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MR imaging is currently the main imaging modality used for the diagnosis and post therapeutic assessment of glioblastomas. Recently, several innovative PET radioactive tracers have been investigated for the evaluation of glioblastomas (GBM). These radiotracers target several biochemical and pathophysiological processes seen in tumors. These include glucose metabolism, DNA synthesis and cell proliferation, amino acid transport, cell membrane biosynthesis, specific membrane antigens such as prostatic specific membrane antigens, fibroblast activation protein inhibitor, translocator protein and hypoxia sensing agents, and antibodies targeting specific cell receptor antigen. This review aims to discuss the clinical value of these PET radiopharmaceuticals in the evaluation and treatment of GBMs., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Quantum transport is often characterized not just by mean observables like the particle or energy current but by their fluctuations and higher moments, which can act as detailed probes of the physical mechanisms at play. However, relatively few theoretical methods are able to access the full counting statistics (FCS) of transport processes through electronic junctions in strongly correlated regimes. While most experiments are concerned with steady state properties, most accurate theoretical methods rely on computationally expensive propagation from a tractable initial state. Here, we propose a simple approach for computing the FCS through a junction directly at the steady state, utilizing the propagator noncrossing approximation. Compared to time propagation, our method offers reduced computational cost at the same level of approximation, but the idea can also be used within other approximations or as a basis for numerically exact techniques. We demonstrate the method's capabilities by investigating the impact of lead dimensionality on electronic transport in the nonequilibrium Anderson impurity model at the onset of Kondo physics. Our results reveal a distinct signature of one dimensional leads in the noise and Fano factor not present for other dimensionalities, showing the potential of FCS measurements as a probe of the environment surrounding a quantum dot., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).)

Hatching synchronisation is widespread in oviparous taxa. It has been demonstrated that many species use sounds to coordinate synchronous hatching, being widespread among archosaurs (birds and crocodilians). Recent studies have shown that some turtle species produce vocalisations from within the egg, but the role of this behaviour in synchronising hatch is untested. The small amount of information about sound production by turtle embryos, limited to a handful of closely related species, precludes any inferences based on differences in their ecology, reproductive behaviour and phylogenetic context. With the goal to investigate if coordinated synchronous behaviour is mediated by within-egg vocalisations in turtles, we recorded clutches from six different turtle species. The selected animals present different ecological and reproductive niches and belong to distinct phylogenetic lineages at the family level. We aimed to understand: (1) what is the phylogenetic distribution of within-egg vocal behaviour among turtles; (2) if asynchronous turtle species vocalise from within the egg; (3) if clutch size influences synchronous behaviour and (4) if within-egg turtle calls follow any phylogenetic signal. The new evidence provides light to the current knowledge about synchronous behaviour and within-egg calls, challenging previous hypothesis that within-egg sounds are accidentally produced as side-effects of other behaviours., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Ecology and Evolution published by John Wiley & Sons Ltd.)

Photosynthesis-the conversion of energy from sunlight into chemical energy-is essential for life on Earth. Yet there is much we do not understand about photosynthetic energy conversion on a fundamental level: how it evolved and the extent of its diversity, its dynamics, and all the components and connections involved in its regulation. In this commentary, researchers working on fundamental aspects of photosynthesis including the light-dependent reactions, photorespiration, and C4 photosynthetic metabolism pose and discuss what they view as the most compelling open questions in their areas of research., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

Purpose: Meconium-stained amniotic fluid (MSAF) often signifies colonization of the amniotic sac by microorganisms. This study investigated additional adverse obstetric outcomes associated with MSAF in deliveries complicated by maternal intrapartum fever (IF)., Methods: This retrospective study included all singleton pregnancies from 2014 to 2020, with intrapartum maternal fever ≥ 38 °C during a trial of labor. In accordance with departmental protocol, all patients received intravenous antibiotic therapy consisting of ampicillin and gentamicin in the absence of allergies to these medications. Subsequent antibiotic therapy was adjusted based on the culture results. Antibiotic treatment was discontinued postpartum after 48 h without fever. Swab cultures were obtained immediately postpartum from both the maternal and fetal sides of the placenta. Maternal and fetal outcomes, along with positive placental cultures, were compared between participants with MSAF&IF and those with clear amniotic fluid &IF (control group)., Results: In comparison to the control group (n = 1089), the MSAF&IF group (n = 264) exhibited significantly higher rates of cesarean delivery (CD) (p = 0.001), CD due to non-reassuring fetal heart rate (p = 0.001), and cord pH ≤ 7.1 (p = 0.004). Positive swab cultures from the placental maternal and fetal sides were more prevalent among the MSAF&IF group (23.1% vs. 17.6%, p = 0.041 and 29.2% vs. 22.9%, p = 0.032, respectively). Placental cultures yielding gastrointestinal pathogens and extended spectrum beta-lactamase were notably more common in the MSAF&IF group compared to controls (p = 0.023). However, there was no significant difference between groups regarding the rate of group B streptococcus positive placental cultures., Conclusions: Women experiencing IF and MSAF during labor face an elevated risk of CD compared to those with IF alone. The presence of MSAF heightens the risk of positive placental cultures, particularly with gastrointestinal and extended spectrum beta-lactamase pathogens., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Describing the ground states of continuous, real-space quantum many-body systems, like atoms and molecules, is a significant computational challenge with applications throughout the physical sciences. Recent progress was made by variational methods based on machine learning (ML) ansatzes. However, since these approaches are based on energy minimization, ansatzes must be twice differentiable. This (a) precludes the use of many powerful classes of ML models; and (b) makes the enforcement of bosonic, fermionic, and other symmetries costly. Furthermore, (c) the optimization procedure is often unstable unless it is done by imaginary time propagation, which is often impractically expensive in modern ML models with many parameters. The stochastic representation of wavefunctions (SRW), introduced in Nat Commun 14, 3601 (2023), is a recent approach to overcoming (c). SRW enables imaginary time propagation at scale, and makes some headway towards the solution of problem (b), but remains limited by problem (a). Here, we argue that combining SRW with path integral techniques leads to a new formulation that overcomes all three problems simultaneously. As a demonstration, we apply the approach to generalized ``Hooke's atoms'': interacting particles in harmonic wells. We benchmark our results against state-of-the-art data where possible, and use it to investigate the crossover between the Fermi liquid and the Wigner molecule within closed-shell systems. Our results shed new light on the competition between interaction-driven symmetry breaking and kinetic-energy-driven delocalization., (Creative Commons Attribution license.)

Background: Despite plausible behavioral and physiological pathways, limited evidence exists on how daily temperature variability is associated with acute mental health-related episodes., Objectives: We aimed to explore associations between daily temperature range (DTR) and mental health-related hospital visits using data of all hospital records in New York State during 1995-2014. We further examined factors that may modify these associations, including age, sex, hospital visit type and season., Methods: Using a case-crossover design with distributed lag non-linear DTR terms (0-6 days), we estimated associations between ZIP Code-level DTR and hospital visits for mood (4.6 million hospital visits), anxiety (2.4 million), adjustment (∼368,000), and schizophrenia disorders (∼211,000), controlling for daily mean temperature, via conditional logistic regression models. We assessed potential heterogeneity by age, sex, hospital visit type (in-patient vs. out-patient), and season (summer, winter, and transition seasons)., Results: For all included outcomes, we observed positive associations from period minimum DTR (0.1 °C) until 25th percentile (5.2 °C) and between mean DTR (7.7 °C) and 90th percentile (12.2 °C), beyond which we observed negative associations. For mood disorders, an increase in DTR from 0.1 °C to 12.2 °C was associated with a cumulative 16.0% increase (95% confidence interval [CI]: 12.8, 19.2%) in hospital visit rates. This increase was highest during transition seasons (32.5%; 95%CI: 26.4, 39.0%) compared with summer (10.7%; 95%CI: 4.8, 16.8%) and winter (-1.6%; 95%CI: -7.6, 4.7%). For adjustment and schizophrenia disorders, the strongest associations were seen among the youngest group (0-24 years) with almost no association in the oldest group (65+ years). We observed no evidence for modification by sex and hospital visit type., Discussion: Daily temperature variability was positively associated with mental health-related hospital visits within specific DTR ranges in New York State, after controlling for daily mean temperature. Given uncertainty on how climate change modifies temperature variability, additional research is crucial to comprehend the implications of these findings, particularly under different scenarios of future temperature variability., 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 Elsevier Inc. All rights reserved.)

Background and Aims: Knowledge is lacking on the relationship between greenness and mortality in cancer survivors who experience coronary artery disease (CAD), a cardio-oncologic population. We aimed to investigate the association between residential greenness exposure and all-cause mortality in a cardio-oncologic population., Methods: Cancer survivors undergoing percutaneous coronary intervention at the Rabin Medical Center in Israel between 2004 and 2014 were included in the study. Clinical data were collected from medical records during index hospitalization and from the Israeli National Cancer Registry. Residential greenness was estimated by the normalized difference vegetation index (NDVI), a satellite-based index derived from Landsat imagery at a 30-meter spatial resolution, with larger values indicating higher levels of vegetative density (ranging between -1 to 1). Mortality follow-up data were obtained through the end of 2021. Cox models were used to assess the hazard ratios (HRs) for all-cause mortality per 1SD increase in NDVI., Results: Among 1,331 patients analyzed [mean (SD) age, 75.6 (10.2) years, 373 (28%) females], the mean (SD) NDVI within a 300-meter radius was 0.12 (0.03). During a median follow-up period of 12.0 (IQR 9.2-14.7) years, 883 (66%) participants died. After adjustment for potential confounding factors, including residential socioeconomic status, air pollution, and smoking, NDVI was inversely associated with mortality hazard [HR (95% CI) = 0.93 (0.86, 0.99); p=.042]. The association was stronger among individuals with more recently (<10 years) diagnosed cancer [HR (95% CI) = 0.89 (0.81, 0.98); p=.019]., Conclusion: In a cohort of cardio-oncologic patients, greenness was independently associated with lower mortality., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

A precise dynamical characterization of quantum impurity models with multiple interacting orbitals is challenging. In quantum Monte Carlo methods, this is embodied by sign problems. A dynamical sign problem makes it exponentially difficult to simulate long times. A multi-orbital sign problem generally results in a prohibitive computational cost for systems with multiple impurity degrees of freedom even in static equilibrium calculations. Here, we present a numerically exact inchworm method that simultaneously alleviates both sign problems, enabling simulation of multi-orbital systems directly in the equilibrium or nonequilibrium steady-state. The method combines ideas from the recently developed steady-state inchworm Monte Carlo framework [Erpenbeck et al., Phys. Rev. Lett. 130, 186301 (2023)] with other ideas from the equilibrium multi-orbital inchworm algorithm [Eidelstein et al., Phys. Rev. Lett. 124, 206405 (2020)]. We verify our method by comparison with analytical limits and numerical results from previous methods., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Pentacene is an important model organic semiconductor in both the singlet exciton fission (SF) and organic electronics communities. We have investigated the effect of changing crystal structure on the SF process, generating multiple triplet excitons from an initial singlet exciton, and subsequent triplet recombination. Unlike for similar organic semiconductors that have strong SF sensitive to polymorphism, we find almost no quantitative difference between the kinetics of triplet pair (TT) formation in the two dominant polymorphs of pentacene. Both pairwise dimer coupling and momentum-space crystal models predict much faster TT formation from the bright singlet excited state of the Bulk vs ThinFilm polymorph, contrasting with the experiment. GW and Bethe-Salpeter equation calculations, including exciton-phonon coupling, reveal that ultrafast phonon-driven transitions in the ThinFilm polymorph compensate the intrinsically slower purely Coulomb-mediated TT formation channel, rationalizing the similarity in observed rates. Taking into account the influence of subtle structural distinctions on both the direct and phonon-mediated SF pathways reveals a predictive capability to these methods, expected to be applicable to a wide variety of molecular crystals., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/).)

Purpose: To study the effect of decreased estimated fetal weight (EFW) percentiles in appropriate for gestational age fetuses., Methods: This retrospective cohort study included women who had second and third trimester ultrasound examinations. Delivery and neonatal outcomes of pregnancies with decreased EFW of ≥  30 percentiles in EFW between ultrasound examinations (decreased growth group) and those without such a decrease (control group) were compared. Deliveries with EFW or birthweight below the 10th percentile were excluded., Results: Among 1610 deliveries, 57 were in the decreased growth group and 1553 in the control group. Maternal characteristics did not differ between the groups except for higher rate of nulliparity in the decreased growth group. We found similar rates of Category II/III monitoring, cesarean deliveries due to non-reassuring fetal heart rate and adverse neonatal outcomes. Neonatal birthweight was lower in the decreased growth group as compared to controls., Conclusions: This study did not find association between the group of appropriate for gestational age fetuses with decreased growth, with adverse outcomes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: This study's objective is to investigate disparities in the rates of gestational diabetes mellitus (GDM) diagnosis, influenced by the timing of the glucose challenge test GCT., Methods: This retrospective cohort study included women with singleton or twin pregnancies exhibiting abnormal GCT result between 24 and 28 weeks of gestation, followed by an oral glucose tolerance test OGTT during the same period. Data regarding pregnancy follow-up from patients' deliveries at a singular tertiary medical from 2014 to 2022 were retrieved. The probability of GDM diagnosis was stratified based on the gestational week of the GCT and the definition of a positive OGTT, delineated by one or two abnormal values., Results: The study included 636 women with abnormal GCT between 24 and 28 weeks of gestation. Of them, 157 unerwent the GCT between 24.0 and 24.6 weeks, 204 between 25.0 and 25.6 weeks, 147 between 26.0 and 26.6 weeks, and 128 between 27.0 and 28.6 weeks. We found that the highest incidence of GDM, defined by one or two pathological values of the OGTT, following the initial screening with a GCT, where abnormal results were defined as values exceeding 140 mg/dL, was diagnosed in patients who underwent GCT between 26.0 and 26.6 weeks of gestation. Conversely, the lowest rates were observed in patients screened between 24.0 and 24.6 weeks of gestation., Conclusion: The timing of screening for GDM using the GCT significantly affects the rate of diagnosis. Clinicians managing pregnancies should consider this data when formulating treatment plans., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Circulating tumor DNA (ctDNA) is emerging as a potential biomarker in early-stage urothelial cancer, but its utility in metastatic disease remains unknown. In the phase 3 KEYNOTE-361 study, pembrolizumab with and without chemotherapy was compared with chemotherapy alone in patients with metastatic urothelial cancer. The study did not meet prespecified efficacy thresholds for statistical significance. To identify potential biomarkers of response, we retrospectively evaluated the association of pre- and posttreatment ctDNA with clinical outcomes in a subset of patients who received pembrolizumab (n = 130) or chemotherapy (n = 130) in KEYNOTE-361. Baseline ctDNA was associated with best overall response (BOR; P = 0.009), progression-free survival (P < 0.001) and overall survival (OS; P < 0.001) for pembrolizumab but not for chemotherapy (all; P > 0.05). Chemotherapy induced larger ctDNA decreases from baseline to treatment cycle 2 than pembrolizumab; however, change with pembrolizumab (n = 87) was more associated with BOR (P = 4.39 × 10 -5 ) and OS (P = 7.07 × 10 -5 ) than chemotherapy (n = 102; BOR: P = 1.01 × 10 -4 ; OS: P = 0.018). Tumor tissue-informed versions of ctDNA change metrics were most associated with clinical outcomes but did not show a statistically significant independent value for explaining OS beyond radiographic change by RECIST v.1.1 when jointly modeled (pembrolizumab P = 0.364; chemotherapy P = 0.823). These results suggest distinct patterns in early ctDNA changes with immunotherapy and chemotherapy and differences in their association with long-term outcomes, which provide preliminary insights into the utility of liquid biopsies for treatment monitoring in metastatic urothelial cancer. Clinical trial registration: NCT02853305 ., (© 2024. Merck & Co., Inc., Rahway, NJ, USA and its affiliates, and The Authors.)

Objective: To determine if there is a correlation between maternal short stature and neonatal birth weight among women with adverse outcomes related to labor dystocia., Methods: The medical records of singleton deliveries with adverse obstetric outcomes related to labor dystocia during 2014-2020, in a single tertiary center, were reviewed. Outcomes included at least one of the following: cesarean delivery (CD) due to cephalopelvic disproportion (CPD), prolonged second stage, shoulder dystocia, third- or fourth-degree perineal tear. Maternal short stature was defined as height below the 10th centile (short stature group) and normal stature was defined as maternal height between the 10th and 90th centiles (normal stature group). Maternal and neonatal characteristics were compared between the groups., Results: A total of 3295 women were included, among them, 307 in the short stature group (9.3%, height 1.52 ± 0.02 m) and 2988 in the normal stature group (90.7%, height 1.63 ± 0.04 m). Evaluating the entire cohort revealed similar neonatal birth weights comparing the short and normal stature groups. A subgroup analysis of women after CD due to CPD (n = 296) revealed lower neonatal birth weights in the short stature group (n = 31) compared with the normal stature group (n = 265) (3215 ± 411 vs 3484 ± 427 g, P = 0.001, respectively). Multivariable linear regression was performed for women who underwent CD due to CPD. After adjusting for obesity and diabetes mellitus, short stature and nulliparity were found to be independently associated with decreased neonatal birth weight (266 g less for short stature, P = 0.001, and 294 g less for nulliparity, P = 0.001)., Conclusions: Among women with short stature, CD due to CPD occurs at lower neonatal birth weights., (© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

A strategy for pandemic preparedness is the development of antivirals against a wide set of viral targets with complementary mechanisms of action. SARS-CoV-2 nsp3-mac1 is a viral macrodomain with ADP-ribosylhydrolase activity, which counteracts host immune response. Targeting the virus' immunomodulatory functionality offers a differentiated strategy to inhibit SARS-CoV-2 compared to approved therapeutics, which target viral replication directly. Here we report a fragment-based lead generation campaign guided by computational approaches. We discover tool compounds which inhibit nsp3-mac1 activity at low nanomolar concentrations, and with responsive structure-activity relationships, high selectivity, and drug-like properties. Using our inhibitors, we show that inhibition of nsp3-mac1 increases ADP-ribosylation, but surprisingly does not translate to demonstrable antiviral activity in cell culture and iPSC-derived pneumocyte models. Further, no synergistic activity is observed in combination with interferon gamma, a main protease inhibitor, nor a papain-like protease inhibitor. Our results question the extent to which targeting modulation of innate immunity-driven ADP-ribosylation can influence SARS-CoV-2 replication. Moreover, these findings suggest that nsp3-mac1 might not be a suitable target for antiviral therapeutics development.

Body fluid detection is an important component in the toolbox of forensic scientists, with saliva playing a particularly critical role in forensic evidence. Given that each body fluid possesses a distinct microbiome, the identification of body fluid based on specific representatives of the microbiota presents an appealing approach for forensic applications. In this study, we have developed a real-time polymerase chain reaction (RT-PCR)-based method for the precise identification of saliva, focusing on three bacteria highly associated with saliva but not with other tested body fluids -Porphyromonas gingivalis, Fusobacterium nucleatum, and Streptococcus salivarius. The inclusion of these three bacterial species enhances the accuracy of detection and reinforces validation. Notably, specific identification of saliva was achievable even at low concentrations where Phadebas, a commonly used method for saliva detection, proved ineffective. Importantly, bacteria-based saliva detection utilizes DNA generated for small tandem repeats (STR) profiling, facilitating seamless integration into forensic laboratories and optimizing DNA sample utilization. This study collectively proposes an effective bacterial DNA-based approach for saliva identification, demonstrating promising potential for forensic applications., Competing Interests: Declaration of Competing Interest The authors affirm the absence of any conflicts of interest related to this investigation., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Fetal sex is independently associated with pregnancy complications and impacts neonatal outcomes. Evidence suggests that females have an advantage over males, with a better outcome in the perinatal period. In addition, fetal outcome in twin gestations is also related to the intrauterine position of the fetus, such as the first, the presenting or second twin. It has been demonstrated that the neonatal outcome of the second fetus is worse than that of the first fetus. This study aimed to examine the influence of fetal sex on obstetric outcomes in twin pregnancies based on the location of the fetus in the uterus., Methods: Retrospective study. Maternal and obstetric outcomes were compared among three groups: male‒male, female‒female, and male‒female groups. Comparisons of neonatal outcomes were performed among the four groups: male A-male B, male A-female B, female A-male B, and female A-female B., Results: A total of 1073 twin gestations were included, comprising 288 male‒male, 288 female‒female, and 497 male‒female gestations. A greater percentage of neonates admitted to the NICU was observed for male fetuses than for female fetuses. Adverse composite neonatal outcome was more common in the male‒male group than in the female‒male group and in the female‒female group., Conclusion: Twin gestation with a first twin male tends to have worse neonatal outcomes than does twin gestation with a first twin female. The presence of a male co-twin increases the risk of adverse outcomes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The COVID-19 pandemic, characterized by its highly contagious nature and devastating death toll, posed a dual threat to both physical and psychological well-being. As a potential intervention to alleviate the psychological impact, values-affirmation involves individuals engaging in the activity of writing about their core values. While its effectiveness in non-WEIRD (i.e. Western, Educated, Industrialized, Rich, Democratic) populations, notably among Chinese adults, has been confirmed, it remains largely unexplored whether the intervention can promote mental health in Chinese adolescents, especially in the context of the COVID-19 pandemic. The purpose of this study thus is to provide the first empirical evaluation of this intervention in promoting well-being and alleviating psychological distress among Chinese adolescents during the COVID-19 pandemic. A total of 2,234 students from 112 secondary schools in China were randomly assigned to an affirmation or control condition. The study found that self-affirmation intervention improved students' life satisfaction, mental health, and self-esteem, as well as buffered a decline of their purpose in life; however, no effects were found for clinical measures of depression, anxiety, and loneliness. The results suggest that self-affirmation interventions, while having limited effects on clinically relevant outcomes, can be an effective approach to boost well-being in adolescents during a major crisis, including in a more historically collectivist culture. Implications for self-affirmation theory and cultural psychology, as well as avenues for future research, are discussed., (© 2023 International Association of Applied Psychology.)

Background: Electronic nicotine delivery systems (ENDS) offer a promising approach to tobacco harm reduction, but many people use both ENDS and combustible cigarettes ("dual use"), which undermines potential risk reduction. To explore the role of ENDS nicotine delivery in promoting switching to ENDS, we conducted a study in which people who smoked cigarettes were offered an ENDS that had previously been shown to replicate the rapid nicotine pharmacokinetics of combustible cigarettes (BIDI ® Stick)., Methods: Twenty-five cigarette smoking adults, not seeking smoking cessation treatment, but open to using ENDS as a cigarette substitute, were provided with a 12-week supply of BIDI ® Stick in tobacco or menthol flavors, during a study that included seven biweekly sessions and a 6-month follow-up. Daily diaries assessed ENDS and cigarette use, and exhaled carbon monoxide (eCO) served as an objective marker of smoke intake. Subjective ratings were collected to assess the rewarding properties of ENDS and combustible cigarettes, and indices of nicotine dependence., Results: Over 12 weeks, ENDS use increased to an average of 15.8 occasions per day (SD = 20.2) and self-reported cigarette consumption decreased by 82% from 16.7 cigarettes/day (SD = 6.0) at baseline to 3.0 cigarettes/day (SD = 4.1) at week 12. The eCO level decreased by 27% from an average of 20.0 ppm (SD = 9.8) at baseline to 14.5 ppm (SD = 9.9) at week 12. Four of 25 participants completely switched to ENDS and were smoking abstinent during weeks 9-12. At 6 months one participant was confirmed to be abstinent. Ratings of subjective reward for the ENDS were very similar to those of participants' usual brands of cigarettes. Dependence level was lower for the ENDS than for combustible cigarettes., Conclusions: In this study, the ENDS effectively replicated the subjective rewarding effects of participants' usual brands of cigarettes and led to a substantial reduction in reported cigarettes/day. Exhaled CO showed less of a decrease, possibly due to compensatory smoking behavior and/or the timing of eCO measurements that might not have reflected smoke intake throughout the day. The relatively low rate of sustained smoking abstinence at 6 months suggests that additional approaches continue to be needed for achieving higher rates of complete switching., Trial Registration: ClinicalTrials.gov identifier NCT05855343., (© 2024. The Author(s).)

The bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction (BASILICA) procedure allows patients with severe aortic stenosis and anatomical challenges from aortic leaflet orientation, positioning of coronary ostia, and height of sinuses of Valsalva to undergo TAVR. We present a case of intraprocedural cardiac arrest secondary to iatrogenic left main coronary artery obstruction following a successful BASILICA procedure., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Dieldrin, an organochlorine pesticide (OCP) widely used for crop protection in the second half of the 20th century till the 70's, is worldwide still present in arable soils. It can be transferred to crops, notably cucurbits, depending on plant species and cultivars. Finding strategies to decrease OCP bioavailability in soil is therefore a main concern. Phytomanagement strategies could provide (i) ready-to-use short term solution for maintaining the production of edible plant parts with dieldrin concentrations below the Maximum Residue Limits (MRL) and (ii) long-term solution for dieldrin phytoextraction reducing progressively its bioavailability in the soil. This field study aimed at determining dieldrin accumulation capacities and allocation pattern in 17 non-Cucurbitaceae species and 10 Cucurbita pepo varieties, and assessing the dieldrin phytoextraction potential of these plant species when grown to maturity in a historically dieldrin-contaminated soil. Out of the non-Cucurbitaceae species, vetiver was the only one able to accumulate significant amounts of dieldrin, which mainly remained in its roots. All C. pepo varieties were able to uptake and translocate high dieldrin amounts into the shoots, leading to the highest phytoextraction potential. Despite the intraspecific variability in dieldrin concentration in zucchini plant parts, mainly in the reproductive organs, the phytoextraction capacity for shoots and fruits was high for all tested varieties (147 to 275 μg dieldrin plant -1 , corresponding to 5.6 % of the n-heptane extractable soil dieldrin), even for the one with low fruit dieldrin concentration. Both food safety and phytoextraction could be achieved by selecting productive zucchini varieties displaying low dieldrin concentration in fruits and high one in shoots., 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 Authors. Published by Elsevier B.V. All rights reserved.)

Background: Cigarette smoking is a leading cause of morbidity and mortality. For adults who smoke cigarettes and cannot or will not quit smoking, smoke-free products, such as nicotine pouches, have been recognized as a potential alternative to smoking combusted cigarettes to reduce harm due to cigarette smoking. The role of flavors in these smoke-free products in tobacco harm reduction has not been fully understood., Objective: This study evaluates the effect of flavors in on! nicotine pouch products (research products) in the reduction of cigarette smoking among adults who smoke cigarettes in their natural environment., Methods: This study uses a sequential, multiple assignment, randomized trial design. Approximately 400 eligible adults who smoke cigarettes will be enrolled and randomized to have access to either the Original (unflavored) on! nicotine pouch product only or a complete flavor profile (ie, Berry, Cinnamon, Citrus, Coffee, Mint, Original, and Wintergreen) of on! nicotine pouch products. After 3 weeks, participants in the Original-only arm will be randomized again, with half remaining in the Original-only arm and half having access to the complete flavor profile for another 3 weeks. Primary outcomes are expired-air carbon monoxide (CO) levels. Secondary outcomes are self-reported cigarette consumption and CO-verified cigarette abstinence., Results: Recruitment and data collection started in September 2023 and is projected to last until March 2025. We anticipate completing the data analysis in 2025. As of May 2024, we have enrolled 314 participants., Conclusions: This study will provide empirical evidence about the effect that flavor availability in smoke-free products may have in reducing cigarette smoking., Trial Registration: ClinicalTrials.gov NCT06072547; https://clinicaltrials.gov/study/NCT06072547., International Registered Report Identifier (irrid): DERR1-10.2196/56565., (©Hui G Cheng, Jed E Rose, Joshua L Karelitz, David R Botts, Tanaia L Botts, Perry N Willette, Gal Cohen. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 21.06.2024.)

While mutational signatures provide a plethora of prognostic and therapeutic insights, their application in clinical-setting, targeted gene panels is extremely limited. We develop a mutational representation model (which learns and embeds specific mutation signature connections) that enables prediction of dominant signatures with only a few mutations. We predict the dominant signatures across more than 60,000 tumors with gene panels, delineating their landscape across different cancers. Dominant signature predictions in gene panels are of clinical importance. These included UV, tobacco, and apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) signatures that are associated with better survival, independently from mutational burden. Further analyses reveal gene and mutation associations with signatures, such as SBS5 with TP53 and APOBEC with FGFR3 S249C . In a clinical use case, APOBEC signature is a robust and specific predictor for resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Our model provides an easy-to-use way to detect signatures in clinical setting assays with many possible clinical implications for an unprecedented number of cancer patients., Competing Interests: Declaration of interests A.Y. and S.R. are inventors on a patent application encompassing the intellectual principle of MESiCA. United States Patent and Trademark Office: application serial no. 63/406,909., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Patch testing is the standard diagnostic test used for patients presenting with symptoms of allergic contact dermatitis. The grading of patch test results classically varies from 1 to 3. The assessment of these results begins with a visual inspection of the presence of erythema, vesiculation, and induration. This leads to a subjectivity in visual evaluation of a patch test. Positive patch testing results can present differently in patients with darker skin tones. A greater variety of images of allergic contact dermatitis in patients with darker skin phototypes can better guide the diagnosis of this condition in skin of color. People with darker phototypes are historically underrepresented in dermatologic images and texts; thus, identifying erythema in darker phototypes may be more difficult for dermatologists, whether or not they were trained in areas of decreased phototype diversity. In this article, we present positive patch testing findings on several different phototypes, with the intention of contributing to images of phototypes underrepresented in dermatology literature., Competing Interests: DISCLOSURES: The authors report no conflicts of interest relevant to the content of this article., (Copyright © 2024. Matrix Medical Communications. All rights reserved.)

Background: A growing literature documents how primary care practices adapted to the COVID-19 pandemic. We examine a topic that has received less attention-how participants in an advanced alternative payment model perceive the model influenced their ability to meet patients' care needs during the pandemic., Methods: Analysis of closed- and open-ended questions from a 2021 survey of 2496 practices participating in the Comprehensive Primary Care Plus (CPC+) model (92% response rate) and a 2021 survey of 993 randomly selected primary care physicians from these practices (55% response rate). Both surveys asked whether respondents agreed or disagreed that they or their practice was "better positioned to meet patients' care needs during the coronavirus pandemic" because of participation in CPC+. Both also included an open-ended question about CPC+'s effects., Results: Half of practices and one-third of physicians agreed or strongly agreed that participating in CPC+ better positioned them to meet patients' care needs during the pandemic. One in 10 practices and 2 in 10 physicians, disagreed or strongly disagreed, while 4 in 10 practices and slightly more than half of physicians neither agreed nor disagreed (or, for physicians, didn't know). The most commonly identified CPC+ activities that facilitated meeting patient care needs related to practices' work on care management (e.g., risk stratification), access (e.g., telehealth), payment outside of fee-for-service (FFS), and staffing (e.g., supporting care managers)., Conclusions: Most CPC+ practices and physicians were positive or neutral about participating in CPC+ in the context of COVID-19, indicating more benefit than risk to payment alternatives to FFS., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Genna Cohen reports financial support was provided by U.S. Department of Health and Human Services, Centers for Medicare & Medicaid Services. Nancy Duda reports financial support was provided by U.S. Department of Health and Human Services, Centers for Medicare & Medicaid Services. Katie Morrison Lee reports financial support was provided by U.S. Department of Health and Human Services, Centers for Medicare & Medicaid Services. Kaylyn Swankoski reports financial support was provided by U.S. Department of Health and Human Services, Centers for Medicare & Medicaid Services. Gillian Giudice reports financial support was provided by U.S. Department of Health and Human Services, Centers for Medicare & Medicaid Services. Maya Palakal reports financial support was provided by U.S. Department of Health and Human Services, Centers for Medicare & Medicaid Services. Caroline Mack reports financial support was provided by U.S. Department of Health and Human Services, Centers for Medicare & Medicaid Services. Ann S. O'Malley reports financial support was provided by U.S. Department of Health and Human Services, Centers for Medicare & Medicaid Services., (Copyright © 2024. Published by Elsevier Inc.)

The ability of Electronic Nicotine Delivery Systems (ENDS) to deliver nicotine is central to their function to substitute for cigarettes, allowing people who smoke to switch away from smoking, thus reducing their exposure to harmful chemicals in cigarette smoke. The nicotine concentration in ENDS e-liquid has proved to be a poor predictor of nicotine uptake in users. Using meta-analytic methods to analyze 12 pharmacokinetic studies of nicotine-salt closed-system ENDS, this paper examines whether the mass of nicotine/puff of aerosol can predict C max in pharmacokinetic studies. C max values were available for 38 products, in 58 use conditions (including both controlled [3 s] and ad libitum puffing), comprising 1769 participant observations. Nicotine/puff data reflected chemical analyses of aerosol obtained under nonintense (3 s) or intense (6 s) machine puffing. Meta-regression analyses (weighted by reliability of C max estimate) assessed the relationship of nicotine/puff to C max . In some models, empirical data were used to impute the variation in C max or the nicotine/puff value under intense puffing. In simple linear models, C max was significantly associated with nicotine/puff under all combinations of intense/nonintense and controlled/ad-libitum conditions, with R 2 values of 0.71-0.77. More complex models based on quadratic effects or log[nicotine/puff] did not generally improve upon more parsimonious linear models. Application of the model illustrates the divergence between nicotine concentration in e-liquids and expected C max when other ENDS parameters vary. The meta-analytic model may have utility in settings where clinical pharmacokinetic data are not available, including product development., (© 2024 John Wiley & Sons Ltd.)

The hyoid apparatus of tetrapods is highly diverse in its morphology. It plays an important role in feeding, breathing, sound production, and various other behaviors. Among turtles, the diversity of the hyoid apparatus has been recurrently linked to their habitat. The ossification of the hyoid corpus is often the main trait used in correlations with "niche" occupancy, an ossified corpus being associated with aquatic environments and a cartilaginous corpus with terrestrial life. Most studies conducted so far have focused on species belonging to Testudinoidea, the clade that occupies the biggest diversity of habitats (i.e., terrestrial, semi-terrestrial, and aquatic animals), while other turtle lineages have been largely understudied. We assessed the adult anatomy of the hyoid apparatus of 92 turtle species from all "families", together with ossification sequences from embryological series of 11 species, some described for the first time here. Using nearly 40 different discrete anatomical characters, we discuss the evolutionary patterns and the biological significance of morphological transformations in the turtle hyoid elements. Morphological changes are strongly associated to feeding modes, with several instances of convergent evolution within and outside the Testudines clade, and are not as strongly connected to habitat as previously thought. Some of the hyoid character states we describe are diagnostic of specific turtle clades, thus providing phylogenetically relevant information., Competing Interests: The authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology.)

Background: In the ongoing, randomised, double-blind phase 3 TOPAZ-1 study, durvalumab, a PD-L1 inhibitor, plus gemcitabine and cisplatin was associated with significant improvements in overall survival compared with placebo, gemcitabine, and cisplatin in people with advanced biliary tract cancer at the pre-planned intermin analysis. In this paper, we present patient-reported outcomes from TOPAZ-1., Methods: In TOPAZ-1 (NCT03875235), participants aged 18 years or older with previously untreated, unresectable, locally advanced, or metastatic biliary tract cancer with an Eastern Cooperative Oncology Group performance status of 0 or 1 and one or more measurable lesions per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) were randomly assigned (1:1) to the durvalumab group or the placebo group using a computer-generated randomisation scheme. Participants received 1500 mg durvalumab or matched placebo intravenously every 3 weeks (on day 1 of the cycle) for up to eight cycles in combination with 1000 mg/m 2 gemcitabine and 25 mg/m 2 cisplatin intravenously on days 1 and 8 every 3 weeks for up to eight cycles. Thereafter, participants received either durvalumab (1500 mg) or placebo monotherapy intravenously every 4 weeks until disease progression or other discontinuation criteria were met. Randomisation was stratified by disease status (initially unresectable vs recurrent) and primary tumour location (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer). Patient-reported outcomes were assessed as a secondary outcome in all participants who completed the European Organisation for Research and Treatment of Cancer's 30-item Quality of Life of Cancer Patients questionnaire (QLQ-C30) and the 21-item Cholangiocarcinoma and Gallbladder Cancer Quality of Life Module (QLQ-BIL21). We calculated time to deterioration-ie, time from randomisation to an absolute decrease of at least 10 points in a patient-reported outcome that was confirmed at a subsequent visit or the date of death (by any cause) in the absence of deterioration-and adjusted mean change from baseline in patient-reported outcomes., Findings: Between April 16, 2019, and Dec 11, 2020, 685 participants were enrolled and randomly assigned, 341 to the durvalumab group and 344 to the placebo group. Overall, 345 (50%) of participants were male and 340 (50%) were female. Data for the QLQ-C30 were available for 318 participants in the durvalumab group and 328 in the placebo group (median follow-up 9·9 months [IQR 6·7 to 14·1]). Data for the QLQ-BIL21 were available for 305 participants in the durvalumab group and 322 in the placebo group (median follow-up 10·2 months [IQR 6·7 to 14·3]). The proportions of participants in both groups who completed questionnaires were high and baseline scores were mostly similar across treatment groups. For global health status or quality of life, functioning, and symptoms, we noted no difference in time to deterioration or adjusted mean changes from baseline were observed between groups. Median time to deterioration of global health status or quality of life was 7·4 months (95% CI 5·6 to 8·9) in the durvalumab group and 6·7 months (5·6 to 7·9) in the placebo group (hazard ratio 0·87 [95% CI 0·69 to 1·12]). The adjusted mean change from baseline was 1·23 (95% CI -0·71 to 3·16) in the durvalumab group and 0·35 (-1·63 to 2·32) in the placebo group., Interpretation: The addition of durvalumab to gemcitabine and cisplatin did not have a detrimental effect on patient-reported outcomes. These results suggest that durvalumab, gemcitabine, and cisplatin is a tolerable treatment regimen in patients with advanced biliary tract cancer., Funding: AstraZeneca., Competing Interests: Declaration of interests HABIII reports consulting or advisory fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, FORMA Therapeutics, GRAIL, Incyte, Novartis, Pfizer, and Vincerx, and and research funding from AbbVie, Agios, Arch, ARMO Biosciences, Array BioPharma, Arvinas, AstraZeneca, Bayer, BIND Therapeutics, BioAtla, BioMed Valley, Biotheryx, Boehringer Ingelheim, Bristol-Myers Squibb, Cancer and Leukemia Group B, Ciclomed, Coordination Pharmaceuticals, CytomX, eFFECTOR Therapeutics, EMD Serono, Foundation Medicine, Gossamer Bio, Gilead Sciences, GlaxoSmithKline, Harpoon Therapeutics, Jiangsu Hengrui, Incyte, Infinity, Janssen, Jounce, Kymab, Lilly, MacroGenics, MedImmune, Merck, Millennium, Takeda, miRNA Therapeutics, Moderna, NGM Biopharmaceuticals, Novartis, Pfizer, Revolution Medicine, Roche, Genentech, Ryvu, Seattle Genetics, TESARO, TG Therapeutics, Verastem, Vertex, XBiotech, and Zymeworks. TO reports honoraria from AbbVie, AstraZeneca, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Nihon Servier, Novartis, ONO, Taiho, Takeda, Teijin, and Yakult; consulting or advisory fees from AstraZeneca, Bayer Yakuhin, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Sumitomo, Eisai, Eli Lilly Japan, Incyte, Meiji Seika Pharma, Mundipharma, Nihon Servier, Nippon Shinyaku, Novartis, ONO, Pfizer, Shire, Taiho, Takara Bio, and Takeda; and research funding from AstraZeneca, Baxter, Bristol-Myers Squibb, Chugai, Sumitomo, Eisai, Eli Lilly Japan, Kyowa Hakko Kirin, Merck, Sharp, & Dohme, Nano Carrier, Novartis, ONO, Pfizer, Syneos Health, and Taiho. AV reports honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb, British Technology Group, Eisai, GlaxoSmithKline, Imaging Equipment, Incyte, Ipsen, Lilly, Merck, Novartis, Pierre Fabre, Roche, Sanofi, Servier, Sirtex, and Terumo; and consulting or advisory fees from AstraZeneca, Bayer, Bristol-Myers Squibb, British Technology Group, Eisai, GlaxoSmithKline, Imaging Equipment, Incyte, Ipsen, Lilly, Merck, Novartis, Pierre Fabre, Roche, Sanofi, Servier, Sirtex, and Terumo. HT reports honoraria from Daiichi Sankyo, Mylan, Taiho, and Yakult, and research funding from AstraZeneca, Daiichi Sankyo, and Taiho. VB reports honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb Russia, Eisai, Merck, Sharp, & Dohme, Novartis, Pfizer, Roche Russia, and Takeda, and travel or accommodation expenses from Bayer, Bristol-Myers Squibb Russia, Merck, Sharp, & Dohme, and Roche Russia. J-FB reports honoraria from AstraZeneca, Bayer, Eisai, Ipsen, Merck, Sharp, & Dohme, and Roche, and consulting or advisory fees from AstraZeneca, Bayer, Eisai, Ipsen, Merck, Sharp, & Dohme, and Roche. MB reports honoraria for participating in patient advisory boards, review of patient materials, and speaking engagements from AstraZeneca, Boehringer Ingelheim, CRC Oncology, EMD Serono, Incyte, Kinnate, Merck, QED Clinical Services, Taiho, and TriSalus. MŻ is an employee of AstraZeneca. JA was an employee of IQVIA at the time of the study and reports consulting or advisory fees from AstraZeneca. NP, JW, MA, NR, and GC are employees of, and hold stock in, AstraZeneca. D-YO reports consulting or advisory fees from ASLAN, AstraZeneca, Basilea, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Roche, Halozyme, Merck Serono, Novartis, Taiho, Turning Point, Yuhan, and Zymeworks, and research funding from Array, AstraZeneca, BeiGene, Eli Lilly, Handok, Merck, Sharp, & Dohme, Novartis, and Servier. All other others declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In this paper we present a new reactive transport code for the efficient simulation of groundwater quality problems. The new code couples the two previously existing tools OpenFoam and PhreeqcRM. The major objective of the development was to transfer and expand the capabilities of the MODFLOW/MT3DMS-family of codes, especially their outstanding ability to suppress numerical dispersion, to a versatile and computationally efficient code for unstructured grids. Owing to the numerous, previously existing transport solvers contained in OpenFoam, the newly developed code achieves this objective and provides a solid basis for future expansions of the code capabilities. The flexibility of the OpenFoam framework is illustrated by the addition of diffusional processes for gaseous compounds in the unsaturated zone and the advection of gases (multiphase transport). The code capabilities and accuracy are illustrated through several examples: (1) a simple 2D case for conservative solute transport under saturated conditions, (2) a gas diffusion case with reactions in the unsaturated zone, (3) a hydrogeologically complex 3D reactive transport problem, and finally (4) the injection of CO 2 into a deep aquifer with acidification being buffered by carbonate minerals., (© 2023 The Authors. Groundwater published by Wiley Periodicals LLC on behalf of National Ground Water Association.)

A description of long-lived photodoped states in Mott insulators is challenging, as it needs to address exponentially separated timescales. We demonstrate how properties of such states can be computed using numerically exact steady state techniques, in particular, the quantum Monte Carlo algorithm, by using a time-local ansatz for the distribution function with separate Fermi functions for the electron and hole quasiparticles. The simulations show that the Mott gap remains robust to large photodoping, and the photodoped state has hole and electron quasiparticles with strongly renormalized properties.

We study bulk particle transport in a Fermi-Hubbard model on an infinite-dimensional Bethe lattice, driven by a constant electric field. Previous numerical studies showed that one dimensional analogs of this system exhibit a breakdown of diffusion due to Stark many-body localization at least up to time that scales exponentially with the system size. Here, we consider systems initially in a spin density wave state using a combination of numerically exact and approximate techniques. We show that for sufficiently weak electric fields, the wave's momentum component decays exponentially with time in a way consistent with normal diffusion. By studying different wavelengths, we extract the dynamical exponent and the generalized diffusion coefficient at each field strength. Interestingly, we find a nonmonotonic dependence of the dynamical exponent on the electric field. As the field increases toward a critical value proportional to the Hubbard interaction strength, transport slows down, becoming subdiffusive. At large interaction strengths, however, transport speeds up again with increasing field, exhibiting superdiffusive characteristics when the electric field is comparable to the interaction strength. Eventually, at the large field limit, localization occurs and the current through the system is suppressed.

The global incidence of syphilis is increasing. Continuity of care challenges the control of sexually transmitted diseases. In this study, we assessed the follow-up and serological decline differences between community- and hospital-diagnosed patients in Israel. A historical cohort study was conducted using the Israel National Syphilis Center (NSC) repository. Patients with a positive non-specific Venereal Disease Research Laboratory (VDRL) test between 2011 and 2020 were included. Rates of serological follow-up and serological titre decreases were compared between hospital- and community-diagnosed patients. The study included 4,445 patients, 2,596 (58.4%) were diagnosed in community clinics and 1,849 (41.6%) in hospitals. Of community-diagnosed patients, 1,957 (75.4%) performed follow-up testing, compared with 834 (51.2%) hospital-diagnosed patients ( p  < 0.001). On multivariate analysis, the odds ratio of serology follow-up among community-diagnosed patients was 2.8 (95 per cent confidence interval (95% CI): 2.2-3.5) that of hospital-diagnosed patients. There were 1,397 (71.4%) community-diagnosed patients with serological titre decrease, compared with 626 (74.9%) hospital-diagnosed patients ( p  = 0.03). On multivariate analysis, this difference diminished. Serological follow-up testing is suboptimal and was performed more often among patients initially diagnosed in the community compared to hospitals. Continuity of care should be improved to promote successful patient care and prevent disease spread.

Background and Aims: Cannabigerol (CBG) is a nonintoxicating cannabinoid synthesized in the Cannabis sativa plant that is incorporated into dietary supplements. This study investigated the influence of dietary fat and an emulsified delivery vehicle on CBG pharmacokinetics (PKs) after oral ingestion by adults. Materials and Methods: Consented participants were enrolled in a double-crossover pilot study and were blinded to the delivery vehicle type (isolate or emulsification) and isocaloric meal condition (low-fat=<5 g fat/meal or high-fat [HF]=>30 g fat/meal). The concentration of CBG in human plasma was measured after a single 25 mg dose of CBG using liquid chromatography-tandem mass spectrometry (LC-MS/MS). PK parameters were calculated using noncompartmental analysis. Results: The PKs of the two delivery systems (emulsified vs. non-emulsified) were significantly impacted by the HF meal condition. Participants in the HF meal group exhibited significantly higher area under the plasma concentration time curve from time 0 to last quantifiable value, maximum concentration, and terminal half-life. Participants in the HF meal group also had a significantly lower terminal elimination rate constant and time to maximum concentration ( T max ), in addition to decreased T max variation. The threshold for bioequivalence between conditions was not met. An exploratory aim correlated anthropometric measures and previous day's dietary intake on PK parameters which yielded inconsistent results across dietary fat conditions. Conclusions: In aggregate, dietary fat had a greater effect on CBG PKs than the emulsified delivery vehicle. This supports accounting for dietary intake in development of therapeutics and administration guidelines for orally delivered CBG.

Objective: To test the reliability of Medicare claims in measuring vertical integration. We assess the accuracy of a commonly used measure of integration, primary care physician (PCP) practices billing Medicare as a hospital outpatient department (HOPD) in claims., Data Sources and Study Setting: Medicare fee-for-service claims, IQVIA, and CPC+ practice surveys for this study., Study Design: We compare measures of integration from Medicare claims to self-reported indicators of integration from IQVIA and a survey of CPC+ participating practice sites., Data Collection/extraction Methods: We measure integration by using site-of-service billing in the 100% sample of Medicare Carrier claims from 2017-2020. In the IQVIA SK&A (2017-2018), OneKey (2019-2020), and practice survey data (2017-2019), we use self-reported responses to measure integration., Principal Findings: We find that currently most PCP practices sites that report themselves as being integrated with a health system do not bill as an HOPD. In 2017, 11% of CPC+ practices were identified as being vertically integrated in claims, while the equivalent numbers in SK&A and surveys were 52% and 54% integration, respectively. A t-test found that both datasets significantly differed from claims (Survey: 41.3%-45.1%; SK&A: 45.3%-51.1%); this gap persists in 2018-2019., Conclusion: Measuring physician-hospital vertical integration accurately is integral to determining consolidation. The overwhelming majority of PCP practice sites not billing as an HOPD may reflect Medicare regulatory changes that have reduced the financial incentives for doing so. These findings have implications for researchers that study the growth in PCP-hospital integration in health care markets., (© 2024 Health Research and Educational Trust.)

Purpose: This study evaluated age-related maternal outcomes of vacuum-assisted vaginal deliveries (VAD)., Methods: This retrospective cohort study included all nulliparous women with singleton VAD in one academic institution. Study group parturients were maternal age ≥ 35 years and controls < 35. Power analysis revealed that 225 women/group would be sufficient to detect a difference in the rate of third- and fourth-degree perineal tears (primary maternal outcome) and umbilical cord pH < 7.15 (primary neonatal outcome). Secondary outcomes were maternal blood loss, Apgar scores, cup detachment, and subgaleal hematoma. Outcomes were compared between groups., Results: From 2014 to 2019, 13,967 nulliparas delivered at our institution. Overall, 8810 (63.1%) underwent normal vaginal delivery, 2432 (17.4%) instrumental, and 2725 (19.5%) cesarean. Among 11,242 vaginal deliveries, 10,116 (90%) involved women < 35, including 2067 (20.5%) successful VAD vs. 1126 (10%) women ≥ 35 years with 348 (30.9%) successful VAD (p < 0.001). Rates of third- and fourth-degree perineal lacerations were 6 (1.7%) with advanced maternal age and 57 (2.8%) among controls (p = 0.259). Cord pH < 7.15 was similar: 23 (6.6%) study group and 156 (7.5%) controls (p = 0.739)., Conclusion: Advanced maternal age and VAD are not associated with higher risk for adverse outcomes. Older, nulliparous women are more likely to undergo vacuum delivery than younger parturients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: We aimed to identify unique patterns of eye-movements measures reflecting inattentive reading among adults with and without ADHD., Method & Results: We recorded eye-movements during uninterrupted text reading of typically developed (TD) and ADHD adults. First, we found significantly longer reading time for the ADHD group than the TD group. Further, we detected cases in which words were reread more than twice and found that such occasions were much more frequent in participants with ADHD than in TD participants. Moreover, we discovered that the first reading pass of these words was less sensitive to the length of the word than the first pass of words read only once, indicating a less meaningful reading., Conclusion: We propose that high rate of words that were reread is a correlate of inattentive reading which is more pronounced among ADHD readers. Implications of the findings in the context of reading comprehension are discussed., 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.

Nonradiative exciton relaxation processes are critical for energy transduction and transport in optoelectronic materials, but how these processes are connected to the underlying crystal structure and the associated electron, exciton, and phonon band structures, as well as the interactions of all these particles, is challenging to understand. Here, we present a first-principles study of exciton-phonon relaxation pathways in pentacene, a paradigmatic molecular crystal and optoelectronic semiconductor. We compute the momentum- and band-resolved exciton-phonon interactions, and use them to analyze key scattering channels. We find that both exciton intraband scattering and interband scattering to parity-forbidden dark states occur on the same ∼100  fs timescale as a direct consequence of the longitudinal-transverse splitting of the bright exciton band. Consequently, exciton-phonon scattering exists as a dominant nonradiative relaxation channel in pentacene. We further show how the propagation of an exciton wave packet is connected with crystal anisotropy, which gives rise to the longitudinal-transverse exciton splitting and concomitant anisotropic exciton and phonon dispersions. Our results provide a framework for understanding the role of exciton-phonon interactions in exciton nonradiative lifetimes in molecular crystals and beyond.

Phase-change memory (PCM) devices have great potential as multilevel memory cells and artificial synapses for neuromorphic computing hardware. However, their practical use is hampered by resistance drift, a phenomenon commonly attributed to structural relaxation or electronic mechanisms primarily in the context of bulk effects. In this study, we reevaluate the electrical manifestation of resistance drift in sub-100 nm Ge 2 Sb 2 Te 5 (GST) PCM devices, focusing on the contributions of bulk vs interface effects. We employ a combination of measurement techniques to elucidate the current transport mechanism and the electrical manifestation of resistance drift. Our steady-state temperature-dependent measurements reveal that resistance in these devices is predominantly influenced by their electrical contacts, with conduction occurring through thermionic emission (Schottky) at the contacts. Additionally, temporal current-voltage characterization allows us to link the resistance drift to a time-dependent increase in the Schottky barrier height. These findings provide valuable insights, pinpointing the primary contributor to resistance drift in PCM devices: the Schottky barrier height for hole injection at the interface. This underscores the significance of contacts (interface) in the electrical manifestation of drift in PCM devices.

The military environment involves stressful situations that may trigger or aggravate suicidal behaviors, such as suicide attempts (SAs), which significantly increase the likelihood of future suicide. This cross-sectional study aims to assess risk factors for severe SAs and non-suicidal self-injury (NSSI) among Israel Defense Forces (IDF) soldiers. Data were retrieved from an IDF computerized self-harm surveillance database and were based on the criteria of the Columbia Suicide Severity Rating Scale (C-SSRS) and the Suicide Attempt Self-Injury Interview (SASII). The cohort included all 1,238 occurrences of self-harm behavior, during 2017-2021. Other investigated variables included adjustment difficulty (AD, as per IDF definition) and psychiatric diagnosis (PD) as reported by mental health officers (MHOs) during recruitment. Higher rates of adjustment difficulties were found among soldiers who had conducted NSSIs. Higher rates of previous psychiatric diagnoses were found among individuals with SAs, and their risk of dying by suicide during military service was twice as high (OR = 2.356; p < .001). If the latter also served in a combat unit, the risk was almost fourfold (OR = .3.860; p < .001). The current study demonstrates a clear difference between IDF soldiers who conduct NSSI vs. those conducting SA with regard to adjustment difficulty (as per IDF definition) and PD.

Objective: To characterize obstetric outcomes and the association with umbilical cord (UC) complications among women complaining of reduced fetal movements (RFMs)., Methods: This retrospective cohort compared women with a perception of RFMs within 2 weeks prior to delivery with women who reported no changes in fetal movements in terms of maternal characteristics and neonatal outcomes. A primary outcome of UC complications at delivery was defined. Multivariable regression analysis was performed to identify independent associations with RFMs and UC complications., Results: In all, 46 103 women were included, 2591 (5.6%) of whom reported RFMs and 43 512 (94.4%) in the control group. Compared with controls, the RFM group was more likely to be nulliparous (42.6% vs 32.2%, P < 0.001), smokers (6.4% vs 5.4%, P = 0.029), or obese (body mass index >30) (16.4% vs 11.6%, P < 0.001). They were also more likely to have an anterior placenta (56.2% vs 51.8%, P < 0.001) and poly/oligohydramnios (0.7% vs 0.4%, P = 0.015 and 3.6% vs 2.1%, P < 0.001, respectively). Induction of labor was more common in the RFM group (33.9% vs 19.7%, P < 0.001), as well as meconium (16.8% vs 15.0%, P = 0.026) and vacuum extractions (10.1% vs 8.0%, P < 0.001). Higher rates of stillbirth and the severe composite neonatal outcome were observed in the RFM group (1.5% vs 0.2%, P < 0.001 and 0.6% vs 0.3%, P = 0.010, respectively). The RFM group was characterized by higher rates of triple nuchal cord (P = 0.015), UC around body or neck (32.2% vs 29.6%, P = 0.010), and true knot (2.3% vs 1.4%, P = 0.002). Multivariable logistic regression found RFMs to be independently associated with triple nuchal cord and with a true cord knot. A sub-analysis including only cases of stillbirth (n = 127) revealed even higher rates of UC complications: 7% of all stillbirths presented with a true cord knot (20% true knots were found in stillbirths preceded by RFMs vs 6.1% in stillbirth cases without RFMs). Additionally, 33.8% of all stillbirths presented with nuchal cord (40% preceded by RFMs vs 33.3% without RFMs)., Conclusions: RFMs are associated with increased risk of UC complications observed at delivery, as well as increased risk of stillbirth and neonatal adverse outcomes., (© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Health care accounts for 9-10% of greenhouse gas (GHG) emissions in the United States. Strategies for monitoring these emissions at the hospital level are needed to decarbonize the sector. However, data collection to estimate emissions is challenging, especially for smaller hospitals. We explored the potential of gradient boosting machines (GBM) to impute missing data on resource consumption in the 2020 survey of a consortium of 283 hospitals participating in Practice Greenhealth. GBM imputed missing values for selected variables in order to predict electricity use and beef consumption (R 2 =0.82) and anesthetic gas desflurane use (R 2 =0.51), using administrative data readily available for most hospitals. After imputing missing consumption data, estimated GHG emissions associated with these three examples totaled over 3 million metric tons of CO 2 equivalent emissions (MTCO 2 e). Specifically, electricity consumption had the largest total carbon footprint (2.4 MTCO 2 e), followed by beef (0.6 million MTCO 2 e) and desflurane consumption (0.03 million MTCO 2 e) across the 283 hospitals. The approach should be applicable to other sources of hospital GHGs in order to estimate total emissions of individual hospitals and to refine survey questions to help develop better intervention strategies.

Aim: We tested the hypothesis that low testosterone alters the effects of intermittent hypoxia (IH) on glucose homeostasis, hepatic oxidative stress, and transcriptomic profile in male mice., Methods: We used sham-operated or orchiectomized (ORX) mice exposed to normoxia (Nx) or IH for 2 weeks. We performed fasting insulin and glucose tolerance tests and assessed fasting and postprandial insulin resistance with the HOMA-IR. The activity of hepatic prooxidant (NADPH oxidase-NOX), antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase-SOD, Cat, GPx), lipid peroxidation (MDA concentration), and the total concentration of glutathione (GSH) were measured under postprandial conditions. mRNA sequencing and pathway enrichment analyses were used to identify hepatic genes underlying the interactions between IH and testosterone., Results: In Sham mice, IH improves fasting insulin sensitivity and glucose tolerance, while there are no effects of IH in ORX mice. In ORX mice, IH induces postprandial hyperinsulinemia, insulin resistance, and a prooxidant profile of enzyme activity (low SOD activity) without altering hepatic MDA and GSH content. ORX and IH altered the expression of genes involved in oxidoreductase activities, cytochromes-dependent pathways, and glutathione metabolism. Among the genes upregulated in ORX-IH mice, the flavin-containing monooxygenases (FMO) are particularly relevant since these are potent hepatic antioxidants that could help prevent overt oxidative stress in ORX-IH mice., Conclusion: Low levels of testosterone in male mice exposed to IH induce post-prandial hyperinsulinemia and insulin resistance and determine the mechanisms by which the liver handles IH-induced oxidative stress., (© 2024 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Background: Patients with endometriosis are known to have altered pain perceptions. Cesarean delivery (CD) is one of the most prevalent surgeries performed worldwide. Appropriate pain control following CD is clinically important to the recovery and relief of patients. This study assessed pain perception and analgesic use after CD among women with or without endometriosis., Methods: This retrospective case control study included women diagnosed with endometriosis, based on clinical or surgical findings, who underwent CD from 2014 to 2022. Controls were matched to the study group by maternal age, BMI (kg/m 2 ), parity, number of previous CDs and by CD indication, in a 2:1 ratio. Post-operative visual analogue scale (VAS) pain scores, on each post-operative day (POD) were compared between groups. Pain intensity was measured and compared using the VAS, range 0 (no pain) to 10 (worst pain). The standard pain relief analgesia protocol in our department includes fixed oral treatment with paracetamol and diclofenac, with the addition of morphine sulphate on POD 0. Analgesic dosages used and the percentage of patients not using the full standard analgesic protocol were compared between groups., Results: As compared to controls (n = 142), the endometriosis group (n = 71) was characterized by higher rates of in-vitro fertilization (IVF) pregnancies and previous abdominal surgeries other than CD (p < .001 for both). Other maternal characteristics between groups did not differ. On POD 0, mean morphine dosage was significantly higher in the endometriosis group compared to the control group (24 mg vs. 22.8 mg, respectively; p = .044). More patients in the endometriosis group used the full standard analgesia protocol or more, as compared to controls. VAS scores were not significantly different between groups., Conclusions: Increased use of analgesics after CD was more common among women with endometriosis. These findings imply that pain relief protocols should be personalized for women with endometriosis., 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.)

Jojoba ( Simmondsia chinensis L.) wax was previously reported to increase cutaneous wound healing, ameliorate acne and psoriasis manifestations, and reduce oxidative stress and inflammation. However, its potential cosmetic properties have not been fully investigated. Thus, the current study aimed to evaluate the anti-inflammatory activities of jojoba wax and its impact on the synthesis of extracellular components following topical application. The fatty acid and fatty alcohol profiles of two industrial and two lab-scale cold-press jojoba waxes were analyzed along with total tocopherol and phytosterol content. The dermo-cosmetic effect of all jojoba wax preparations was evaluated ex-vivo , using the human skin organ culture model, which emulates key features of intact tissue. The ability of jojoba wax to reduce secreted levels of key pro-inflammatory cytokines and the safety of the applications in the ex-vivo model were evaluated. In addition, the impact on the synthesis of pro-collagen and hyaluronic acid levels upon treatment was investigated. The results demonstrate that topically applied jojoba wax can reduce LPS-induced secretion of IL-6, IL-8, and TNFα by approx. 30% compared to untreated skin. This effect was enhanced when treatment was combined with low non-toxic levels of Triton X-100, and its efficacy was similar to the anti-inflammatory activity of dexamethasone used as a positive control. In addition, mRNA and protein levels of collagen III and synthesis of hyaluronic acid were markedly increased upon topical application of jojoba. Moreover, the enhanced content of extracellular matrix (ECM) components correlated with the enhanced expression of TGFβ1. Collectively, our results further demonstrate that jojoba can reduce local skin inflammation, and this effect may be increased by emulsifier which increases its bioavailability. In addition, the finding that topical application of jojoba wax enhances the synthesis of pro-collagen and hyaluronic acid and may be beneficial in the treatment of age-related manifestations., 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 © 2024 Tietel, Melamed, Ogen-Shtern, Eretz-Kdosha, Silberstein, Ayzenberg, Dag and Cohen.)

Objectives: To understand the role of health information technology (IT) vendors and health IT functionality in supporting advanced primary care., Study Design: We synthesized multiple rounds of surveys and interviews (2017-2022) from a mixed-methods evaluation of Comprehensive Primary Care Plus (CPC+), a multipayer model developed by CMS. CPC+ was the first federal advanced primary care reform effort that formalized health IT vendors' roles in supporting health IT implementation and specified detailed health IT requirements for practices., Methods: We conducted content analysis to identify cross-cutting themes related to health IT for both practices and vendors, comparing similarities and differences across participants and (when possible) over time., Results: Vendors and practices reported advances in registries and dashboards for improved information management within the practice as well as strengthened relationships between vendors and practices that supported health IT implementation. However, CPC+ practices noted several gaps or challenges using existing functionalities, and both vendors and practices reported broader challenges for more transformative health IT change, particularly the lack of interoperable health information exchange needed to support care management and care coordination. Key factors constraining vendors' investment in further advances included long product development schedules, making it difficult to respond to rapidly evolving model requirements. Vendors also shared that CPC+ practices represented a small fraction of their client base, so investing in developing new functionality was not strategic unless it was more broadly relevant outside CPC+., Conclusions: Continued collaboration among health IT vendors, practices, policy makers, and payers could support continued technological improvements, particularly related to information exchange and communication. Aligning requirements more closely with other federal and private models could also help mitigate the risk for vendors.

Parkinson's disease is the fastest-growing neurologic disease with seemingly no means of prevention. Intrinsic risk factors (age, sex, and genetics) are inescapable, but environmental factors are not. We identified repeated blows to the head in sports/combat as a potential new risk factor. 23% of PD cases in females were attributable to pesticide/herbicide exposure, and 30% of PD in males were attributable to pesticides/herbicides, military-related chemical exposures, and repeated blows to the head, and therefore could have potentially been prevented., (© 2023. The Author(s).)

Nonequilibrium quantum transport is of central importance in nanotechnology. Its description requires the understanding of strong electronic correlations that couple atomic-scale phenomena to the nanoscale. So far, research in correlated transport has focused predominantly on few-channel transport, precluding the investigation of cross-scale effects. Recent theoretical advances enable the solution of models that capture the interplay between quantum correlations and confinement beyond a few channels. This problem is the focus of this study. We consider an atomic impurity embedded in a metallic nanosheet spanning two leads, showing that transport is significantly altered by tuning only the phase of a single local hopping parameter. Furthermore─depending on this phase─correlations reshape the electronic flow throughout the sheet, either funneling it through the impurity or scattering it away from a much larger region. This demonstrates the potential for quantum correlations to bridge length scales in the design of nanoelectronic devices and sensors.

Cyclin-dependent kinases 4/6 (CDK4/6) inhibitors such as palbociclib are approved for the treatment of metastatic estrogen receptor-positive (ER+) breast cancer in combination with endocrine therapies and significantly improve outcomes in patients with this disease. However, given the large number of possible pairwise drug combinations and administration schedules, it remains unclear which clinical strategy would lead to best survival. Here, we developed a computational, cell cycle-explicit model to characterize the pharmacodynamic response to palbociclib-fulvestrant combination therapy. This pharmacodynamic model was parameterized, in a Bayesian statistical inference approach, using in vitro data from cells with wild-type estrogen receptor (WT-ER) and cells expressing the activating missense ER mutation, Y537S, which confers resistance to fulvestrant. We then incorporated pharmacokinetic models derived from clinical data into our computational modeling platform. To systematically compare dose administration schedules, we performed in silico clinical trials based on integrating our pharmacodynamic and pharmacokinetic models as well as considering clinical toxicity constraints. We found that continuous dosing of palbociclib is more effective for lowering overall tumor burden than the standard, pulsed-dose palbociclib treatment. Importantly, our mathematical modeling and statistical analysis platform provides a rational method for comparing treatment strategies in search of optimal combination dosing strategies of other cell-cycle inhibitors in ER+ breast cancer., Significance: We created a computational modeling platform to predict the effects of fulvestrant/palbocilib treatment on WT-ER and Y537S-mutant breast cancer cells, and found that continuous treatment schedules are more effective than the standard, pulsed-dose palbociclib treatment schedule., (© 2023 The Authors; Published by the American Association for Cancer Research.)

We report the results of the COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. We discovered a noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2400 compounds) for this campaign were shared rapidly and openly, creating a rich, open, and intellectual property-free knowledge base for future anticoronavirus drug discovery.