a pre-existing complex ADHD diagnosis demonstrates how symptoms of inattention or hyperactivity may convolute underlying or newly emerging social interaction difficulties. We highlight how children who are diagnosed with ADHD should be screened or evaluated for autism in the right clinical setting, such as evident persistence of social interaction impairment despite ADHD treatment.

Henry's Law Constants and Indoor Partitioning of Microbial Volatile Organic Compounds.

Microbial volatile organic compounds (MVOCs) play an essential role in many environmental fields, such as indoor air quality. Long-term exposure to odorous and toxic MVOCs can negatively affect the health of occupants. Recently, the involvement of surface reservoirs in indoor chemistry has been realized, which signifies the importance of the phase partitioning of volatile organic pollutants. However, reliable partition coefficients of many MVOCs are currently lacking. Equilibrium partition coefficients, such as Henry's law constant, H, are crucial for understanding the environmental behavior of chemicals. This study aims to experimentally determine the H values and their temperature dependence for key MVOCs under temperature relevant to the indoor environment. The H values were determined with the inert gas-stripping (IGS) method and variable phase ratio headspace (VPR-HS) technique. A two-dimensional partitioning model was applied to predict the indoor phase distribution of MVOCs and potential exposure pathways to the residences. The findings show that the MVOCs are likely distributed between the gas and weakly polar (e.g., organic-rich) reservoirs indoors. Temperature and the volume of reservoirs can sensitively affect indoor partitioning. Our results give a more comprehensive view of indoor chemical partitioning and exposure.

Patient attendance at molecular tumor board: A new means of shared decision making?

Patient engagement in medical decision-making improves patient related outcomes through compliance and patient satisfaction. The Inova Schar Cancer Institute has a weekly molecular tumor board (MTB) to match comprehensive genomic sequencing results with targeted therapies for patients. Primary oncologists extended MTB invitations to their patients. Ultimately, 20 of the 139 patients attended and completed pre- and post MTB surveys. There was a statistically significant change from the pre- to post- survey for the question "I am satisfied with how well informed I am about targeted therapy" with P = 0.016. Patients who attended MTB reported higher levels of satisfaction with their knowledge of targeted therapy after MTB as compared to before. A more holistic method of studying this practice would include sampling a larger patient population and a formal evaluation of the physicians' experience with patients attending.

High school health education: The impact of medical student led instruction in northern Nevada high schools.

Health education is an important topic in high school given its lasting effect on learners. Medical students are in a unique position to deliver this curriculum as they can provide information from a relatable standpoint. Ten medical students created a health education program, The Healthier Nevada Project (HNVP), designed for high school students using four modules focused on adolescent public health concerns: substance use and addiction, exercise, personal relationships, and stress and mental health. The curriculum was administered to over 700 health class students at three schools in Reno, Nevada, U.S.A., from August 2019-March 2020. This cross-sectional study measured whether the modules increased students' comfort level, familiarity, and likelihood of discussing each topic with a healthcare provider. The method of evaluation was pre- and post-Likert scale surveys with 7-10 questions regarding students' understanding of each topic, knowledge of related resources, and likelihood of future discussions with healthcare providers. Linear regression analysis showed significant increases in mean scores (in all cases p < 0.0001) for all four modules after the training. The modules were adjusted for the cluster effect of School and showed no significant two-way interaction between pre- and post-survey, although overall differences between schools were present. These findings indicate that HNVP significantly increased students' knowledge, comfort, and likelihood of discussing each topic with a healthcare professional following module administration. Future efforts will aim to evaluate the long-term impact of HNVP on student behavior and evaluate if presenter type influences program success among adolescents.

The complete mitochondrial genome of the chocolate chip sea cucumber Isostichopus badionotus (Echinodermata: Holothuroidea).

The chocolate chip sea cucumber, Isostichopus badionotus (Selenka 1867), is an ecologically and biomedically important species. In this study, we report the complete mitogenome sequence of the sea cucumber, I. badionotus (Echinodermata: Holothuroidea). The mitochondrial genome consisted of 16,319 bp, with 13 protein-coding genes, 22 tRNA genes, and 2 rRNA genes. The total nucleotide composition consisted of 31.61% A, 29.20% T, 23.48% C, 15.71% G, with a high A + T content of 60.81%. Phylogenetic analysis using the complete mitochondrial genome of I. badionotus is helpful in studying the evolution of beneficial adaptations to aid in bioremediation and biomedical research and development.

Reperfusion therapy with recombinant human relaxin-2 (Serelaxin) attenuates myocardial infarct size and NLRP3 inflammasome following ischemia/reperfusion injury via eNOS-dependent mechanism.

AIMS: The preconditioning-like infarct-sparing and anti-inflammatory effects of the peptide hormone relaxin following ischemic injury have been studied in the heart. Whether reperfusion therapy with recombinant human relaxin-2, serelaxin, reduces myocardial infarct size and attenuates the subsequent NLRP3 inflammasome activation leading to further loss of functional myocardium following ischemia/reperfusion (I/R) injury is unknown. METHODS AND RESULTS: After baseline echocardiography, adult male wild-type C57BL or eNOS knockout mice underwent myocardial infarction (MI) by coronary artery ligation for 30 min followed by 24 h reperfusion. Mice were treated with either serelaxin (10 µg/kg; sc) or saline 1 h prior to ischemia or 5 min before reperfusion. In both pre-treatment and reperfusion therapy arms, serelaxin improved survival at 24 h post MI in wild-type mice (79% and 82%) as compared with controls (46% and 50%, P = 0.01), whereas there was no difference in survival between serelaxin- and saline-treated eNOS knockout mice. Moreover, serelaxin significantly reduced infarct size (64% and 67% reduction, P < 0.05), measured with TTC staining, and preserved LV fractional shortening (FS) and end-systolic diameter (LVESD) in wild-type mice as compared with controls (P < 0.05). Interestingly, caspase-1 activity in the heart tissue, a measure of inflammasome formation, was markedly reduced in serelaxin-treated wild-type mice compared with controls at 24 h post-MI in both treatment modalities (P < 0.05). Genetic deletion of eNOS abolished the infarct-sparing and anti-inflammatory effects of serelaxin as well as functional preservation. Serelaxin plasma levels assessed at 5 min and 1 h after treatment, using ELISA, approximated physiologic relaxin levels during pregnancy in mice and parallels that in humans. CONCLUSION: Serelaxin attenuates myocardial I/R injury and the subsequent caspase-1 activation via eNOS-dependent mechanism.

Hovering performance of Anna's hummingbirds (Calypte anna) in ground effect.

Aerodynamic performance and energetic savings for flight in ground effect are theoretically maximized during hovering, but have never been directly measured for flying animals. We evaluated flight kinematics, metabolic rates and induced flow velocities for Anna's hummingbirds hovering at heights (relative to wing length R = 5.5 cm) of 0.7R, 0.9R, 1.1R, 1.7R, 2.2R and 8R above a solid surface. Flight at heights less than or equal to 1.1R resulted in significant reductions in the body angle, tail angle, anatomical stroke plane angle, wake-induced velocity, and mechanical and metabolic power expenditures when compared with flight at the control height of 8R. By contrast, stroke plane angle relative to horizontal, wingbeat amplitude and wingbeat frequency were unexpectedly independent of height from ground. Qualitative smoke visualizations suggest that each wing generates a vortex ring during both down- and upstroke. These rings expand upon reaching the ground and present a complex turbulent interaction below the bird's body. Nonetheless, hovering near surfaces results in substantial energetic benefits for hummingbirds, and by inference for all volant taxa that either feed at flowers or otherwise fly close to plant or other surfaces.