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Despite the common assumption that citations are indicative of an article's scientific merit, increasing evidence indicates that citation counts are largely driven by variables unrelated to quality. In this article, we treat people's decisions of what to cite as an instance of memory retrieval and show that observed citation patterns are well accounted for by a model of memory. The proposed exposure model anticipates that small alterations in factors that affect people's ability to retrieve to-be-cited articles from memory early in their life cycle are magnified over time and can lead to the emergence of highly cited papers. This effect occurs even when there is no variation in the starting point exposure probabilities (i.e. when assuming a level playing field where all articles are treated equally and of equal 'quality'), and is exacerbated by natural variation in retrievability of articles due to encoding. We discuss the implications of the model within the context of research evaluation and hiring, tenure and promotion decisions., Competing Interests: We declare we have no competing interests., (© 2024 The Authors.)

Introduction: Digital tomosynthesis (DT) has emerged as a potential imaging modality for evaluating anatomic structures in veterinary medicine. This study aims to validate the diagnostic yield of DT in identifying predefined anatomic structures in feline cadaver heads, comparing it with conventional intraoral dental radiography (DR)., Methods: A total of 16 feline cadaver heads were utilized to evaluate 19 predefined clinically relevant anatomic structures using both DR and DT. A semi-quantitative scoring system was employed to characterize the ability of each imaging method to identify these structures., Results: DT demonstrated a significantly higher diagnostic yield compared to DR for all evaluated anatomic structures. Orthogonal DT imaging identified 13 additional anatomic landmarks compared to a standard 10-view feline set obtained via DR. Moreover, DT achieved statistically significant higher scores for each of these landmarks, indicating improved visualization over DR., Discussion: These findings validate the utility of DT technology in reliably identifying clinically relevant anatomic structures in the cat skull. This validation serves as a foundation for further exploration of DT imaging in detecting dentoalveolar and other maxillofacial bony lesions and pathologies in cats., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Soltero-Rivera, Nguyen, Goldschmidt, Hatcher and Arzi.)

Objective: Chordomas are rare tumors of the skull base and spine believed to arise from the vestiges of the embryonic notochord. These tumors are locally aggressive and frequently recur following resection and adjuvant radiotherapy. Proton therapy has been introduced as a tissue-sparing option because of the higher level of precision that proton-beam techniques offer compared with traditional photon radiotherapy. This study aimed to compare recurrence in patients with chordomas receiving proton versus photon radiotherapy following resection by applying tree-based machine learning models., Methods: The clinical records of all patients treated with resection followed by adjuvant proton or photon radiotherapy for chordoma at Mayo Clinic were reviewed. Patient demographics, type of surgery and radiotherapy, tumor recurrence, and other variables were extracted. Decision tree classifiers were trained and tested to predict long-term recurrence based on unseen data using an 80/20 split., Results: Fifty-three patients with a mean ± SD age of 55.2 ± 13.4 years receiving surgery and adjuvant proton or photon therapy to treat chordoma were identified; most patients were male. Gross-total resection was achieved in 54.7% of cases. Proton therapy was the most common adjuvant radiotherapy (84.9%), followed by conventional or external-beam radiation therapy (9.4%) and stereotactic radiosurgery (5.7%). Patients receiving proton therapy exhibited a 40% likelihood of having recurrence, significantly lower than the 88% likelihood observed in those treated with nonproton therapy. This was confirmed on logistic regression analysis adjusted for extent of tumor resection and tumor location, which revealed that proton adjuvant radiotherapy was associated with a decreased risk of recurrence (OR 0.1, 95% CI 0.01-0.71; p = 0.047) compared with photon therapy. The decision tree algorithm predicted recurrence with an accuracy of 90% (95% CI 55.5%-99.8%), with the lowest risk of recurrence observed in patients receiving gross-total resection with adjuvant proton therapy (23%)., Conclusions: Following resection, adjuvant proton therapy was associated with a lower risk of chordoma recurrence compared with photon therapy. The described machine learning models were able to predict tumor progression based on the extent of tumor resection and adjuvant radiotherapy modality used.

Background: Studies have linked prenatal maternal psychosocial stress to childhood wheeze/asthma but have rarely investigated factors that may mitigate risks., Objective: To investigate associations between prenatal stress and childhood wheeze/asthma, evaluating factors that may modify stress effects., Methods: Participants included 2056 mother-child dyads from Environmental influences on Child Health Outcomes (ECHO)-PATHWAYS, a consortium of 3 prospective pregnancy cohorts (the Conditions Affecting Neurocognitive Development and Learning in Early Childhood study, The Infant Development and Environment Study, and a subset of the Global Alliance to Prevent Prematurity and Stillbirth study) from 6 cities. Maternal stressful life events experienced during pregnancy (PSLEs) were reported using the Pregnancy Risk Assessment Monitoring System Stressful Life Events questionnaire. Parents reported child wheeze/asthma outcomes at age 4 to 6 years using standardized questionnaires. We defined outcomes as ever asthma, current wheeze, current asthma, and strict asthma. We used modified Poisson regression with robust standard errors (SEs) to estimate risk ratios (RRs) and 95% CI per 1-unit increase in PSLE, adjusting for confounders. We evaluated effect modification by child sex, maternal history of asthma, maternal childhood traumatic life events, neighborhood-level resources, and breastfeeding., Results: Overall, we observed significantly elevated risk for current wheeze with increasing PSLE (RR, 1.09 [95% CI, 1.03-1.14]), but not for other outcomes. We observed significant effect modification by child sex for strict asthma (P interaction = .03), in which risks were elevated in boys (RR, 1.10 [95% CI, 1.02-1.19]) but not in girls. For all other outcomes, risks were significantly elevated in boys and not in girls, although there was no statistically significant evidence of effect modification. We observed no evidence of effect modification by other factors (P interactions > .05)., Conclusion: Risk of adverse childhood respiratory outcomes is higher with increasing maternal PSLEs, particularly in boys., (Copyright © 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose: Chimeric antigen receptor (CAR) and T-cell receptor (TCR) T-cell therapies are effective in a subset of patients with solid tumors, but new approaches are needed to universally improve patient outcomes. Here, we developed a technology to leverage the cooperative effects of IL15 and IL21, two common cytokine-receptor gamma chain family members with distinct, pleiotropic effects on T cells and other lymphocytes, to enhance the efficacy of adoptive T cells., Experimental Design: We designed vectors that induce the constitutive expression of either membrane-tethered IL15, IL21, or IL15/IL21. We used clinically relevant preclinical models of transgenic CARs and TCRs against pediatric and adult solid tumors to determine the effect of the membrane-tethered cytokines on engineered T cells for human administration., Results: We found that self-delivery of these cytokines by CAR or TCR T cells prevents functional exhaustion by repeated stimulation and limits the emergence of dysfunctional natural killer (NK)-like T cells. Across different preclinical murine solid tumor models, we observed enhanced regression with each individual cytokine but the greatest antitumor efficacy when T cells were armored with both., Conclusions: The coexpression of membrane-tethered IL15 and IL21 represents a technology to enhance the resilience and function of engineered T cells against solid tumors and could be applicable to multiple therapy platforms and diseases. See related commentary by Ruffin et al., p. 1431., (©2023 American Association for Cancer Research.)

The COVID-19 pandemic has led to significantly increased human exposure to the widely used disinfectants quaternary ammonium compounds (QACs). Xenobiotic metabolism serves a critical role in the clearance of environmental molecules, yet limited data are available on the routes of QAC metabolism or metabolite levels in humans. To address this gap and to advance QAC biomonitoring capabilities, we analyzed 19 commonly used QACs and their phase I metabolites by liquid chromatography-ion mobility-tandem mass spectrometry (LC-IM-MS/MS). In vitro generation of QAC metabolites by human liver microsomes produced a series of oxidized metabolites, with metabolism generally occurring on the alkyl chain group, as supported by MS/MS fragmentation. Discernible trends were observed in the gas-phase IM behavior of QAC metabolites, which, despite their increased mass, displayed smaller collision cross-section (CCS) values than those of their respective parent compounds. We then constructed a multidimensional reference SQLite database consisting of m / z , CCS, retention time ( rt ), and MS/MS spectra for 19 parent QACs and 81 QAC metabolites. Using this database, we confidently identified 13 parent QACs and 35 metabolites in de-identified human fecal samples. This is the first study to integrate in vitro metabolite biosynthesis with LC-IM-MS/MS for the simultaneous monitoring of parent QACs and their metabolites in humans.

Objective: This study aimed to synthesize the available evidence on probiotic administration during pregnancy for the prevention of preeclampsia and its effects on related maternal, fetal, and newborn outcomes., Data Sources: Six databases were systematically searched for eligible studies, namely Ovid MEDLINE, Embase, CINAHL, Cochrane, Global Index Medicus, and the Maternity and Infant Care Database, from inception to August 2, 2023., Study Eligibility Criteria: Randomized controlled trials that evaluated the effects of probiotic administration on women during any stage of pregnancy were eligible for inclusion., Methods: The protocol was registered with the International Prospective Register of Systematic Reviews under identifier CRD42023421613. Evaluating study eligibility, extracting data, assessing risk of bias (ROB-2 tool), and rating certainty (Grading of Recommendations, Assessment, Development and Evaluations) were conducted independently by 2 authors. The primary outcomes were incidence of preeclampsia, eclampsia, and maternal mortality. A meta-analysis was performed, and the results were reported as risk ratios with 95% confidence intervals., Results: A total of 29 trials (7735 pregnant women) met the eligibility criteria. There was heterogeneity across the trials in the population of enrolled women and the type of probiotic tested (20 different strains), although most used oral administration. Probiotics may make no difference to the risk of preeclampsia (risk ratio, 1.14; 95% confidence interval, 0.84-1.53; 11 trials; 2401 women; low certainty evidence), preterm birth at <37 weeks' gestation (risk ratio, 0.93; 95% confidence interval, 0.66-1.30; 18 trials, 4016 women; low certainty evidence), or gestational age at delivery (mean difference, -0.03 weeks [≈0.2 days]; 95% confidence interval, -0.16 to 0.10 weeks [≈ -1.1 to 0.7 days]; 13 trials, 2194 women; low certainty evidence). It is difficult to assess the effects of probiotics on other secondary outcomes because the evidence was of very low certainty, however, no benefits or harms were observed., Conclusion: Limited evidence suggests that probiotic supplementation does not affect the risk for preeclampsia. Further high-quality trials are needed to definitively assess the benefits and possible harms of probiotic supplementation during pregnancy. There is also a lack of data from trials that included women who were undernourished or who experienced microbial dysbiosis and for whom probiotic supplementation might be useful., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Stigmatization, hostility, and violence towards the Asian American and Pacific Islander (AAPI) community have increased sharply during the COVID-19 pandemic. It is important to conduct research to promote understanding of the effects of such stigmatization on the AAPI community. Accordingly, the present study used a combined minority stress and integrated threat framework to examine whether factors related to AAPI identity would moderate the relationship between stigmatization/threat associated with AAPI identity and increased psychological distress and behavioral vigilance. AAPI individuals were recruited online from both Turk Prime and Reddit and completed measures of perceived stigmatization; integrated threat; depression, anxiety, and stress; and behavioral vigilance. Perceptions of stigmatization and threat predicted relevant outcomes both as individual predictors and in multivariate analyses. However, factors relating to the strength of AAPI identification did not moderate the effects of stigmatization and threat on psychological distress and behavioral vigilance, which is a result that failed to support this aspect of the broader conceptual model on which this project was based. Instead, these proposed moderators were themselves predicted by stigmatization and threat variables. The implications of these findings for effective interventions to alleviate the negative consequences of anti-Asian stigmatization are discussed.

The health consequences associated with using electronic cigarettes (ECs) are of great public interest because of their potential role in smoking cessation. In 110 participants, including 41 nonusers, 34 people who exclusively use ECs (EC group), and 35 people who smoke tobacco cigarettes (TCs) including 12 dual users (collectively called the TC-D group), the heart rate (HR), blood pressure (BP), and heart rate variability (HRV) were compared at baseline. People in the EC or the TC-D groups were also compared after using a 4th generation EC with or without nicotine, a TC with or without nicotine (TC-D group only), and a straw-control. Baseline HR, BP, and HRV parameters were not different among the EC, the TC-D, and nonuser groups. In people who exclusively use ECs, acute nicotine-EC use increased HR and BP, and produced changes in HRV patterns suggestive of increased cardiac sympathetic influence. In people in the TC-D group, BP increased similarly after acutely smoking a nicotine-TC or a nicotine-EC. However, the increase in HR was significantly greater after smoking a TC compared with the nicotine-EC despite similar acute increases in plasma nicotine. Overall, all exposures containing nicotine significantly increased HR and BP in both cohorts when compared with non-nicotine exposures. Since acute EC use 1 ) produces an abnormal HRV pattern associated with increased cardiac sympathetic tone in people who chronically use ECs, and 2 ) similar hemodynamic increases compared with acute TC smoking in people who chronically smoke TCs including dual users, the role of ECs as part of a harm reduction strategy is questioned. NEW & NOTEWORTHY We found that nicotine, not the non-nicotine constituents in tobacco cigarette (TC) or electronic cigarette (EC) emissions, may be the instigator of the acute, potentially adverse, changes in hemodynamics and heart rate variability (HRV) that were recorded several minutes after tobacco product use. Furthermore, acute EC use produced an abnormal HRV pattern associated with increased cardiac risk in people who chronically smoke ECs and produced similar hemodynamic increases compared with acute TC use in people who chronically smoke TCs, including people who are dual users.

Competing Interests: Conflict of Interest None.

Direct oral anticoagulants (DOACs) for venous thromboembolism (VTE) treatment are of interest in oncology due to ease of administration and lack of need for therapeutic monitoring compared to other anticoagulants. Data supporting their use in patients with hematologic malignancies post-hematopoietic stem cell transplant (HCT) are limited. The purpose of the study is to characterize DOAC use in HCT patients. This multicenter, retrospective cohort analysis included allogeneic and autologous HCT recipients. The primary outcome was major bleeding. Secondary outcomes included clinically relevant non-major bleeding (CRNMB)/minor bleeding and VTE recurrence. Of 126 patients, 91 (72.2%) patients received an autologous HCT, and 35 (27.8%) patients received an allo-HCT. No major bleeding occurred in either transplant recipient groups. In autologous HCT recipients, CRNMB/minor bleeding occurred in four (4.4%) patients and VTE recurrence occurred in one (1.1%) patient. For allogeneic HCT recipients, CRNMB/minor bleeding occurred in five (14.3%) patients and VTE recurrence occurred in two (5.7%) patients. For patients that experienced a CRNMB, five (100%) of the allogeneic HCT and two (50%) of the autologous HCT recipients were thrombocytopenic at the time of bleeding. Only 38.5% of patients who experienced a drug-drug interaction requiring DOAC dose adjustment received the appropriate dose adjustment. DOACs were associated with low rates of recurrent VTE and no major bleeding events, similar to published data on DOAC use in the general cancer patient population. This suggests that DOACs may be safe therapeutic options with proactive management of drug interactions and careful monitoring for bleeding events, especially in the allogeneic HCT population where minor bleeding rates were slightly higher., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Associating contexts with rewards depends on hippocampal circuits, with local inhibitory interneurons positioned to play an important role in shaping activity. Here, we demonstrate that the encoding of context-reward memory requires a ventral hippocampus (vHPC) to nucleus accumbens (NAc) circuit that is gated by cholecystokinin (CCK) interneurons. In a sucrose conditioned place preference (CPP) task, optogenetically inhibiting vHPC-NAc terminals impaired the acquisition of place preference. Transsynaptic rabies tracing revealed vHPC-NAc neurons were monosynaptically innervated by CCK interneurons. Using intersectional genetic targeting of CCK interneurons, ex vivo optogenetic activation of CCK interneurons increased GABAergic transmission onto vHPC-NAc neurons, while in vivo optogenetic inhibition of CCK interneurons increased cFos in these projection neurons. Notably, CCK interneuron inhibition during sucrose CPP learning increased time spent in the sucrose-associated location, suggesting enhanced place-reward memory. Our findings reveal a previously unknown hippocampal microcircuit crucial for modulating the strength of contextual reward learning., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Vertebral artery dissections are a rare pathology that carries a high risk of stroke in a younger population. They may be caused by minor mechanisms and the index of suspicion should be high. Treatment with anticoagulation or antiplatelets should follow if no surgical management is indicated.We describe a case of a female in her 30s who fell backward off a swing and rolled over her head and complained of continued posterior neck pain. The patient was found to have a vertebral artery dissection on MRI. The patient was then anticoagulated with high-dose apixaban and low-dose aspirin.The emergency medicine provider should be aware of possible low-impact mechanisms that can cause vertebral artery dissection and should have a high index of suspicion. If surgical management is not indicated, anticoagulation should be initiated., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Consuming ultra-processed foods may increase exposure to phthalates, a group of endocrine disruptors prevalent in food contact materials., Objectives: Investigate associations between ultra-processed food intake and urinary phthalates during pregnancy, and evaluate whether ultra-processed foods mediate socioeconomic disparities in phthalate exposures., Methods: In a socioeconomically diverse sample of 1031 pregnant women from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) Study in the urban South, the Block Food Frequency Questionnaire was administered and urinary phthalate metabolites were measured in the second trimester. Linear regressions modeled associations between phthalates and overall ultra-processed food consumption, individual ultra-processed foods, and exploratory factor analysis dietary patterns. Causal mediation analyses examined whether ultra-processed food intake mediates relationships between socioeconomic disparities and phthalate exposures., Results: Ultra-processed foods constituted 9.8-59.0 % (mean = 38.6 %) of participants' diets. 10 % higher dietary proportion of ultra-processed foods was associated with 13.1 % (95 %CI: 3.4 %-22.9 %) higher molar sum concentrations of di(2-ethylhexyl) phthalate metabolites (ΣDEHP). 10 % higher consumption of minimally-processed foods was associated with lower ΣDEHP (10.8 %: 3.4 %-22.9 %). Ultra- and minimally-processed food consumption were not associated with non-DEHP metabolites. Standard deviation higher consumptions of hamburger/cheeseburger, French fries, soda, and cake were associated with 10.5 % (4.2 %-17.1 %), 9.2 % (2.6 %-16.2 %), 7.4 % (1.4 %-13.6 %), and 6.0 % (0.0 %-12.4 %), respectively, higher ΣDEHP. Exploratory factor analysis corroborated positive associations of processed food with ΣDEHP, and uncovered a healthy dietary pattern associated with lower urinary ΣDEHP, mono(2-ethyl-5-hydroxyhexyl) (MEHHP), mono(2-ethyl-5-carboxypentyl) (MECPP), mono(2-carboxymethylhexyl) (MCMHP), and mono-isononyl (MINP) phthalates. Significant indirect effects indicated that lower income and education levels were associated with 1.9 % (0.2 %-4.2 %) and 1.4 % (0.1 %-3.3 %) higher ΣDEHP, respectively, mediated via increased ultra-processed food consumption., Conclusions: Consumption of ultra-processed foods may increase exposure to phthalates. Policies to reduce dietary phthalate exposures from food packaging and processing are needed, as socioeconomic barriers can preclude dietary recommendations as a sole means to reduce phthalate exposures., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The association between cumulative burden of unfavorable social determinants of health (SDoH) and all-cause mortality has not been assessed by atherosclerotic cardiovascular disease (ASCVD) status on a population level in the United States., Methods: We assessed the association between cumulative social disadvantage and all-cause mortality by ASCVD status in the National Health Interview Survey, linked to the National Death Index., Results: In models adjusted for established clinical risk factors, individuals experiencing the highest level of social disadvantage (SDoH-Q4) had over 1.5 (aHR = 1.55; 95%CI = 1.22, 1.96) and 2-fold (aHR = 2.21; 95% CI = 1.91, 2.56) fold increased risk of mortality relative to those with the most favorable social profile (SDoH-Q1), respectively for adults with and without ASCVD; those experiencing co-occurring ASCVD and high social disadvantage had up to four-fold higher risk of mortality (aHR = 3.81; 95%CI = 3.36, 4.32)., Conclusions: These findings emphasize the importance of a healthcare model that prioritizes efforts to identify and address key social and environmental barriers to health and wellbeing, particularly in individuals experiencing the double jeopardy of clinical and social risk., Competing Interests: Disclosure The authors have no disclosures to report., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Acute oral toxicity (AOT) data inform the acute toxicity potential of a compound and guides occupational safety and transportation practices. AOT data enable the categorization of a chemical into the appropriate AOT Globally Harmonized System (GHS) category based on the severity of the hazard. AOT data are also utilized to identify compounds that are Dangerous Goods (DGs) and subsequent transportation guidance for shipping of these hazardous materials. Proper identification of DGs is challenging for novel compounds that lack data. It is not feasible to err on the side of caution for all compounds lacking AOT data and to designate them as DGs, as shipping a compound as a DG has cost, resource, and time implications. With the wealth of available historical AOT data, AOT testing approaches are evolving, and in silico AOT models are emerging as tools that can be utilized with confidence to assess the acute toxicity potential of de novo molecules. Such approaches align with the 3R principles, offering a reduction or even replacement of traditional in vivo testing methods and can also be leveraged for product stewardship purposes. Utilizing proprietary historical in vivo AOT data for 210 pharmaceutical compounds (PCs), we evaluated the performance of two established in silico AOT programs: the Leadscope AOT Model Suite and the Collaborative Acute Toxicity Modeling Suite. These models accurately identified 94% and 97% compounds that were not DGs (GHS categories 4, 5, and not classified (NC)) suggesting that the models are fit-for-purpose in identifying PCs with low acute oral toxicity potential (LD50 >300 mg/kg). Utilization of these models to identify compounds that are not DGs can enable them to be de-prioritized for in vivo testing. This manuscript provides a detailed evaluation and assessment of the two models and recommends the most suitable applications of such models., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Mechanochemistry and oleochemistry and their combination have been known for centuries. Nevertheless, bioeconomy and circular economy concepts is much more recent and has motivated a regain of interest of dedicated research to improve alternative technologies for the valorization of biomass feedstocks. Accordingly, this review paper aims essentially at outlining recent breakthroughs obtained in the field of mechanochemistry and oleochemicals such as triglycerides, fatty acids, and glycerol derivatives. The review discusses advances obtained in the production of small chemicals derived from oils with a brief overview of vegetable oils, mechanochemistry and the use of mechanochemistry for the synthesis of biodiesel, lipidyl-cyclodextrine, dimeric and labelled fatty acids, calcium diglyceroxide, acylglycerols, benzoxazine and solketal. The paper also briefly overviews advances and limits for an industrial application., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Len, Duhan, Ouyang, Nguyen and Lochab.)

Objective: We aimed to identify all available studies describing measures or indicators used to monitor 41 intrapartum care practices described in the 2018 WHO intrapartum care recommendations, with a view to informing development of standardised measurement of implementing these recommendations., Design: Systematic scoping review., Methods: We conducted a scoping review to identify studies reporting measures of intrapartum care published between 1 January 2000 and 28 June 2021. Primary and secondary outcome measures included study characteristics (publication year, journal, country and World Bank classification) and intrapartum care measure characteristics (definition, numerator, denominator, measurement level and measurement approach). We searched MEDLINE, EMBASE, CINAHL, Cochrane Library, the Maternity and Infant Care Database, Global Index Medicus and grey literature using structured search terms related to included recommendations, focusing on respectful and supportive care, and clinical practices performed throughout labour and birth. The measures identified were classified by the WHO recommendation and their characteristics reported., Results: We identified 150 studies which described 1331 intrapartum care measures. These measures corresponded to 35 of the 41 included WHO recommendations, and represented all domains of the WHO recommendations (care throughout labour and birth, first stage of labour, second stage of labour, third stage of labour). A total of 40.1% (534 of 1331 measures) of measures were related to respectful maternity care. Most studies used a questionnaire or survey measurement approach (522 of 1331 measures, 39.2%)., Conclusion: This scoping review presents a database of existing intrapartum care measures used to monitor the quality of intrapartum care globally. There is no clear consensus on a core set of measures for evaluating the practice of the WHO's intrapartum care recommendations. This review provides a foundation to support the development of a core set of internationally standardised intrapartum care measures for the WHO intrapartum care recommendations, highlighting key areas requiring consensus and validation, and measure development., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Second-trimester ultrasound is the standard technique for fetal anatomy evaluation in the United States despite international guidelines and literature that suggest that first-trimester timing may be superior in patients with obesity. First-trimester imaging performs well in cohorts of participants with obesity., Objective: Our aim was to compare the completion rate of a first-trimester fetal anatomy ultrasound scan with that of a second-trimester fetal anatomy ultrasound scan among pregnant people with a body mass index ≥35 kg/m 2 ., Study Design: This randomized controlled trial enrolled participants with a body mass index ≥35 kg/m 2 with a singleton gestation and who presented before 14+0/7 weeks of gestation. Participants were randomized to receive an ultrasound assessment of anatomy at either 12+0/7 to 13+6/7 weeks or at 18+0/7 to 22+6/7 weeks. The primary outcome was completion rate (percentage of scans that optimally imaged all the required fetal structures). Secondary outcomes included the necessity of a transvaginal approach, completion rates for each individual view, number of anomalies identified and missed in each group, scan duration, and patient perspectives. A 1-year pilot sample was analyzed using Bayesian methods for the primary outcome with a neutral prior and frequentist analyses for the remaining outcomes., Results: A total of 128 participants were enrolled, and 1 withdrew consent; 62 subjects underwent a first-trimester ultrasound scan and 62 underwent a second-trimester ultrasound scan. A total of 2 participants did not attend the research visits, and 1 sought termination of pregnancy. In the first-trimester group, 66% (41/62) of ultrasound scans were completed in comparison with 53% (33/62) in the second-trimester ultrasound group (Bayesian relative risk, 1.20; 95% credible interval, 0.91-1.73). When compared with a second-trimester scan plus a follow-up ultrasound, a first-trimester ultrasound plus a second-trimester ultrasound was equally successful in completing the anatomy views (76%). First-trimester anatomy ultrasound scans required a transvaginal approach in 63% (39/62) of cases and had a longer duration than a second-trimester ultrasound scan. No anomalies were missed in either group. First-trimester ultrasound participants who responded to a survey described that they were very satisfied with the technique., Conclusion: In pregnant subjects with a body mass index ≥35 kg/m 2 , a single first-trimester anatomy ultrasound scan was more likely to obtain all the recommended anatomic views than a single second-trimester ultrasound scan. An evaluation of anatomy at 12+0/7 to 13+6/7 weeks' gestation plus an evaluation at 18+0/7 to 22+6/7 led to complete anatomic evaluation 4 weeks earlier than 2 second trimester scans. Assessment of ultrasound duration in a clinical setting is needed to ensure feasibility outside of a research setting., (Copyright © 2023 Elsevier Inc. All rights reserved.)

During pregnancy, estrogens and testosterone influence brain development, resulting in sex-typical behavioral phenotypes. Prenatal testosterone exposure is associated with more male-typical behaviors in rodents, monkeys, and humans; however, few studies have examined the relationship between maternal sex hormones within the normal range and sex-dimorphic behaviors. In this study, we examined associations between prenatal estrogens and testosterone and sex-typical play in The Infant Development and the Environment Study (TIDES), a multicenter pregnancy cohort. We collected prenatal serum during the first trimester (mean=11.1 ± 2.6 weeks) and assessed child play behavior using the maternally completed Pre-School Activities Inventory (PSAI) at a mean age of 4.5 ± 0.3 years. This analysis includes mother-child pairs with complete data on hormones, play behavior, and covariates (n = 192 boys and 207 girls). No associations were seen between testosterone and PSAI scores in boys or girls or between estrogens and PSAI scores in boys. In girls, we observed an inverse relationship between feminine PSAI scores and both estradiol (E2) and estriol (E3) in multivariable linear regression analyses (E2: -0.11 [95% CI -0.20, -0.02]; E3: -0.44 [95% CI -0.83,-0.04]). Because the relationship between sex hormones and PSAI scores appeared nonlinear, we fit piecewise regression models to better fit the data and identify inflection points (point at which there is a significant change in slope). Piecewise regression analyses yielded inverse associations between masculine PSAI scores and estrone (E1) at values of E1 > 1340 pg/mL and E2 at values of E2 > 2870 pg/mL in girls. Further studies are needed to better understand the role of prenatal sex steroids on sexually dimorphic behavior., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Several methods exist for detecting genetic relatedness or identity by comparing DNA information. These methods generally require genotype calls, either single-nucleotide polymorphisms or short tandem repeats, at the sites used for comparison. For some DNA samples, like those obtained from bone fragments or single rootless hairs, there is often not enough DNA present to generate genotype calls that are accurate and complete enough for these comparisons. Here, we describe IBDGem, a fast and robust computational procedure for detecting genomic regions of identity-by-descent by comparing low-coverage shotgun sequence data against genotype calls from a known query individual. At less than 1× genome coverage, IBDGem reliably detects segments of relatedness and can make high-confidence identity detections with as little as 0.01× genome coverage., (© The American Genetic Association. 2023.)

Although photosensitization remains a major toxicological endpoint for the safety assessment of cosmetic products and their raw materials, there is no validated in vitro method available for the evaluation of this adverse effect so far. Given that previous studies have proposed that the Interleukine-18 (IL-18) plays a key role in keratinocyte-driven pro-inflammatory responses specific of the skin sensitization process, we hypothesize that IL-18 might be used as a specific biomarker for in vitro photosensitization assessment. The aim of the present study was the set-up of a new in vitro assay using IL-18 as a biomarker for the identification of photosensitizers in a reconstructed human epidermis (RHE) model. EpiCS™ RHE were incubated with a set of 16 known sensitising / phototoxic / photosensitizing substances and exposed to ultra-violet (UV) irradiation. Then, the cell viability was analysed by MTT assay, while the IL-18 secretion was quantified by ELISA. Preliminary assays have shown that 1 h of incubation followed by a recovery period of 23 h induced the highest IL-18 production in response to UV exposure. This protocol was used to test 16 substances and a ratio of IL-18 production (UV+/UV- ratio) was then generated. Our data shows that the cut-off of 1.5 (UV+/UV- ratio) is the most predictive model among the tested conditions, being capable of identifying true positive photosensitizers (8 of 9) with a good prediction in comparison with in vivo data. In a nutshell, our data suggests that the PhotoSENSIL-18 is a promising in vitro method for identification of photosensitizing substances. Although further studies are necessary to optimize the model, we foresee that the PhotoSENSIL-18 assay can be used in the context of an Integrative Approach to Testing and Assessment (IATA) of chemicals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) enters the respiratory tract, where it infects the alveoli epithelial lining. However, patients have sequelae that extend well beyond the alveoli into the pulmonary vasculature and, perhaps, beyond to the brain and other organs. Because of the dynamic events within blood vessels, histology does not report platelet and neutrophil behavior. Because of the rapid nontranscriptional response of these cells, neither single-cell RNA sequencing nor proteomics report robustly on their critical behaviors. We used intravital microscopy in level-3 containment to examine the pathogenesis of SARS-CoV-2 within 3 organs in mice expressing human angiotensin converting enzyme 2 (ACE-2) ubiquitously (CAG-AC-70) or on epithelium (K18-promoter). Using a neon-green SARS-CoV-2, we observed both the epithelium and endothelium infected in AC70 mice but only the epithelium in K18 mice. There were increased neutrophils in the microcirculation but not in the alveoli of the lungs of AC70 mice. Platelets formed large aggregates in the pulmonary capillaries. Despite only neurons being infected within the brain, profound neutrophil adhesion forming the nidus of large platelet aggregates were observed in the cerebral microcirculation, with many nonperfused microvessels. Neutrophils breached the brain endothelial layer associated with a significant disruption of the blood-brain-barrier. Despite ubiquitous ACE-2 expression, CAG-AC-70 mice had very small increases in blood cytokine, no increase in thrombin, no infected circulating cells, and no liver involvement suggesting limited systemic effects. In summary, our imaging of SARS-CoV-2-infected mice gave direct evidence that there is a significant perturbation locally in the lung and brain microcirculation induced by local viral infection leading to increased local inflammation and thrombosis in these organs., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objectives: To evaluate the appropriateness of the medication management for anyone who might have been affected by the Horizon New Jersey Health Medicaid Health Maintenance Organization (HNJH Medicaid HMO) formulary update from empagliflozin to ertugliflozin and to then optimize drug selection and monitoring., Study Design: This is a single-center, 2-phase, pilot project led by 2 pharmacy students and the lead clinical pharmacist at a federally qualified health center in Trenton, New Jersey., Methods: The primary outcome of the study is the number and percentage of patients whose prescription was changed inappropriately from empagliflozin to ertugliflozin. Secondary outcomes include the number and percentage of patients whose prescription was changed inappropriately because of failure to consider cardiovascular history and/or missed renal function checks and whether pharmacists were able to optimize therapy. Data were generated from electronic health record reports and analyzed in Microsoft Excel., Results: A total of 126 unique patients were identified as receiving empagliflozin and/or ertugliflozin and 16 patients were switched from empagliflozin to ertugliflozin, all of whom had HNJH Medicaid HMO. Thirteen of the 16 (81.3%) patients were managed inappropriately based on their history of cardiovascular disease or inappropriate renal monitoring. Pharmacists recommended 22 interventions for patients who received empagliflozin and/or ertugliflozin, and all recommendations were accepted by providers., Conclusions: Following the HNJH Medicaid HMO's coverage update from empagliflozin to ertugliflozin, some patients received inappropriate therapy and providers accepted clinical pharmacists' recommendations to optimize therapy.

Purpose: Prior work developed a shortened 16-item version of the Social Responsiveness Scale (SRS), a quantitative measure of social communication and autism spectrum disorder (ASD)-related traits. However, its properties for use in risk factor estimation have not been fully tested compared to the full SRS. We compared the associations between gestational age (previously established risk factor for ASD) and the 65-item "full" and 16-item "short" versions of the SRS to test the shortened version's ability to capture associations in epidemiologic analyses of ASD risk factors., Methods: We used data from participants in the Environmental influences on Child Health Outcomes (ECHO) Program (n = 2,760). SRS scores were collected via maternal/caregiver report when children were aged 2.5-18 years. We compared estimates of associations between gestational age and preterm birth between the full and short SRS using multivariable linear regression, quantile regression, and prediction methods., Results: Overall, associations based on full and short SRS scores were highly comparable. For example, we observed positive associations between preterm birth with both full ([Formula: see text]=2.8; 95% CI [1.7, 4.0]) and short ([Formula: see text]=2.9; 95% CI [1.6, 4.3]) SRS scores. Quantile regression analyses indicated similar direction and magnitude of associations across the distribution of SRS scores between gestational age with both short and full SRS scores., Conclusion: The comparability in estimates obtained for full and short SRS scores with an "established" ASD risk factor suggests ability of the shortened SRS in assessing associations with potential ASD-related risk factors and has implications for large-scale research studies seeking to reduce participant burden., (© 2023. The Author(s).)

Extinction memory retrieval is influenced by spatial contextual information that determines responding to conditioned stimuli (CS). However, it is poorly understood whether contextual representations are imbued with emotional values to support memory selection. Here, we performed activity-dependent engram tagging and in vivo single-unit electrophysiological recordings from the ventral hippocampus (vH) while optogenetically manipulating basolateral amygdala (BLA) inputs during the formation of cued fear extinction memory. During fear extinction when CS acquire safety properties, we found that CS-related activity in the vH reactivated during sleep consolidation and was strengthened upon memory retrieval. Moreover, fear extinction memory was facilitated when the extinction context exhibited precise coding of its affective zones. Last, these activity patterns along with the retrieval of the fear extinction memory were dependent on glutamatergic transmission from the BLA during extinction learning. Thus, fear extinction memory relies on the formation of contextual and stimulus safety representations in the vH instructed by the BLA.

Electronic cigarettes are often used for smoking cessation as a harm reduction strategy, but studies comparing risks of electronic cigarettes (ECs) and tobacco cigarettes (TCs) are scarce. Ventricular repolarization in people who smoke TCs is abnormal. Baseline repolarization was compared among nonusers (people who do not use TCs or ECs) and people who use ECs or TCs. The acute effects of ECs and TCs on metrics of ventricular repolarization were then compared in people who chronically smoke. A total of 110 participants (59 female), including 35 people (21 females) in the TC cohort, 34 people (17 females) in the EC cohort, and 41 people (21 females) in the nonuser cohort, were included. None of the primary outcomes, T peak-end (T p-e ), T p-e /QT, and T p-e /QT c , were different among the three cohorts at supine baseline, even when adjusted for sex. When compared with the control exposure standing after acutely using the EC but not the TC, significantly prolonged all three primary indices of ventricular repolarization in people who smoke TCs. The major new finding in this study is that in people who smoke TCs, using an EC compared with a TC significantly prolongs ventricular repolarization. Furthermore, in our subgroup analysis by sex, this adverse effect on repolarization is found only in male, not female, smokers. In summary, chronic TC smoking is the most prevalent, modifiable risk factor for cardiovascular death, including sudden cardiac death. If used for smoking cessation, ECs should only be used in the short term since they too carry their own risks; this risk appears to be greatest in males compared with females who smoke. NEW & NOTEWORTHY The major new finding in this study is that in people who smoke tobacco cigarettes, using an electronic cigarette but not a tobacco cigarette acutely and significantly prolongs several metrics of ventricular repolarization, including T peak -T end , T peak -T end /QT, and T peak -T end /QT c . Furthermore, in our subgroup analysis by sex, this adverse effect on repolarization is found only in male, not female, smokers.

Pancreatic ductal adenocarcinoma (PDA) is highly aggressive and has few treatment options. To personalize therapy, it is critical to delineate molecular subtypes and understand inter- and intra-tumoral heterogeneity. Germline testing for hereditary genetic abnormalities is recommended for all patients with PDA and somatic molecular testing is recommended for all patients with locally advanced or metastatic disease. KRAS mutations are present in 90% of PDA, while 10% are KRAS wild type and are potentially targetable with epidermal growth factor receptor blockade. KRAS G12C inhibitors have shown activity in G12C-mutated cancers, and novel G12D and pan-RAS inhibitors are in clinical trials. DNA damage repair abnormalities, germline or somatic, occur in 5-10% of patients and are likely to benefit from DNA damaging agents and maintenance therapy with poly-ADP ribose polymerase inhibitors. Fewer than 1% of PDA harbor microsatellite instability high status and are susceptible to immune checkpoint blockade. Albeit very rare, occurring in <1% of patients with KRAS wild-type PDAs, BRAF V600E mutations, RET and NTRK fusions are targetable with cancer agnostic Food and Drug Administration-approved therapies. Genetic, epigenetic, and tumor microenvironment targets continue to be identified at an unprecedented pace, enabling PDA patients to be matched to targeted and immune therapeutics, including antibody-drug conjugates, and genetically engineered chimeric antigen receptor or T-cell receptor - T-cell therapies. In this review, we highlight clinically relevant molecular alterations and focus on targeted strategies that can improve patient outcomes through precision medicine., Competing Interests: Zhen DB: research funding: Astra Zeneca, Bristol Myers Squibb, Cornerstone, Daiichi Sankyo, Eli Lilly, Legend, Merck, Roche; scientific advisory boards: Ipsen, QED Therapeutics, Cornerstone Safyan RA: no conflicts of interest Konnick E: no conflicts of interest Nguyen R: no conflicts of interest Pritchard C: no conflicts of interest Chiorean EG: research funding AADi, Boehringer-Ingelheim, Clovis, Fibrogen, Merck, Lonza, BioMed Valley, Erasca, Roche, Novartis; scientific advisory boards: Astellas, Ipsen, Pfizer, G1 Therapeutics, Merus, BMS, Foundation One., (© The Author(s), 2023.)

Noradrenergic neuroblastoma is characterized by a core transcriptional regulatory circuitry (CRC) comprised of transcription factors (TF) such as PHOX2B, HAND2, and GATA3, which form a network with MYCN. At normal physiologic levels, MYCN mainly binds to promoters but when aberrantly upregulated as in neuroblastoma, MYCN also binds to enhancers. Here, we investigated how MYCN invades enhancers and whether CRC TFs play a role in this process. HAND2 was found to regulate chromatin accessibility and to assist MYCN binding to enhancers. Moreover, HAND2 cooperated with MYCN to compete with nucleosomes to regulate global gene transcription. The cooperative interaction between MYCN and HAND2 could be targeted with an Aurora A kinase inhibitor plus a histone deacetylase inhibitor, resulting in potent downregulation of both MYCN and the CRC TFs and suppression of MYCN-amplified neuroblastoma tumor growth. This study identifies cooperation between MYCN and HAND2 in neuroblastoma and demonstrates that simultaneously targeting MYCN and CRC TFs is an effective way to treat this aggressive pediatric tumor., Significance: HAND2 and MYCN compete with nucleosomes to regulate global gene transcription and to drive a malignant neuroblastoma phenotype., (©2023 American Association for Cancer Research.)

A major challenge for clustering algorithms is to balance the trade-off between homogeneity, i.e. , the degree to which an individual cluster includes only related sequences, and completeness, the degree to which related sequences are broken up into multiple clusters. Most algorithms are conservative in grouping sequences with other sequences. Remote homologs may fail to be clustered together and instead form unnecessarily distinct clusters. The resulting clusters have high homogeneity but completeness that is too low. We propose Complet+, a computationally scalable post-processing method to increase the completeness of clusters without an undue cost in homogeneity. Complet+ proves to effectively merge closely-related clusters of protein that have verified structural relationships in the SCOPe classification scheme, improving the completeness of clustering results at little cost to homogeneity. Applying Complet+ to clusters obtained using MMseqs2's clusterupdate achieves an increased V-measure of 0.09 and 0.05 at the SCOPe superfamily and family levels, respectively. Complet+ also creates more biologically representative clusters, as shown by a substantial increase in Adjusted Mutual Information (AMI) and Adjusted Rand Index (ARI) metrics when comparing predicted clusters to biological classifications. Complet+ similarly improves clustering metrics when applied to other methods, such as CD-HIT and linclust. Finally, we show that Complet+ runtime scales linearly with respect to the number of clusters being post-processed on a COG dataset of over 3 million sequences. Code and supplementary information is available on Github: https://github.com/EESI/Complet-Plus., Competing Interests: The authors declare there are no competing interests., (©2023 Nguyen et al.)

Objectives: To assess the composition by gender of Australian clinical practice guideline development panels; to explore guideline development-related factors that influence the composition of panels., Design, Setting, Participants: Survey of clinical guidelines published in Australia during 2010-2020 that observed the 2016 NHMRC Standards for Guidelines, identified (June 2021) in the NHMRC Clinical Practice Guideline Portal or by searching the Guideline International Network guidelines library, the Trip medical database, and PubMed. The gender of contributors to guideline development was inferred from gendered titles (guideline documents) or pronouns (online biographies)., Main Outcome Measures: The overall proportion of guideline panel members - the guideline contributors who formally considered evidence and formulated recommendations (ie, guideline panel chairs and members) - who were women., Results: Of 406 eligible guidelines, 335 listed the names of people who contributed to their development (82%). Of 7472 named contributors (including 511 guideline panel chairs [6.8%] and 5039 guideline panel members [67.4%]), 3514 were men (47.0%), 3345 were women (44.8%), and gender could not be determined for 612 (8.2%). A total of 215 guideline panel chairs were women (42.1%), 280 were men (54.8%); 2566 guideline panel members were men (50.9%), 2071 were women (41.1%). The proportion of female guideline panel members was smaller than 40% for 179 guidelines (53%) and larger than 60% for 71 guidelines (21%). The median guideline proportion of female panel members was smaller than 50% for all but two years (2017, 2018)., Conclusions: The representation of women in health leadership roles in Australia does not reflect their level of participation in the health care workforce. In particular, clinical guideline development bodies should develop transparent policies for increasing the participation of women in guideline development panels., (© 2023 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

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.

Background: Although most patients with newly diagnosed high-risk neuroblastoma (NB) achieve remission after initial therapy, more than 50% experience late relapses caused by minimal residual disease (MRD) and succumb to their cancer. Therapeutic strategies to target MRD may benefit these children. We developed a new chimeric antigen receptor (CAR) targeting glypican-2 (GPC2) and conducted iterative preclinical engineering of the CAR structure to maximize its anti-tumor efficacy before clinical translation., Methods: We evaluated different GPC2-CAR constructs by measuring the CAR activity in vitro. NOD-SCID mice engrafted orthotopically with human NB cell lines or patient-derived xenografts and treated with human CAR T cells served as in vivo models. Mechanistic studies were performed using single-cell RNA-sequencing., Results: Applying stringent in vitro assays and orthotopic in vivo NB models, we demonstrated that our single-chain variable fragment, CT3, integrated into a CAR vector with a CD28 hinge, CD28 transmembrane, and 4-1BB co-stimulatory domain (CT3.28H.BBζ) elicits the best preclinical anti-NB activity compared with other tested CAR constructs. This enhanced activity was associated with an enrichment of CD8 + effector T cells in the tumor-microenvironment and upregulation of several effector molecules such as GNLY , GZMB , ZNF683 , and HMGN2 . Finally, we also showed that the CT3.28H.BBζ CAR we developed was more potent than a recently clinically tested GD2-targeted CAR to control NB growth in vivo., Conclusion: Given the robust preclinical activity of CT3.28H.BBζ, these results form a promising basis for further clinical testing in children with NB., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

As the most abundant natural biopolymer on earth, celluloses have long-term emerged as a capable platform for diverse purposes. In the context of metal nanoparticles applied to catalysis, the alternatives to traditional catalyst supports by using biomass-derived renewable materials, likely nanocelluloses, have been paid a great effort, in spite of being less exploited. In this study, cellulose nanocrystals were isolated from corn leaf via chemical treatment involving alkalizing, bleaching and acid hydrolysis. The crystallinity of obtained cellulose was evaluated in each step, focusing on the effects of reactant concentration and reaction time. Cellulose nanocrystals were characterized by powder X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), evidencing the presence of cellulose nanospheres (crystallinity index of 67.3% in comparison with 38.4% from untreated raw material) in the size range of 50 nm. Without using any additional surfactants or stabilizers, silver nanoparticles (AgNPs) well-dispersed on the surface of cellulose nanocrystals (silver content of 5.1 wt%) could be obtained by a simple chemical reduction using NaBH 4 at room temperature. The catalytic activity was evaluated in the selective reductions of 4-nitrophenol towards 4-aminophenol and methyl orange towards aromatic amine derivatives in water at room temperature. The effects of catalyst amount and reaction time were also studied in both reduction processes, showing near-quantitative conversions within 5 minutes and obeying the pseudo-first-order kinetics, with the apparent kinetic rate constants of 8.9 × 10 -3 s -1 (4-nitrophenol) and 13.6 × 10 -3 s -1 (methyl orange). The chemical structure of the catalytic system was found to be highly stable during reaction and no metal leaching was detected in reaction medium, evidencing adaptability of cellulose nanocrystals in immobilizing noble metal nanoparticles., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Purpose: Exposures early in life, beginning in utero, have long-term impacts on mental and physical health. The ECHO prenatal and early childhood pathways to health consortium (ECHO-PATHWAYS) was established to examine the independent and combined impact of pregnancy and childhood chemical exposures and psychosocial stressors on child neurodevelopment and airway health, as well as the placental mechanisms underlying these associations., Participants: The ECHO-PATHWAYS consortium harmonises extant data from 2684 mother-child dyads in three pregnancy cohort studies (CANDLE [Conditions Affecting Neurocognitive Development and Learning in Early Childhood], TIDES [The Infant Development and Environment Study] and GAPPS [Global Alliance to Prevent Prematurity and Stillbirth]) and collects prospective data under a unified protocol. Study participants are socioeconomically diverse and include a large proportion of Black families (38% Black and 51% White), often under-represented in research. Children are currently 5-15 years old. New data collection includes multimodal assessments of primary outcomes (airway health and neurodevelopment) and exposures (air pollution, phthalates and psychosocial stress) as well as rich covariate characterisation. ECHO-PATHWAYS is compiling extant and new biospecimens in a central biorepository and generating the largest placental transcriptomics data set to date (N=1083)., Findings to Date: Early analyses demonstrate adverse associations of prenatal exposure to air pollution, phthalates and maternal stress with early childhood airway outcomes and neurodevelopment. Placental transcriptomics work suggests that phthalate exposure alters placental gene expression, pointing to mechanistic pathways for the developmental toxicity of phthalates. We also observe associations between prenatal maternal stress and placental corticotropin releasing hormone, a marker of hormonal activation during pregnancy relevant for child health. Other publications describe novel methods for examining exposure mixtures and the development of a national spatiotemporal model of ambient outdoor air pollution., Future Plans: The first wave of data from the unified protocol (child age 8-9) is nearly complete. Future work will leverage these data to examine the combined impact of early life social and chemical exposures on middle childhood health outcomes and underlying placental mechanisms., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. We sought to correct the multiple organ dysfunction of the F508del CF-causing mutation using systemic delivery of peptide nucleic acid gene editing technology mediated by biocompatible polymeric nanoparticles. We confirmed phenotypic and genotypic modification in vitro in primary nasal epithelial cells from F508del mice grown at air-liquid interface and in vivo in F508del mice following intravenous delivery. In vivo treatment resulted in a partial gain of CFTR function in epithelia as measured by in situ potential differences and Ussing chamber assays and correction of CFTR in both airway and GI tissues with no off-target effects above background. Our studies demonstrate that systemic gene editing is possible, and more specifically that intravenous delivery of PNA NPs designed to correct CF-causing mutations is a viable option to ameliorate CF in multiple affected organs.

Purpose: Half of the patients with high-risk neuroblastoma who receive GD2-targeted mAb do not achieve long-term remissions. Recently, the antibody hu14.18 has been linked to IL2 (hu14.18-IL2) to enhance its efficacy and shown promising preclinical and clinical activity. We developed two new immunocytokines (IC) by linking two other γc cytokines, IL15 and IL21, to hu14.18. The purpose of this study was to compare hu14.18-IL15 and -IL21 with hu14.18-IL2 in their ability to induce antibody-dependent cell-mediated cytotoxicity (ADCC) against neuroblastoma., Experimental Design: We assessed ADCC of hu14.18-IL15 and -IL2 (human cytokines, cross-reactive to mouse) against GD2low and GD2high neuroblastoma cell lines in vitro. T-cell-deficient mice with orthotopic patient-derived xenografts (PDX) and immunocompetent mice with transplantable orthotopic neuroblastoma were used to test all three ICs, including hu14.18-IL21 (murine IL21, not cross-reactive to human). Mechanistic studies were performed using single-cell RNA-sequencing (scRNA-seq)., Results: hu14.18-IL15 and hu14.18-IL2 mediated equivalent in vitro ADCC by human NK cells. When combined with chemotherapy, all three ICs similarly controlled the growth of PDXs in nude mice with murine NK effector cells. However, hu14.18-IL15 and -IL21 outperformed hu14.18-IL2 in immunocompetent mice with syngeneic neuroblastoma, inducing complete tumor regressions and extending survival. scRNA-seq data revealed an increase in CD8+ T cells and M1 tumor-associated macrophages and decreased regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment., Conclusions: Hu14.18-IL15 and Hu14.18-IL21 exhibit robust preclinical activity, warranting further consideration for clinical testing in patients with GD2-expressing neuroblastoma., (©2022 American Association for Cancer Research.)

Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Virtual exercise has become more common as emerging and converging technologies make active virtual reality games (AVRGs) a viable mode of exercise for health and fitness. Our lab has previously shown that AVRGs can elicit moderate to vigorous exercise intensities that meet recommended health benefit guidelines. Dissociative attentional focuses during AVRG gameplay have the potential to widen the gap between participants' perception of exertion and actual exertion., Objective: The aim of this study was to determine actual exertion (AEx) vs. perceived exertion (PEx) levels during AVRGs by measuring heart rate (HR) and ratings of perceived exertion (RPE) in two different settings., Materials and Methods: HR and RPE were collected on participants ( N = 32; age 22.6 ± 2.6) during 10 min of gameplay in LabS and GymS using the HTC VIVE with the following games played: Fruit Ninja VR (FNVR), Beat Saber (BS), and Holopoint (HP)., Results: Participants exhibited significantly higher levels of AEx compared to reported PEx for all three AVRGs (Intensity): FNVR [AEx = 11.6 ± 1.8 (Light), PEx = 9.0 ± 2.0 (Very Light)], BS [AEx = 11.3 ± 1.7 (Light), PEx = 10.3 ± 2.1 (Very Light)], HP [AEx = 13.1 ± 2.3 (Somewhat Hard), PEx = 12.3 ± 2.4 (Light-Somewhat Hard)]. Additionally, participants playing in the GymS experienced significantly higher levels of AEx [12.4 ± 2.3 (Light-Somewhat Hard)] and PEx [10.8 ± 2.5 (Very Light-Light)] compared to the LabS [AEx = 11.6 ± 1.8 (Light), PEx = 10.3 ± 2.6 (Very Light-Light)]., Conclusion: Perceptions of exertion may be lower than actual exertion during AVRG gameplay, and exertion levels can be influenced by the setting in which AVRGs are played. This may inform VR developers and health clinicians who aim to incorporate exercise/fitness regimens into upcoming 'virtual worlds' currently being developed at large scales (i.e., the "metaverse")., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Stewart, Villaneuva, Hahn, Ortiz-Delatorre, Wolf, Nguyen, Bolter, Kern and Bagley.)

Background: Postnatal exposures, including breastfeeding, may influence asthma development., Objective: To investigate the association between breastfeeding duration and child asthma., Methods: We studied 2021 mother-child dyads in the ECHO PATHWAYS consortium of prospective pregnancy cohorts (GAPPS, CANDLE, TIDES). Women reported the duration of any and exclusive breastfeeding and child asthma outcomes during follow-up at child age 4 to 6 years. Outcomes included current wheeze (previous 12 months), ever asthma, current asthma (having ≥2 of current wheeze, ever asthma, medication use in past 12-24 months), and strict current asthma (ever asthma with either or both current wheeze and medication use in past 12-24 months). We used multivariable logistic regression to assess associations (odds ratios and 95% confidence intervals) between breastfeeding and asthma outcomes adjusting for potential confounders. We assessed effect modification by mode of delivery, infant sex, and maternal asthma., Results: Among women, 33%, 13%, 9%, and 45% reported 0 to less than 2, 2 to 4, 5 to 6, and more than 6 months of any breastfeeding, respectively. The duration of any breastfeeding had a protective linear trend with ever asthma but no other outcomes. There was a duration-dependent protective association of exclusive breastfeeding and child asthma outcomes (eg, current asthma adjusted odds ratio [95% confidence interval], 0.64 [0.41-1.02], 0.61 [0.38-0.98], and 0.52 (0.31-0.87) for 2to 4 months, 5 to 6 months, and more than 6 months, respectively, compared with <2 months). For exclusive breastfeeding, protective associations were stronger in dyads with children born by vaginal vs cesarean delivery although interactions did not reach statistical significance (P interactions 0.12-0.40)., Conclusion: Longer duration of exclusive breastfeeding had a protective association with child asthma., (Copyright © 2022 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The Tpeak-end(Tp-e) has not been compared in all 12 ECG leads in healthy adults to determine if the Tp-e varies across leads. If there is variation, it remains uncertain, which lead(s) are preferred for recording in order to capture the maximal Tp-e value., Objective: The purpose of the current study was to determine the optimal leads, if any, to capture the maximal Tp-e interval in healthy young adults., Methods: In 88 healthy adults (ages 21-38 years), including derivation (n = 21), validation (n = 20), and smoker/vaper (n = 47) cohorts, the Tp-e was measured using commercial computer software (LabChart Pro 8 with ECG module, ADInstruments) in all 12 leads at rest and following a provocative maneuver, abrupt standing. Tp-e was compared to determine which lead(s) most frequently captured the maximal Tp-e interval., Results: In the rest and abrupt standing positions, the Tp-e was not uniform among the 12 leads; the maximal Tp-e was most frequently captured in the precordial leads. At rest, grouping leads V2-V4 resulted in detection of the maximum Tp-e in 85.7% of participants (CI 70.7, 99.9%) versus all other leads (p < .001). Upon abrupt standing, grouping leads V2-V6 together, resulted in detection of the maximum Tp-e 85.0% of participants (CI 69.4, 99.9% versus all other leads; p < .001). These findings were confirmed in the validation cohort, and extended to the smoking/vaping cohort., Conclusion: If only a subset of ECG leads will be recorded or analyzed for the Tp-e interval, selection of the precordial leads is preferred since these leads are most likely to capture the maximal Tp-e value., (© 2022 The Authors. Annals of Noninvasive Electrocardiology published by Wiley Periodicals LLC.)