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Bracken fern (Pteridiumsp.) is a viable and vigorous plant with invasive potential, ingestion of which causes chronic illness and cancers in farm animals. Bracken is a suspected human carcinogen, and exposure can result from ingestion of bracken-contaminated water, dairy products, or meat derived from livestock grazing on bracken fern. Bracken is also consumed in the diets of some communities. Ptaquiloside (PTQ), a known bracken carcinogen, is an illudane-type glycoside that forms a highly reactive electrophile, PTQ dienone, known to produce N7-guanine and N3-adenine adducts in DNA. Here, we demonstrate for the first time that PTQ dienone also produces an O6-alkylguanine (O6-PTBguanine) in DNA. Since O6-alkylguanines in DNA can be mutagenic, this work provides a potential mechanistic link between PTQ exposure and carcinogenicity. O6-PTBguanine is poorly repaired by O6-methylguanine-DNA methyltransferase that acts on other O6-alkylguanines, further highlighting the potential risk of exposure to bracken and PTQ.

IntroductionElectronic nicotine delivery systems (ENDS) are known to contain heavy metals such as lead (Pb), nickel (Ni) and chromium (Cr). The presence of heavy metals in ENDS may be due to contamination of e-liquids or leaching from elements of the ENDS device. This study investigates differences in ENDS metal concentrations between product type, year of purchase, country of purchase and e-liquid flavour.MethodsVarious open-system (refill e-liquids; n=116) and closed-system (prefilled with e-liquid; n=120) products were purchased in 2017 and 2018 from the USA, England, Canada and Australia. Electrothermal atomic absorption spectroscopy was used to analyse each product for Pb, Ni and Cr. Multiple linear regression and Kruskal-Wallis non-parametric statistical tests were conducted using GraphPad.ResultsLinear regression showed system type, year of purchase (not supported by Kruskal-Wallis), country of purchase and flavour type each had significant impacts on heavy metal concentrations. Open-system e-liquid samples showed no quantifiable levels of heavy metals. Closed-system samples contained concerningly high concentrations of Pb, Ni and Cr. Closed-system samples from the USA commonly displayed higher average heavy metal concentrations than those from England. Some fruit and mint-flavoured closed-system products showed higher heavy metal concentrations than tobacco-flavoured products.ConclusionThe presence of heavy metals only in closed-system products suggests that metals may be leaching from ENDS device parts. Highly variable heavy metal concentrations between ENDS products demonstrate that various product characteristics may affect the degree of leaching and that there is a need for further regulation of these products.

PARP inhibitors have attracted considerable interest in drug discovery due to the clinical success of first-generation agents such as olaparib, niraparib, rucaparib, and talazoparib. Their success lies in their ability to trap PARP to DNA; however, first-generation PARP inhibitors were not strictly optimized for trapping nor for selectivity among the PARP enzyme family. Previously we described the discovery of the second-generation PARP inhibitor AZD5305, a selective PARP1-DNA trapper. AZD5305 maintained the antitumor efficacy of first-generation PARP inhibitors while exhibiting lower hematological toxicity. Recently, there has been interest in central nervous system (CNS)-penetrant PARP inhibitors for CNS malignancies and other neurological conditions; however, AZD5305 is not CNS penetrant. Herein we describe the discovery and optimization of a series of CNS-penetrant, PARP1-selective inhibitors and PARP1-DNA trappers, culminating in the discovery of AZD9574, a compound that maintains the PARP1 selectivity of AZD5305 with improved permeability, reduced efflux, and increased CNS penetration.

The growing threat of antimicrobial resistance (AMR) necessitates innovative strategies beyond conventional antibiotics. In response, we developed a rapid one-step method to sythesize antimicrobial peptide (AMP) ε-poly-L-lysine stabilized selenium nanoparticles (ε-PL-Se NPs). These polycrystalline NPs with highly positive net surface charges, exhibited superior antimicrobial activity against a broad panel of pathogens, including the Gram-positive and -negative bacteria Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Pseudomonas aeruginosaand their drug-resistant counterparts, as well as the yeast Candida albicans. Notably, 10PL-Se NPs exhibited 6-log reduction of methicillin-resistant S. aureus(MRSA) at a concentration of 5 μg/mL within 90 min, with minimum bactericidal concentrations (MBCs) below 50 μg/mL for all tested bacterial strains. The minimum fungicidal concentration (MFC) of 10PL-Se NPs against C. albicanswas 26 ± 10 μg/mL. Crucially, bacteria exposed to ε-PL-Se NPs exhibited significantly delayed resistance development compared to the conventional antibiotic kanamycin. S. aureusdeveloped resistance to kanamycin after ∼72 generations, whereas resistance to 10PL-Se NPs emerged after ∼216 generations. Remarkably, E. colishowed resistance to kanamycin after ∼39 generations but failed to develop resistance to 10PL-Se NPs even after 300 generations. This work highlights the synergistic interactions between ε-PL and Se NPs, offering a robust and scalable strategy to combat AMR.

Adverse events (AEs) experienced by children and adults with congenital heart disease (CHD) on ventricular assist devices (VADs) are sometimes unique to these populations. The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) and the Academic Research Consortium (ARC) aimed to harmonize definitions of pediatric and CHD AEs for use in clinical trials, registries, and regulatory evaluation. Data from the ACTION registry and adjudication committee were used to adapt general mechanical circulatory support ARC definitions. This ACTION-ARC international expert panel of trialists, clinicians, patients, families, statisticians, biomedical engineers, device developers, and regulatory agencies drafted and iterated definitions harmonized to ACTION data and existing literature during sessions conducted between December 2022 and May 2023, followed by dissemination across clinical/research audiences and professional organizations and further revision. Both email-linked, internet-based surveys and in-person discussions were used as a modified Delphi process. Nineteen AE types were identified and defined, including seven new event types and six event types that were deleted and will no longer be collected, achieving consensus. ACTION-ARC paired rigorous development with methodical stakeholder involvement and dissemination to define pediatric VAD AEs to facilitate assimilation of data across future clinical trials and evaluation of devices for VAD-supported children and adults with CHD.

Tissue-engineered vascular grafts (TEVGs) have emerged as a potential alternative to autologous grafts for replacing small-diameter blood vessels during bypass surgery. The axial alignment of endothelial cells (ECs) and the circumferential alignment of smooth muscle cells (SMCs) are crucial for functional native blood vessels (NBVs). However, achieving this cellular alignment in TEVGs remains a formidable challenge. In this study, TEVGs were developed using a low-cost technique that aligned ECs axially and SMCs circumferentially within hours. The TEVGs comprised an electrospun polycaprolactone (PCL) layer and a gelatin methacryloyl (GelMA) cast layer. A freezing-induced alignment technique was developed that partially aligns the electrospun fibers axially, thereby promoting rapid axial alignment of ECs. Furthermore, SMCs cultured in a GelMA layer with intermediate stiffness (5–12 kPa) surrounding a PCL tube could promote conformation of the SMCs to the curvature of the PCL tube, resulting in their spontaneous circumferential alignment. Additionally, the TEVGs demonstrated mechanical properties similar to those of NBVs, which could facilitate future translation. This approach represents a significant advance in tissue engineering, enabling the fabrication of TEVGs with appropriate mechanical properties that recapitulate key NBV cell structural features within hours using a scalable and accessible method.

We sought to develop a contemporary risk assessment tool for use in pediatric ventricular assist device (VAD) candidates to estimate risk for mortality on the device using readily available preimplantation clinical data. Training and testing datasets were created from Advanced Cardiac Therapies Improving Outcomes Network (ACTION) registry data on patients supported with a VAD from 2012 to 2021. Potential risk factors for mortality were assessed and incorporated into a simplified risk prediction model utilizing an open-source, gradient-boosted decision tree machine learning library, known as random forest. Predictive performance was assessed by the area under the receiver operating characteristic curve in the testing dataset. Nine significant risk factors were included in the final predictive model which demonstrated excellent discrimination with an area under the curve of 0.95. In addition to providing a framework for establishing pediatric-specific risk profiles, our model can help inform team expectations, guide optimal patient selection, and ultimately improve patient outcomes.

Ventricular assist device (VAD) options vary for children in different weight groups. This study evaluates contemporary device usage and outcomes for children based on weight. Data from the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) registry were examined for patients with dilated cardiomyopathy (DCM) in 4 weight cohorts: <8 kg, 8–20 kg, 21–40 kg, and >40 kg, for devices implanted 3/2013–10/2020. Adverse event rates and ultimate outcome (deceased, alive on device, transplanted, or ventricular recovery) were analyzed. 222 DCM patients were identified with 24% in cohort 1, 23% in cohort 2, 15% in cohort 3, and 38% in cohort 4. Of 272 total implants, paracorporeal pulsatile devices were most common (95%) in cohorts 1 and 2 and intracorporeal continuous devices (81%) in cohorts 3 and 4. Stroke was noted in 17%, 12%, 6%, and 4% of cohorts, respectively (Cohort 1 vs. 4 and 2 vs. 4 – p= 0.01; other comparisons – not significant). Incidences of major bleeding, device malfunction, and infection was not different. All cohorts had >90% positive outcomes. Stroke incidence was higher in smaller cohorts, but other outcomes were similar. Positive outcomes were attained in over 90% across all weight groups, demonstrating excellent outcomes using current VADs in this DCM population.

Engineering biointerfaces with nanoscale clustering of integrin‐binding cell adhesive peptides is critical for promoting receptor redistribution into signaling complexes. Skeletal muscle cells are exquisitely sensitive to integrin‐mediated signaling, yet biomaterials supporting myogenesis through control of the density and nanodistribution of ligands have not been developed. Here, materials are developed with tailorable cell adhesive ligands distribution at the interface by independently controlling their global and local density to enhance myogenesis, by promoting myoblast growth and myotube formation. To this end, RGD‐functionalized low‐fouling polymer surfaces with global ligand densities (G) from 0–7 µg peptide/mg polymer and average local ligand densities (L) from 1–6.3 ligands/cluster, are generated and characterized. Cell studies demonstrate improvements in cell adhesion, spreading, growth, and myotube formation up to a density of 7 µg peptide/mg polymer with 4 ligands/cluster. Optimizing ligand density and distribution also promotes early myofiber maturation, identified by increased MF20 marker protein expression and sarcomere‐forming myotubes. At higher ligand densities, these cell properties are decreased, indicating that ligand multivalency is a critical parameter for tailoring cell‐material interactions, to a certain threshold. The findings provide new insights for designing next‐generation biomaterials and hold promise for improved engineering of skeletal muscle. This study presents biomaterial surface design for skeletal muscle tissue regeneration through molecular nanoengineering of cell adhesive ligands. Using RAFT polymerization and polymer blending, ligand nanoclusters with controlled distribution are developed. Results indicate a biphasic response in which optimal ligand clustering enhanced myoblast adhesion, proliferation, and myogenesis, highlighting the necessity of precise biomimetic interface design in muscle tissue engineering.

Individuals with opioid use disorder are at elevated suicide risk, but systematic screening in this population is rarely done. This study assessed the effects of targeted clinical decision support prompts on structured suicide risk assessment completion.

The one-dimensional aggregation theory was applied to the small angle neutron scattering (SANS) analyzed data of surfactant solutions. Plots of the hydrophobic bonding energy Eto form an aggregate against the number-average aggregation number n were found to be powerful to estimate the compositional ratios of different aggregate species co-existing in a gross sample solution.One-dimensional aggregate theory was applied to the SANS-analyzed data of micelle solutions. Plots of the hydrophobic bonding energy E(E1, E2and E3) to form a micelle against the number-average aggregation number n were found to provide the compositional ratios (XI, XIIand XIII) of three micelle species (I, II and III) co-existing in a gross sample.

Both common and rare genetic variants influence complex traits and common diseases. Genome-wide association studies have identified thousands of common-variant associations, and more recently, large-scale exome sequencing studies have identified rare-variant associations in hundreds of genes1–3. However, rare-variant genetic architecture is not well characterized, and the relationship between common-variant and rare-variant architecture is unclear4. Here we quantify the heritability explained by the gene-wise burden of rare coding variants across 22 common traits and diseases in 394,783 UK Biobank exomes5. Rare coding variants (allele frequency < 1 × 10−3) explain 1.3% (s.e. = 0.03%) of phenotypic variance on average—much less than common variants—and most burden heritability is explained by ultrarare loss-of-function variants (allele frequency < 1 × 10−5). Common and rare variants implicate the same cell types, with similar enrichments, and they have pleiotropic effects on the same pairs of traits, with similar genetic correlations. They partially colocalize at individual genes and loci, but not to the same extent: burden heritability is strongly concentrated in significant genes, while common-variant heritability is more polygenic, and burden heritability is also more strongly concentrated in constrained genes. Finally, we find that burden heritability for schizophrenia and bipolar disorder6,7is approximately 2%. Our results indicate that rare coding variants will implicate a tractable number of large-effect genes, that common and rare associations are mechanistically convergent, and that rare coding variants will contribute only modestly to missing heritability and population risk stratification.

BackgroundThe e-cigarette market has rapidly evolved, with a shift towards higher nicotine concentration and salt-based products, such as JUUL; however, the implications for youth vaping remain unclear.MethodsRepeat cross-sectional online surveys were conducted in 2017, 2018 and 2019, with national samples of youth aged 16–19 years recruited from commercial panels in Canada (n=12 018), England (n=11 362) and the USA (n=12 110). Regression models examined differences between countries and over time in the types of e-cigarette products used (design and nicotine content), reasons for using brands and differences in patterns of use, sociodemographics and dependence symptoms by brand/nicotine content.ResultsIn 2019, the use of pod- or cartridge-style e-cigarettes was greater in Canada and the USA than England, with Smokand JUULthe leading brands in all countries. In 2019, youth vapers in England were less likely to report using e-cigarettes with ≥2% nicotine (12.8%) compared with Canada (40.5%; adjusted OR (AOR)=4.96; 95% CI 3.51 to 7.01) and the USA (37.0%; AOR=3.99, 95% CI 2.79 to 5.71) and less likely to report using nicotine salt-based products (12.3%) compared with Canada (27.1%; AOR=2.77, 95% CI 1.93 to 3.99) and the USA (21.9%; AOR=2.00, 95% CI 1.36 to 2.95). In 2019, self-reported use of products with higher nicotine concentration was associated with significantly greater frequency of vaping, urges to vape and perceived vaping addiction (p<0.05 for all).ConclusionsThe use of high-nicotine salt-based products is associated with greater symptoms of dependence, including JUULand other higher-nicotine brands. Greater use of high-nicotine salt-based products may account for recent increases in the frequency of vaping among youth in Canada and the USA.

ObjectivesThe e-cigarette or vaping product use-associated lung injury (EVALI) outbreak caused serious lung injuries in over 2800 people in the USA in 2019. By February 2020, most cases were determined as linked with vaping tetrahydrocannabinol (THC), including black market products using vitamin E acetate. This study examined smokers’ EVALI awareness, knowledge and perceived impact on their e-cigarette interest approximately 16 months after its peak.DesignBetween January and February 2021, we surveyed 1018 adult current smokers from a nationally representative US research panel. Participants were asked if they had heard about EVALI prior to COVID-19, knew its main cause, and if EVALI had impacted their interest in future e-cigarette use.ResultsApproximately 54% of smokers had heard of EVALI. Among those who had heard of EVALI (n=542), 37.3% believed its maincause was e-cigarettes used to vape nicotine, like JUUL. Fewer (16.6%) thought the main cause was products for vaping marijuana/THC, and 20.2% did not know. About 29% had heard vitamin E acetate was associated with EVALI, and 50.9% indicated EVALI made them less interested in using e-cigarettes in the future. EVALI awareness was significantly associated with e-cigarette risk perceptions (ie, that e-cigarettes are as harmful as smoking).ConclusionsDespite the passage of time, considerable lack of knowledge and misperceptions about EVALI remain among those who smoke. Our findings suggest the need for continued efforts to promote better understanding of EVALI and appropriate behavioural and policy responses.

The sport of ice hockey has reached worldwide popularity, and it continues to grow. With this growth, however, there has also been an increase in the number of injuries related to the high-speed physical nature of the sport. Upper extremity related traumas and maladies are amongst the most commonly experienced injuries in this population of athletes. The objective of this narrative review is to appraise the current literary landscape as to the epidemiology, treatment, and return to play experienced with the most common upper extremity orthopedic injuries related to ice hockey play.

IntroductionBetween 2015 and 2018, Canada banned menthol cigarettes. This study pooled data from two pre–post cohort studies (the Ontario Menthol Ban Study, and the International Tobacco Control Policy Evaluation (ITC) Canada Survey, conducted in seven provinces) to derive more precise estimates of the impact of Canada’s menthol ban on quitting and to apply these estimates to project the impact of a menthol ban in the USA.MethodsWeighted multivariable logistic analyses compared post-ban quit success of menthol smokers with non-menthol smokers (for daily smokers and for all (daily + non-daily) smokers), controlling for sex, age, ethnicity, education, baseline smoking status, baseline cigarettes per day and study regions. Projections to the USA were created by multiplying the effect size of the Canadian menthol ban on quitting (percentage of increased quitting among menthol smokers) by the number of menthol smokers overall and among African Americans, from the 2019 National Survey on Drug Use and Health.ResultsAfter the menthol cigarette ban, menthol smokers were more likely than non-menthol smokers to have quit smoking among daily smokers (difference=8.0%; 95% CI: 2.4% to 13.7%,p=0.005) and all (daily+non-daily) smokers (difference=7.3%; 95% CI: 2.1% to 12.5%,p=0.006). The projected number of smokers who would quit after a US menthol ban would be 789 724 daily smokers (including 199 732 African Americans) and 1 337 988 daily+non-daily smokers (including 381 272 African Americans).ConclusionsThis pooled analysis of Canada’s menthol cigarette ban provides the foundation for estimating the impact of menthol bans in the USA and other countries. Projections suggest that a US menthol cigarette ban would have a substantial impact on increasing quitting.

High-intensity sweet-liking has been linked to alcohol use disorder (AUD) risk. However, the neural underpinning of this association is poorly understood. To find a biomarker predictive of AUD, 140 participants (social and heavy drinkers, ages 21–26) underwent functional magnetic resonance imaging (fMRI) during a monetary incentive delay (MID) task and stimulation with high (SucroseHigh)- and low-concentration sucrose, as well as viscosity-matched water. On another day after imaging, and just before free-access intravenous alcohol self-administration, participants experienced a 30 mg% alcohol prime (10 min ascent) using the Computerized Alcohol Infusion System. Principal component analysis (PCA) of subjective responses (SR) to the prime’s ascending limb generated enjoyable (SRenjoy) and sedative (SRsed) intoxication components. Another PCA created one component reflective of self-administered alcohol exposure (AE) over 90 min. Component loadings were entered as regressors in a voxel-wise general linear fMRI model, with reward type as a fixed factor. By design, peak prime breath alcohol concentration was similar across participants (29 ± 3.4 mg%). SRenjoyon the prime’s ascending limb correlated positively with [SucroseHigh > Water] in the supplementary motor area and right dorsal anterior insula, implicating the salience network. Neither SR component correlated with the brain’s response to MID. AE was unrelated to brain reward activation. While these findings do not support a relationship between alcohol self-administration and (1) subjective liking of or (2) regional brain response to an intensely sweet taste, they show that alcohol’s enjoyable intoxicating effects on the rising limb correspond with anterior insular and supplementary motor area responses to high-concentration sucrose taste. No such associations were observed with MID despite robust activation in those regions. Insula and supplementary motor area responses to intense sensations relate to a known risk factor for AUD in a way that is not apparent with a secondary (monetary) reward.

Herein, the diverging dielectrophoretic (DEP) electrode is designed to extract the vapor bubbles generated in a flow-boiling evaporator. The DEP and hydrodynamic forces acting on the undeformable single vapor bubble in the diverging electrode are estimated by the uncoupled flow and electrostatic simulation. The Maxwell stress, static pressure, and viscous shear stress on the bubble surface are considered. The diverging DEP electrode successfully generates a net force that acts on the bubble in the flow direction. The DEP force is dominant against drag at a low imposed mass flux and high applied electric field, where heat transfer enhancement could be expected. A large DEP force pushing the bubble toward the electrode is found when the bubble is close to the electrode.

Linkage disequilibrium (LD) is the correlation among nearby genetic variants. In genetic association studies, LD is often modeled using large correlation matrices, but this approach is inefficient, especially in ancestrally diverse studies. In the present study, we introduce LD graphical models (LDGMs), which are an extremely sparse and efficient representation of LD. LDGMs are derived from genome-wide genealogies; statistical relationships among alleles in the LDGM correspond to genealogical relationships among haplotypes. We published LDGMs and ancestry-specific LDGM precision matrices for 18 million common variants (minor allele frequency >1%) in five ancestry groups, validated their accuracy and demonstrated order-of-magnitude improvements in runtime for commonly used LD matrix computations. We implemented an extremely fast multiancestry polygenic prediction method, BLUPx-ldgm, which performs better than a similar method based on the reference LD correlation matrix. LDGMs will enable sophisticated methods that scale to ancestrally diverse genetic association data across millions of variants and individuals.

The canonical paradigm for converting genetic association to mechanism involves iteratively mapping individual associations to the proximal genes through which they act. In contrast, in the present study we demonstrate the feasibility of extracting biological insights from a very large region of the genome and leverage this strategy to study the genetic influences on autism. Using a new statistical approach, we identified the 33-Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of autism’s common polygenic influences. The region also includes the mechanistically cryptic and autism-associated 16p11.2 copy number variant. Analysis of RNA-sequencing data revealed that both the common polygenic influences within 16p and the 16p11.2 deletion were associated with decreased average gene expression across 16p. The transcriptional effects of the rare deletion and diffuse common variation were correlated at the level of individual genes and analysis of Hi-C data revealed patterns of chromatin contact that may explain this transcriptional convergence. These results reflect a new approach for extracting biological insight from genetic association data and suggest convergence of common and rare genetic influences on autism at 16p.

ContextMore than half of all spinal cord injuries (SCI) occur at the cervical level leading to loss of upper limb function, restricted activity and reduced independence. Several technologies have been developed to assist with upper limb functions in the SCI population.ObjectiveThere is no clear clinical consensus on the effectiveness of the current assistive technologies for the cervical SCI population, hence this study reviews the literature in the years between 1999 and 2019.MethodsA systematic review was performed on the state-of-the-art assistive technology that supports and improves the function of impaired upper limbs in cervical SCI populations. Combinations of terms, covering assistive technology, SCI, and upper limb, were used in the search, which resulted in a total of 1770 articles. Data extractions were performed on the selected studies which involved summarizing details on the assistive technologies, characteristics of study participants, outcome measures, and improved upper limb functions when using the device.ResultsA total of 24 articles were found and grouped into five categories, including neuroprostheses (invasive and non-invasive), orthotic devices, hybrid systems, robots, and arm supports. Only a few selected studies comprehensively reported characteristics of the participants. There was a wide range of outcome measures and all studies reported improvements in upper limb function with the devices.ConclusionsThis study highlighted that assistive technologies can improve functions of the upper limbs in SCI patients. It was challenging to draw generalizable conclusions because of factors, such as heterogeneity of recruited participants, a wide range of outcome measures, and the different technologies employed.

IMPORTANCE: The United Network for Organ Sharing (UNOS) evaluates donor risk for acute transmission of HIV, hepatitis B, or hepatitis C based on US Public Health Services (PHS)–specific criteria. However, recent data regarding use and outcomes of those donors with PHS risk criteria among pediatric and adult heart transplant recipients are lacking. OBJECTIVE: To compare use and outcomes of graft from donors with PHS risk criteria vs those with a standard-risk donor (SRD) in children vs adults in a contemporary cohort. DESIGN, SETTING, AND PARTICIPANTS: This cohort was a nationwide analysis of heart transplants in the US that used data from the UNOS database. Participants were children (&lt;18 years old) and adults (≥18 years old) who received a heart transplant from January 1, 2010, to December 31, 2021. EXPOSURES: UNOS-defined donor risk status. MAIN OUTCOMES AND MEASURES: Trend analysis compared changes in PHS risk criteria use among children and adults. Patient survival was analyzed using Kaplan-Meier curves with log rank and Cox proportional hazards to compare PHS risk-criteria outcomes vs SRD-criteria outcomes in children and adult heart transplant recipients. Additional analysis was performed among adults who received a PHS–risk criteria graft that was previously declined for pediatric recipients. RESULTS: Of 5115 pediatric transplant recipients (donor without PHS risk median [IQR] age, 5 [0-13] years and donor with PHS risk median [IQR] age, 8 [0-14] years) and 30 289 adult heart transplant recipients (donor without PHS risk median [IQR] age, 56 [46-63] years and donor with PHS risk median [IQR] age, 57 [47-63] years), PHS risk criteria comprised 8% in children vs 25% in adults. PHS criteria are being increasingly used over the past decade with the proportion of recipients transplanted with PHS risk-criteria donors being approximately 3 times greater among adult recipients than children recipients. Pediatric recipients of a PHS risk-criteria donor had greater pretransplant ventilatory support, whereas adult recipients of a PHS risk-criteria donor had greater pretransplant extracorporeal membrane oxygenation use. Patient survival was similar between pediatric recipients of PHS risk-criteria grafts vs SRD-criteria grafts and slightly higher among adult recipients of PHS risk-criteria grafts vs SRD-criteria grafts. The 1778 adult recipients who received a PHS criteria-risk donor that was previously declined for pediatric recipients had similar patient survival recipients compared with SRD-criteria donors (HR, 0.92; 95% CI, 0.81-1.03; P = .18). CONCLUSIONS AND RELEVANCE: In the current era, a 3-fold greater proportion of adult recipients receive a PHS risk-criteria graft compared with children despite similar posttransplant patient survival. The ongoing organ donor shortage underscores the need for consideration of PHS risk criteria where these donors remain underused.

AbstractThe mission of the U.S. Department of Energy (DOE) Office of Nuclear Energy is to advance nuclear power to meet the nation’s energy, environmental, and national security needs. Advanced nuclear technology development, as well as support for the current nuclear power industry, requires a robust infrastructure for experimentation, testing, design evolution, and component qualification. The current lack of fast neutron spectrum testing capabilities has been identified as a significant gap in the U.S. infrastructure that impedes the development of next-generation nuclear reactors—many of which require a fast neutron spectrum for operation—and equally impacts the United States’ ability to regain global technology leadership in this arena. To close the gap and support advanced technology development, the DOE has established the Versatile Test Reactor (VTR) project to provide high-performance testing capability, specifically, a fast neutron source to develop, test, and qualify advanced fuels and materials for the next generation of advanced reactors and existing commercial reactors. This paper describes the establishment of the project, the identification of its mission and requirements, and the design approach and status.

Heterogeneity in the clinical presentation of SARS-CoV-2 infection and COVID-19 progression underscores the urgent need to identify individual-level susceptibility factors that affect infection vulnerability and disease severity. Tobacco product use is a potential susceptibility factor. In this Personal View, we provide an overview of the findings of peer-reviewed, published studies relating tobacco product use to SARS-CoV-2 infection and COVID-19 outcomes, with most studies focusing on cigarette smoking in adults. Findings pertaining to the effects of tobacco product use on the incidence of SARS-CoV-2 infection are inconsistent. However, evidence supports a role for cigarette smoking in increasing the risk of poor COVID-19 outcomes, including hospital admission, progression in disease severity, and COVID-19-related mortality. We discuss the potential effects of tobacco use behaviour on SARS-CoV-2 transmission and infection, and highlight the pathophysiological changes associated with cigarette smoking that could promote SARS-CoV-2 infection and increased disease severity. We consider the biological mechanisms by which nicotine and other tobacco product constituents might affect immune and inflammatory responses to SARS-CoV-2 infection. Finally, we identify current knowledge gaps and suggest priorities for research to address acute and post-acute health outcomes of COVID-19 during and after the pandemic.

Cancer is a systemic manifestation of aberrant cell cycle activity and dysregulated cell growth. Genetic mutations can determine tumor onset by either augmenting cell division rates or restraining normal controls such as cell cycle arrest or apoptosis. As a result, tumor cells not only undergo uncontrolled cell division but also become compromised in their ability to exit the cell cycle accurately. Regulation of cell cycle progression is enabled by specific surveillance mechanisms known as cell cycle checkpoints, and aberrations in these signaling pathways often culminate in cancer. For instance, DNA damage checkpoints, which preclude the generation and augmentation of DNA damage in the G1, S, and G2 cell cycle phases, are often defective in cancer cells, allowing cell division in spite of the accumulation of genetic errors. Notably, tumors have evolved to become dependent on checkpoints for their survival. For example, checkpoint pathways such as the DNA replication stress checkpoint and the mitotic checkpoint rarely undergo mutations and remain intact because any aberrant activity could result in irreparable damage or catastrophic chromosomal missegregation leading to cell death. In this review, we initially focus on cell cycle control pathways and specific functions of checkpoint signaling involved in normal and cancer cells and then proceed to examine how cell cycle control and checkpoint mechanisms can provide new therapeutic windows that can be exploited for cancer therapy.

There are minimal data describing outcomes in ambulatory pediatric and young adult ventricular assist device (VAD)-supported patient populations. We performed a retrospective analysis of encounter-level data from 2006 to 2017 Nationwide Emergency Department Sample (NEDS) to compare emergency department (ED) resource utilization and outcomes for pediatric (≤18 years, n = 494) to young adult (19–29 years, n = 2,074) VAD-supported patient encounters. Pediatric encounters were more likely to have a history of congenital heart disease (11.3% vs.4.8%). However, Pediatric encounters had lower admission/transfer rates (37.8% vs.57.8%) and median charges ($3,334 (IQR $1,473–$19,818) vs.$13,673 ($3,331–$45,884)) (all p< 0.05). Multivariable logistic regression modeling revealed that age itself was not a predictor of admission, instead high acuity primary diagnoses and medical complexity were: (adjusted odds ratio; 95% confidence intervals): cardiac (3.0; 1.6–5.4), infection (3.4; 1.7–6.5), bleeding (3.9; 1.7–8.8), device complication (7.2; 2.7–18.9), and ≥1 chronic comorbidity (4.1; 2.5–6.7). In this largest study to date describing ED resource use and outcomes for pediatric and young adult VAD-supported patients, we found that, rather than age, high acuity presentations and comorbidities were primary drivers of clinical outcomes. Thus, reducing morbidity in this population should target comorbidities and early recognition of VAD-related complications.

The devastating effects of the coronavirus disease 2019 (COVID-19) pandemic have made clear a global necessity for antiviral strategies. Most fatalities associated with infection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) result at least partially from uncontrolled host immune response. Here, we use an antisense compound targeting a previously identified microRNA (miRNA) linked to severe cases of COVID-19. The compound binds specifically to the miRNA in question, miR-2392, which is produced by human cells in several disease states. The safety and biodistribution of this compound were tested in a mouse model via intranasal, intraperitoneal, and intravenous administration. The compound did not cause any toxic responses in mice based on measured parameters, including body weight, serum biomarkers for inflammation, and organ histopathology. No immunogenicity from the compound was observed with any administration route. Intranasal administration resulted in excellent and rapid biodistribution to the lungs, the main site of infection for SARS-CoV-2. Pharmacokinetic and biodistribution studies reveal delivery to different organs, including lungs, liver, kidneys, and spleen. The compound was largely cleared through the kidneys and excreted via the urine, with no accumulation observed in first-pass organs. The compound is concluded to be a safe potential antiviral treatment for COVID-19.

Promoting athlete wellbeing has become a priority in elite sport, and the COVID-19 pandemic has accentuated the need for a comprehensive understanding of risk and protective factors. Existing sport research has not yet considered whether specific cognitive factors such as dispositional mindfulness and executive function may protect athletes against psychological distress. In a sample of high-performance Australian football athletes (n= 27), we administered measures of dispositional mindfulness (MAAS), executive function (AOSPAN; eStroop), and psychological distress (APSQ) at pre-season, coinciding with the initial (2020) COVID-19-related sport shutdown in Australia. Measures of executive function and psychological distress were re-administered at the end of the COVID-19 affected competitive season in 2020. Athletes reported significantly elevated psychological distress relative to previous estimates of distress among high-performance athletes established in prior studies. Executive functions, including working memory and inhibitory control were not significantly associated with psychological distress or dispositional mindfulness at either timepoint. However, baseline mindfulness was associated with reduced distress at both pre-season (r = −0.48, p= .03) and end of season (r = −0.56, p= .004), suggesting that dispositional mindfulness may have afforded protective buffering against symptoms of distress. Correlation data alone does not establish a directional connection from mindfulness to reduced distress, and future research is required to elucidate this association and/or establish the mechanism/s by which dispositional mindfulness may protect against psychological distress in this population.

Introduction: Prenatal alcohol exposure (PAE) impacts an estimated 5% or more children born in the USA and is associated with life-long neuropsychological deficits. Early identification is essential but access to diagnostic evaluation is limited. This study reports on the effectiveness of training child psychologists to identify and measure the salient physical features of PAE. Methods: Children, 8–13 years, were divided into two groups: (1) children meeting criteria for PAE (n= 46) and (2) typically developing controls without PAE (TD; n= 36). Child psychologists were trained to reliability measure height, weight, occipital frontal circumference (OFC), and the characteristic facial features of FASD independent of knowledge of PAE history. Results: Groups differed significantly on meeting the diagnostic criteria proposed by Hoyme et al. (Pediatrics, 138:e20154256, 2016) on height, OFC, upper vermillion border, philtrum, and palpebral fissure length.They did not differ on weight. All children in the alcohol exposed group could be classified as meeting criteria for an FASD whereas none in the unexposed group met criteria. Discussion: This study demonstrated that child psychologists, blind to PAE history, could be reliably trained to assess the physical features of children with PAE. Because early diagnosis and intervention is of paramount importance, we propose that inclusive diagnostic criteria for FASD and the use of psychologists and other allied health professionals, trained to screen for the diagnosis, should be expanded in clinical practice.

Articular cartilage defects caused by injury frequently lead to osteoarthritis, a painful and costly disease. Despite widely used surgical methods to treat articular cartilage defects and a plethora of research into regenerative strategies as treatments, long-term clinical outcomes are not satisfactory. Failure to integrate repair tissue with native cartilage is a recurring issue in surgical and tissue-engineered strategies, seeing eventual degradation of the regenerated or surrounding tissue. This review delves into the current understanding of why continuous and robust integration with native cartilage is so difficult to achieve. Both the intrinsic limitations of chondrocytes to remodel injured cartilage, and the significant challenges posed by a compromised biomechanical environment are described. Recent scaffold and cell-based techniques to repair cartilage are also discussed, and limitations of existing methods to evaluate integrative repair. In particular, the importance of evaluating the mechanical integrity of the interface between native and repair tissue is highlighted as a meaningful assessment of any strategy to repair this load-bearing tissue.Impact statementThe failure to integrate grafts or biomaterials with native cartilage is a major barrier to cartilage repair. An in-depth understanding of the reasons cartilage integration remains a challenge is required to inform cartilage repair strategies. In particular, this review highlights that integration of cartilage repair strategies is frequently assessed in terms of the continuity of tissue, but not the mechanical integrity. Given the load-bearing nature of cartilage, evaluating integration in terms of interfacial strength is essential to assessing the potential success of cartilage repair methods.

ObjectivesStudies examining perceptions of ‘modified risk tobacco product’ (MRTP) messages for e-cigarettes and smokeless tobacco have indicated consumers want statistics and quantification of harm reduction. However, limited research exists on reactions to quantitative MRTP messages.DesignWe conducted 12 focus groups in the USA in 2019—6 focused on e-cigarette messages and 6 on snus messages. Eight groups were with current smokers (ages 21–66) and four with young adult (ages 18–25) non-smokers (n=57). Participants discussed messages stating that use of snus and vaping products have been estimated by scientists to be about 90% and 95% less harmful than smoking cigarettes, respectively.ResultsSeveral participants agreed the messages strongly communicated that the products are less harmful than cigarettes, were attention getting and could be ‘convincing’. However, participants expressed scepticism about the source and accuracy of the stated figures, and some noted the claims could be misleading and attractive to young people. Comments also reflected some claim misunderstandings (eg, that e-cigarettes only pose a 5% chance of harm). Participants also agreed that stating e-cigarette risks ‘are unlikely to exceed 5% of cigarette smoking harms’ was confusing and less impactful than the ‘95% less harmful’ wording.ConclusionsQuantitative claims suggesting high levels of reduced risk when comparing e-cigarettes or smokeless tobacco/snus relative to cigarettes may be successful in gaining attention and being persuasive for some audiences, particularly, if from more credible sources. However, message developers, users and evaluators should be mindful of message limitations and aim to mitigate unintended consequences.

ObjectiveTo evaluate heated tobacco product (HTP) awareness, trial and current use among adult cigarette smokers and vaping product users in four countries with varying regulations governing HTP sales.DesignData came from Wave 2 of the ITC Four Country Smoking and Vaping Survey, collected from February to July 2018. Respondents were current and former smokers and/or users of vaping products (18 years or older) from Canada (CA; n=3778), England (EN; n=4848), the USA (US; n=2846) and Australia (AU; n=1515). At the time of the survey, only Canada and England permitted the sale of contemporary HTPs (eg, IQOS).ResultsOverall, 30.2% of respondents reported being aware of HTPs (CA=30.4%; EN=31.0%; US=30.2%; AU=27.4%; p=0.346), 2.4% had ever tried HTPs (CA=3.3%; EN=2.4%; US=2.0%; AU=0.9%; p=0.001) and 0.9% currently used HTPs at least monthly (CA=0.8%; EN=1.2%; US=0.7%; AU=0.2%; p<0.001). Trial and current use were higher among those who concurrently smoked and vaped (at least monthly) versus other nicotine use categories (trial: 10.9% v. 1.2%–2.0%, p<0.001; current use: 8.4% v. 0.1%–1.0%, p<0.001). In multivariable analyses, HTP awareness did not differ across countries, whereas odds of trial and current use were lower where HTPs were unavailable. Odds of HTP trial did not differ by regulatory environment when restricting analysis to HTP-aware concurrent smokers–vapers.ConclusionApproximately one third of respondents were aware of HTPs, even in the USA and Australia, where contemporary HTPs were not yet on the market. Trial and use were uncommon, except among concurrent smokers–vapers. Restrictions on availability may have limited HTP use generally, but less so for concurrent smokers–vapers.

ObjectiveThe current study examined indicators of dependence among youth cigarette smokers and e-cigarette users in Canada, England and the USA, including changes between 2017 and 2019.MethodsData are from repeated cross-sectional online surveys conducted in 2017, 2018 and 2019 with national samples of youth aged 16–19 years, in Canada (n=12 018), England (n=11 362) and the USA (n=12 110). Measures included perceived addiction to cigarettes/e-cigarettes, frequency of experiencing strong urges to smoke/use an e-cigarette, plans to quit smoking/using e-cigarettes and past attempts to quit. Logistic regression models were fitted to examine differences between countries and changes over time.ResultsThe proportion of ever-users who vaped frequently was significantly higher in 2019 compared with 2017 for all outcomes in each country. Between 2017 and 2019, the proportion of past 30-day vapers reporting strong urges to vape on most days or more often increased in each country (Canada: 35.3%, adjusted OR (AOR) 1.69, 95% CI 1.20 to 2.38; England: 32.8%, AOR 1.55, 1.08 to 2.23; USA: 46.1%, AOR 1.88, 1.41 to 2.50), along with perceptions of being ‘a little’ or ‘very addicted’ to e-cigarettes (Canada: 48.3%, AOR 1.99, 1.44 to 2.75; England: 40.1%, AOR 1.44, 1.03 to 2.01; USA: 53.1%, AOR 1.99, 1.50 to 2.63). Indicators of dependence among smokers were consistently greater than e-cigarette users, although differences had narrowed by 2019, particularly in Canada and the USA.ConclusionsPrevalence of dependence symptoms among young e-cigarette users increased between 2017 and 2019, more so in Canada and the USA compared with England. Dependence symptom prevalence was lower for e-cigarettes than smoking; however, the gap has narrowed over time.

Study design: Systematic review. Objective: To systematically review the evidence for the effectiveness of telerehabilitation as an intervention for people with spinal cord injury (SCI) in low-and middle-income countries (LMICs). Setting: Not applicable. Methods: MEDLINE (Ovid), Embase (Ovid), Pubmed and Global Health databases were used to identify studies published between 1946–2020 meeting the following criteria: (1) patients with SCI diagnosis; (2) in LMIC; (3) an outcome measuring clinical functional ability, quality of life or all-cause mortality reduction. The risk of bias in studies was graded using revised Cochrane risk-of-bias tool in randomised trials (RoB 2) and risk-of-bias tool in non-randomised trials (ROBINS-I). Evidence levels were graded with Grading of Recommendations, Assessment, Development and Evaluations (GRADE). Results: In total, 107 articles were identified from the initial search. After screening, five studies were included. Some significant improvements to quality of life and pressure ulcer management were observed, alongside some improvement in functional ability with suggested improvement to depression scores. Telerehabilitation alleviated participants’ sense of social isolation, improved satisfaction scores and assisted them to remember techniques for SCI management. Telerehabilitation was valued by health professionals. There was no reduction in all-cause mortality. Conclusion: There is insufficient evidence to recommend telerehabilitation as an intervention to treat and manage SCI in LMICs, although there is an indication of potential patient benefit. Further research is required to better understand the causal mechanisms underpinning the use of telerehabilitation and establish its efficacy, in the context of resource-limited settings.

ABSTRACTObjectiveFeelings of fatigue and low energy compromise quality of life in college students and are influenced by sleep quality, sedentary time, and physical activity (PA) in an interactive manner and differentially by sex, warranting further investigation.MethodCollege students (n = 693; 78% female) were assessed for sleep quality (Pittsburgh Sleep Quality Index), sedentary time (Sedentary Behavior Questionnaire), and PA (Godin Leisure-Time Exercise Questionnaire). State mental and physical energy and fatigue were assessed via the Mental and Physical State and Trait Energy and Fatigue Scales. Structural equation modeling was used to explore associations among variables of interest in the complete sample and by sex after controlling for anxiety, depression, and perceived stress.ResultsIn the complete sample, PA predicted all outcomes in expected directions (βrange = −.103 – .119; all p < .05); however, sleep quality and sedentary time were not predictors (p > .05). For males, only sleep quality predicted mental and physical energy and physical fatigue (all p < .05) whereas among females, only physical activity predicted mental fatigue and physical energy and fatigue (all p < .05). Sedentary time did not significantly predict any outcomes in males or females.ConclusionsPA is related to mental and physical energy and fatigue among college students. Sex differences were evident with sleep quality for males and PA for females, being more closely related to energy and fatigue outcomes. Research targeting these health behaviors and interactive effects on feelings of energy and fatigue in this cohort are warranted.

ObjectiveTo evaluate the impact of menthol cigarette bans in seven Canadian provinces between 2016 and 2018.MethodsLongitudinal data from the Canadian arm of the 2016 and 2018 ITC Four Country Smoking and Vaping Survey. 1098 non-menthol and 138 menthol smokers were surveyed pre-menthol and post-menthol cigarette bans. Multivariate logistic regression models examined associations between pre-post ban changes in smoking behaviour, including differences between menthol and non-menthol smokers in quit attempts and quitting.ResultsAt follow-up, 59.1% of pre-ban menthol smokers switched to non-menthol cigarettes; 21.5% quit smoking and 19.5% still smoked menthols, primarily purchased from First Nations reserves. Menthol smokers were more likely than non-menthol smokers to make a quit attempt (adjusted OR (aOR)=1.61, 95% CI 1.03 to 2.51), and to remain quit (aOR=2.30, 95% CI 1.06 to 5.01). Menthol smokers did not differ significantly from non-menthol smokers in quit success (aOR=1.72, 95% CI 0.98 to 3.01); however, daily menthol smokers were more likely than daily non-menthol smokers to quit (aOR=2.21, 95% CI 1.15 to 4.24), and daily menthol smokers who quit before the ban were more likely than daily non-menthol smokers to remain quit (aOR=2.81, 95% CI 1.15 to 6.85).ConclusionsAlthough menthol smokers were most likely to switch to non-menthol cigarettes, the menthol ban was also significantly associated with higher rates of quit attempts and quit success among menthol smokers compared with non-menthol smokers, and may have helped to prevent relapse among menthol smokers who had quit smoking before the ban. Results confirm and extend evaluation of Ontario’s menthol ban across provinces covering 83% of the Canadian population.

Disease-associated single-nucleotide polymorphisms (SNPs) generally do not implicate target genes, as most disease SNPs are regulatory. Many SNP-to-gene (S2G) linking strategies have been developed to link regulatory SNPs to the genes that they regulate in cis. Here, we developed a heritability-based framework for evaluating and combining different S2G strategies to optimize their informativeness for common disease risk. Our optimal combined S2G strategy (cS2G) included seven constituent S2G strategies and achieved a precision of 0.75 and a recall of 0.33, more than doubling the recall of any individual strategy. We applied cS2G to fine-mapping results for 49 UK Biobank diseases/traits to predict 5,095 causal SNP–gene-disease triplets (with S2G-derived functional interpretation) with high confidence. We further applied cS2G to provide an empirical assessment of disease omnigenicity; we determined that the top 1% of genes explained roughly half of the SNP heritability linked to all genes and that gene-level architectures vary with variant allele frequency.

IntroductionOn 18 May 2020, New York State enacted legislation banning the sale of vaping products with distinguishable flavours (other than tobacco). According to this new statute, vaping products are deemed flavoured if they include a statement, whether expressed or implied, that have distinguishable tastes or aromas other than tobacco. This study aimed to determine how manufacturers responded.MethodsWe collected 555 vaping products from daily vapers (238 preban and 317 postban). We compared preban and postban labelling of products for expressed and implied flavour descriptions, graphics and colours. Flavouring chemicals and concentrations were identified using chromatography methods and were compared preban and postban.ResultsAnalysis of the labels preban and postban did not reveal a change in products with expressed flavoured descriptors (45.8% vs 44.2%) and a minimal decrease in implied descriptors (22.3% vs 14.5%). An increase in products without any descriptors was observed (28.2% vs 37.2%) notably within products from a popular pod brand. The average concentration of eight popular flavourings identified preban was 1.4±2.7 compared with 2.3±3.5 mg/mL (p<0.001) postban. No significant changes between individual flavouring concentrations in the most popular refill solutions and pods were found.ConclusionWhile a majority of products appeared to remain non-compliant, this study suggests that enactment of legislation on vaping products making expressed or implied flavour claims may result in some manufacturer changes to product labelling including removal of flavour descriptors. However, use of flavouring additives in vaping products appeared not to be impacted by the ban.

Peanuts are known to contain nutrients that deliver cardiovascular and health benefits. One such compound is oleic acid, an omega-9 monounsaturated fatty acid, which occurs naturally in peanuts in the concentration range 40–55% m/m, while some varieties are known to contain oleic acid above 75% m/m. These high oleic peanuts have been shown to have cardiovascular health benefit by lowering lipid levels. Breeders are therefore interested in selecting for peanuts with high oleic acid content in a rapid, non-destructive manner. Near infrared spectra acquired on single peanut kernels was used to classify the kernels as either high oleic content or normal, low oleic content, by means of partial least squares discriminant analysis with an overall error rate in classification of 3.3%.

Peanuts are known to contain nutrients that deliver cardiovascular and health benefits. One such compound is oleic acid, an omega-9 monounsaturated fatty acid, which occurs naturally in peanuts in the concentration range 40–55% m/m, while some varieties are known to contain oleic acid above 75% m/m. These high oleic peanuts have been shown to have cardiovascular health benefit by lowering lipid levels. Breeders are therefore interested in selecting for peanuts with high oleic acid content in a rapid, non-destructive manner. Near infrared spectra acquired on single peanut kernels was used to classify the kernels as either high oleic content or normal, low oleic content, by means of partial least squares discriminant analysis with an overall error rate in classification of 3.3%.

ABSTRACTObjective:Lack of mental energy is one of the leading reasons adults turn to dietary supplements, with three out of ten supplement users hoping to improve their energy level; even more consume caffeine-containing products for the same reason. Despite this interest from consumers, there is no consensus scientific definition of mental energy or sole validated instrument for measuring it. We performed this review to summarize main findings from research regarding the influence of natural dietary compounds on three aspects of mental energy: cognition (vigilance), motivation (to do mental work), and mood (feelings of energy and/or absence of feelings of fatigue).Methods:A narrative review of key papers.Results:In addition to caffeine, a number of other compounds, including the polyphenols, which are found in all plant-derived products, and the phytochemicals in culinary herbs and herbal products such as Panaxginseng and Ginkgo biloba, have been shown in animal models to modulate neurotransmitter activity potentially relevant to mental energy. Inadequate intake of B vitamins could also potentially have a negative effect on mental energy due to their role in overall energy production, as precursors of key cofactors in the citric acid cycle, as well as their role in brain function and neurotransmitter synthesis. Consumption of some of these products may have direct or indirect effects on one or more elements of mental energy.Conclusion:Large, prospective clinical trials of these products using appropriate, validated instruments designed to measure mental energy may be worthwhile if sufficient evidence exists to justify such trials.

Poly(ADP-ribose) polymerase (PARP) inhibitors have transformed the therapeutic landscape for advanced ovarian cancer and expanded treatment options for other tumor types, including breast, pancreas, and prostate cancer. Yet, despite the success of PARP inhibitors in our current therapeutic armamentarium, not all patients benefit because of primary resistance, whereas different acquired resistance mechanisms can lead to disease progression on therapy. In addition, the toxicity profile of PARP inhibitors, primarily myelosuppression, has led to adverse events in a proportion of patients as monotherapy, and has limited the use of PARP inhibitors for certain rational combination strategies, such as chemotherapy and targeted therapy regimens. Currently approved PARP inhibitors are essentially equipotent against PARP1 and PARP2 enzymes. In this review, we describe the development of next-generation PARP1-selective inhibitors that have entered phase I clinical trials. These inhibitors have demonstrated increased PARP1 inhibitory potency and exquisitely high PARP1 selectivity in preclinical studies—features that may lead to improved clinical efficacy and a wider therapeutic window. First-in-human clinical trials seeking to establish the safety, tolerability, and recommended phase II dose, as well as antitumor activity of these novel agents, have commenced. If successful, this next-generation of PARP1-selective agents promises to build on the succeses of current PARP inhibitor treatment paradigms in cancer medicine.

Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1–DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25(AZD5305), a potent and selective PARP1 inhibitor and PARP1–DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.