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We stabilize a chosen radio frequency beat note between two optical fields derived from the same mode-locked laser pulse train in order to coherently manipulate quantum information. This scheme does not require access or active stabilization of the laser repetition rate. We implement and characterize this external lock, in the context of two-photon stimulated Raman transitions between the hyperfine ground states of trapped 171Yb(+) quantum bits.

Cerebral palsy (CP) affects 2/1000 live-born children. Multiple antenatal factors, including preterm delivery, low birth weight, infection/inflammation, multiple gestation, and other pregnancy complications, are mostly associated with CP in both the preterm and term infant, with birth asphyxia playing a minor role. Owing to the increasing survival of the very preterm and very low birth weight infant secondary to improvements in neonatal and obstetric care, the incidence of CP may be increasing. The focus of this paper is to explore antenatal antecedents as etiologies of CP and the impact of obstetric care on the prevention of CP. [ABSTRACT FROM AUTHOR]

PURPOSE. To explore the experiences of fathers of infants newly diagnosed with severe congenital heart disease. DESIGN. An analysis of qualitative data collected as part of a larger longitudinal study of parenting the medically fragile infant. PARTICIPANTS. Eight fathers whose infants were hospitalized for severe congenital heart disease, were technology dependent at time of enrollment, and were expected to have serious chronic health problems at discharge. DATA COLLECTION MEASURES. Semistructured interviews in the hospital and the home until the child reached 15 months adjusted age. RESULTS. Findings indicate that fathers experience four interrelated conflicting reactions: the joy of seeing the child born and becoming a father, plus the sadness and loss associated with the baby's illness; the challenge of becoming attached while dealing with fears about the infant's vulnerability and potential death; the need to try to maintain control while feeling a loss of control; and the struggle to remain strong for others while hiding their intense emotions. These findings extend the previous limited research about fathers by identifying the unique conflicts fathers of seriously ill infants experience in coping with the child's diagnosis and treatment. Findings have implications for intervening with fathers during the early diagnostic phase of a serious illness, particularly serious congenital heart disease. [ABSTRACT FROM AUTHOR]

Background: Continuous myelination of cerebral white matter (WM) during adolescence overlaps with the formation of higher cognitive skills and the onset of many neuropsychiatric disorders. We developed a miniature-pig model of adolescent brain development for neuroimaging and neurophysiological assessment during this critical period. Minipigs have gyroencephalic brains with a large cerebral WM compartment and a well-defined adolescence period., Methods: Eight Sinclair™ minipigs (Sus scrofa domestica) were evaluated four times during weeks 14-28 (40, 28 and 28 days apart) of adolescence using monocular visual stimulation (1 Hz)-evoked potentials and diffusion MRI (dMRI) of WM. The latency for the pre-positive 30 ms (PP30), positive 30 ms (P30) and negative 50 ms (N50) components of the flash visual evoked potentials (fVEPs) and their interhemispheric latency (IL) were recorded in the frontal, central and occipital areas during ten 60-second stimulations for each eye. The dMRI imaging protocol consisted of fifteen b-shells (b = 0-3500 s/mm 2 ) with 32 directions/shell, providing measurements that included fractional anisotropy (FA), radial kurtosis, kurtosis anisotropy (KA), axonal water fraction (AWF), and the permeability-diffusivity index (PDI)., Results: Significant reductions (p < 0.05) in the latency and IL of fVEP measurements paralleled significant rises in FA, KA, AWF and PDI over the same period. The longitudinal latency changes in fVEPs were primarily associated with whole-brain changes in diffusion parameters, while fVEP IL changes were related to maturation of the corpus callosum., Conclusions: Good agreement between reduction in the latency of fVEPs and maturation of cerebral WM was interpreted as evidence for ongoing myelination and confirmation of the minipig as a viable research platform. Adolescent development in minipigs can be studied using human neuroimaging and neurophysiological protocols and followed up with more invasive assays to investigate key neurodevelopmental hypotheses in psychiatry., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Quantum processors and atomic clocks based on trapped ions often utilize an ion's hyperfine transition as the qubit state or frequency reference, respectively. These states are a good choice because they are insensitive in first order to magnetic field fluctuations, leading to long coherence times and stable frequency splittings. In trapped ions, however, these states are still subject to the second order AC Zeeman effect due to the necessary presence of an oscillating magnetic field used to confine the ions in a Paul trap configuration. Here, we measure the frequency shift of the 2S1/2 hyperfine transition of a 171Yb+ ion caused by the radio frequency (RF) electromagnetic field used to create confinement in several microfabricated surface trap designs. By comparing different trap designs, we show that two key design modifications significantly reduce the AC Zeeman effect experienced by the ion: (1) an RF ground layer routed directly below the entire RF electrode, and (2) a symmetric RF electrode. Both of these changes lead to better cancellation of the AC magnetic field and, thus, overall reduced frequency shifts due to the AC Zeeman effect and reduced variation across the device. These improvements enable a more homogeneous environment for quantum computing and can reduce errors for precision applications such as atomic clocks., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Objective: Obesity increases osteoarthritis (OA) risk due to adipose tissue dysfunction with associated metabolic syndrome and excess weight. Lipodystrophy syndromes exhibit systemic metabolic and inflammatory abnormalities similar to obesity without biomechanical overloading. Here, we used lipodystrophy mouse models to investigate the effects of systemic versus intra-articular adipose tissue dysfunction on the knee., Methods: Intra-articular adipose tissue development was studied using reporter mice. Mice with selective lipodystrophy of intra-articular adipose tissue were generated by conditional knockout (cKO) of Bscl2 in Gdf5-lineage cells, and compared with whole-body Bscl2 knockout (KO) mice with generalised lipodystrophy and associated systemic metabolic dysfunction. OA was induced by surgically destabilising the medial meniscus (DMM) and obesity by high-fat diet (HFD). Gene expression was analysed by quantitative RT-PCR and tissues were analysed histologically., Results: The infrapatellar fat pad (IFP), in contrast to overlying subcutaneous adipose tissue, developed from a template established from the Gdf5-expressing joint interzone during late embryogenesis, and was populated shortly after birth by adipocytes stochastically arising from Pdgfrα-expressing Gdf5-lineage progenitors. While female Bscl2 KO mice with generalised lipodystrophy developed spontaneous knee cartilage damage, Bscl2 cKO mice with intra-articular lipodystrophy did not, despite the presence of synovial hyperplasia and inflammation of the residual IFP. Furthermore, male Bscl2 cKO mice showed no worse cartilage damage after DMM. However, female Bscl2 cKO mice showed increased susceptibility to the cartilage-damaging effects of HFD-induced obesity., Conclusion: Our findings emphasise the prevalent role of systemic metabolic and inflammatory effects in impairing cartilage homeostasis, with a modulatory role for intra-articular adipose tissue., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Hyperemesis gravidarum has a reported incidence of approximately 0.3-3% of pregnancies. Without treatment, refractory hyperemesis gravidarum can result in dehydration, electrolyte deficiencies, and severe nutritional deficiencies, resulting in significant maternal morbidity. The overall goals of inpatient management of refractory hyperemesis gravidarum are the resumption of oral intake to an adequate level to maintain hydration and nutrition, including the ability to tolerate oral pharmacotherapy. Patients initially are stabilized with rehydration and electrolyte repletion. There are numerous pharmacotherapeutics available that can be administered intravenously to control symptoms when oral intake is not an option. However, despite maximizing typical antiemetics, there will be cases refractory to these medications, and alternative pharmacotherapeutics and nutrition-support modalities must be considered. Mirtazapine, olanzapine, corticosteroids, and gabapentin are examples of alternative pharmacotherapeutics, and enteral and parenteral nutrition are alternative therapies that can be used when oral intake is not tolerated for prolonged time periods with ongoing weight loss. In refractory cases of hyperemesis gravidarum, the risks and benefits of these alternative forms of management must be considered, along with the risks of undertreated hyperemesis gravidarum and the overall effect of hyperemesis gravidarum on patients' quality of life., Competing Interests: Financial Disclosure Shannon M. Clark reports receiving payment from the ACOG COVID Champion Network and from UpToDate as an author. The other authors did not report any potential conflicts of interest., (Copyright © 2024 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Despite a great need for healthcare, unhoused individuals encounter significant barriers to utilizing public healthcare systems. Given the inequities in access to healthcare, accompanied by disabilities and health risks associated with homelessness, self-efficacy for self-care is particularly critical. As a primary purpose of this article, we describe a self-care intervention (Health Advocacy Behavioral Activation), which was implemented within a long-standing participatory community action research project for homeless shelters, and report evidence of the intervention's effectiveness in enhancing self-efficacy for self-care. Participants included 62 residents of the St. Vincent de Paul Gateway Shelter for Men (Dayton, Ohio). Shelter residents with disabilities and those without disability benefited approximately equally from the intervention and both showed statistically significant pre- to post-intervention improvements in self-efficacy for self-care. Recommendations for future research examining the effectiveness of the intervention are provided. As a secondary (supplementary) purpose, we report preliminary evidence of psychometric validation for a new instrument (Scale of Self-Efficacy for Self-Care), which was developed in service of our primary purpose (i.e., to examine the effects of intervention on self-efficacy for self-care) because a literature search did not identify an appropriate measure. Because this new instrument fills a void in the literature, we anticipate that it will be useful in practice and research, and so we delineate research recommendations for additional psychometric validation of this measure. Because of the barriers that unhoused people encounter with regard to access to healthcare in the community, self-care interventions provided (and evaluated) on-site (e.g., in homeless shelters) are necessary.

Background: The impact and downstream effects of the chemotherapy supply chain in Ethiopia are not well understood. The purpose of this study was to identify perceived gaps in supply chain and characterize their impact on patient care., Methods: A concurrent mixed-method study was conducted at a large academic cancer center in Ethiopia. In-depth interviews (IDIs) and surveys were completed in collaboration with external stakeholders with knowledge about chemotherapy supply chain in Ethiopia. Thematic coding was used for qualitative analysis of IDI and descriptive statistics were used to summarize quantitative survey data., Results: Six stakeholders participated in the IDIs and seven completed surveys. IDIs revealed that most chemotherapeutic agents are purchased by the Ethiopian Pharmaceutical Supply Agency (EPSA) and are distributed to cancer treatment centers. A free-market purchasing option also exists, but for chemotherapy obtained outside of government-subsidized channels, the potential for substandard or falsified chemotherapy was a concern. Participants expressed confidence that the correct treatment was administered to patients, but viewpoints on reliability and consistency of medication supply were variable. Quantitative data from the survey showed that participants were not confident that medications are prepared safely and correctly. Improper storage and manipulation of high-risk medications remain a significant risk to staff., Conclusions: This study provides insight from a healthcare staff perspective on how gaps in the chemotherapy supply chain process impact patient care in a low-income country. Inventory management, disruptions in supply chain, and product integrity were perceived as the largest gaps in the current chemotherapy supply chain structure., 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.

Calculating observable properties of chemical systems is often classically intractable and widely viewed as a promising application of quantum information processing. Here, we introduce a new framework for solving generic quantum chemical dynamics problems using quantum logic. We experimentally demonstrate a proof-of-principle instance of our method using the QSCOUT ion-trap quantum computer, where we experimentally drive the ion-trap system to emulate the quantum wavepacket dynamics corresponding to the shared-proton within an anharmonic hydrogen bonded system. Following the experimental creation and propagation of the shared-proton wavepacket on the ion-trap, we extract measurement observables such as its time-dependent spatial projection and its characteristic vibrational frequencies to spectroscopic accuracy (3.3 cm -1 wavenumbers, corresponding to >99.9% fidelity). Our approach introduces a new paradigm for studying the chemical dynamics and vibrational spectra of molecules and opens the possibility to describe the behavior of complex molecular processes with unprecedented accuracy.

Optimal chemotherapy management is substandard in low and middle-income countries. We aimed to identify major gaps to design interventional strategies for improved chemotherapy management at Tikur Anbessa Specialized Hospital (TASH), Ethiopia. This study was conducted using an observational checklist, open-ended questions, record review, and key informant interviews of department heads and focal persons at TASH. Findings were categorized into specific themes that developed. Chemotherapy represented 60.2% of the hospital medication budget. Drug utilization was quantified via monthly consumption documentation and forecasting. However, unreliable data resulted in frequent stockouts (unavailability of the item when it is needed) of chemotherapy with only 67.8% availability. Thirteen healthcare personnel (9 nurses, 2 pharmacists and 2 hospital cleaners) were interviewed: all clinical staff but neither of hospital cleaners believed that they were at risk of hazardous agents. Challenges identified included inadequate and frequent stockouts (unavailability of the item when it is needed) of personal protective equipment, lack of standardized guidelines for chemotherapy handling, admixture, and disposal, lack of designated preparation rooms, and lack of training. All nine nurses handled chemotherapy admixtures despite only two nurses previously receiving in-service training. Most of the participants had never witnessed the disposal of anticancer drugs. Prompted by the results of this study, a dialogue was initiated among members of TASH, the American Cancer Society and the University of North Carolina to implement action-oriented projects to address the gaps identified at TASH. These gaps directly and indirectly affect care and treatment outcomes of patients at a large cancer center. Collaborations with well-resourced centers are potential models for improving chemotherapy management.

Objectives: Fibroblasts in synovium include fibroblast-like synoviocytes (FLS) in the lining and Thy1 + connective-tissue fibroblasts in the sublining. We aimed to investigate their developmental origin and relationship with adult progenitors., Methods: To discriminate between Gdf5 -lineage cells deriving from the embryonic joint interzone and other Pdgfrα -expressing fibroblasts and progenitors, adult Gdf5-Cre;Tom;Pdgfrα-H2BGFP mice were used and cartilage injury was induced to activate progenitors. Cells were isolated from knees, fibroblasts and progenitors were sorted by fluorescence-activated cell-sorting based on developmental origin, and analysed by single-cell RNA-sequencing. Flow cytometry and immunohistochemistry were used for validation. Clonal-lineage mapping was performed using Gdf5-Cre;Confetti mice., Results: In steady state, Thy1 + sublining fibroblasts were of mixed ontogeny. In contrast, Thy1-Prg4 + lining fibroblasts predominantly derived from the embryonic joint interzone and included Prg4 -expressing progenitors distinct from molecularly defined FLS. Clonal-lineage tracing revealed compartmentalisation of Gdf5 -lineage fibroblasts between lining and sublining. Following injury, lining hyperplasia resulted from proliferation and differentiation of Prg4 -expressing progenitors, with additional recruitment of non- Gdf5 -lineage cells, into FLS. Consistent with this, a second population of proliferating cells, enriched near blood vessels in the sublining, supplied activated multipotent cells predicted to give rise to Thy1 + fibroblasts, and to feed into the FLS differentiation trajectory. Transcriptional programmes regulating fibroblast differentiation trajectories were uncovered, identifying Sox5 and Foxo1 as key FLS transcription factors in mice and humans., Conclusions: Our findings blueprint a cell atlas of mouse synovial fibroblasts and progenitors in healthy and injured knees, and provide novel insights into the cellular and molecular principles governing the organisation and maintenance of adult synovial joints., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Diabetic ketoacidosis (DKA) is a rare, but potentially life-threatening complication of diabetes. Certain physiological changes during pregnancy predispose pregnant individuals to developing DKA. Early recognition and aggressive treatment are essential to avoid maternal and fetal morbidity and mortality. Although laboratory values can help to support, pregnant patients with DKA may not meet the usual criteria and the diagnosis can be made clinically. The key components to treatment include volume replacement, insulin infusion, correction of serum potassium, and fetal monitoring. With appropriate treatment, maternal mortality is low. After recovery, steps should be taken to avoid recurrence., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction and Hypothesis: We hypothesized that elective induction of labor (eIOL) at 39 weeks is protective of levator ani muscle injury (LAMI) and is associated with decreased pelvic symptoms at 6 weeks postpartum compared to expectant management of labor., Methods: Prospective cohort pilot study of uncomplicated, primiparous women with a singleton, vertex gestation enrolled immediately post-vaginal delivery (VD). Subjects were dichotomized into two groups based on labor management: eIOL without complication defined by the ARRIVE trial versus spontaneous VD between 39 weeks 0/7 and 42 weeks 5/7 or no indication for IOL prior to 40 weeks 5/7 . The primary outcome was LAMI at 6 weeks postpartum as evidenced by any of the following ultrasound measures: (1) increased levator hiatal area (LHA) > 2500 mm 2 , (2) increased elasticity index (EI, > 75th quartile) or (3) levator enthesis avulsion., Results: Analysis represents 45/102 consented women from July 2019-October 2020 (eIOL n = 22 and spontaneous VD, n = 23). Neither maternal, clinical, sociodemographic characteristics nor pelvic symptoms differed between groups. Fewer women had LAMI as defined by the primary outcome with eIOL (n = 5, 23.8%) compared to spontaneous VD (n = 15, 65.2%), p = 0.008. Levator enthesis was more deformable (increased EI) with spontaneous VD as compared to the eIOL [10.66 (8.99) vs. 5.68 (2.93), p = 0.046]. On univariate logistic regression women undergoing spontaneous VD had unadjusted OR of 6.0 (1.6-22.5, p = 0.008) of sustaining LAMI compared to those undergoing eIOL., Conclusions: Composite measures of LAMI though not pelvic floor symptoms were markedly increased in women undergoing spontaneous VD compared to those undergoing eIOL at 39 weeks., (© 2022. The International Urogynecological Association.)

Magnesium doped Amorphous Calcium Carbonate was synthesised from precursor solutions containing varying amounts of calcium, magnesium, H 2 O and D 2 O. The Mg/Ca ratio in the resultant Amorphous Calcium Carbonate was found to vary linearly with the Mg/Ca ratio in the precursor solution. All samples crystallised as aragonite. No Mg was found in the final aragonite crystals. Changes in the Mg to Ca ratio were found to only marginally effect nucleation rates but strongly effect crystal growth rates. These results are consistent with a dissolution-reprecipitation model for aragonite formation via an Amorphous Calcium Carbonate intermediate.

An early inflammatory insult is the most recognized risk factor associated with neurodevelopmental psychiatric disorders, even more so than genetic variants. Notably, complement component 4 (C4), a molecule involved in inflammatory responses, has been strongly associated with schizophrenia (SZ) and its role in other neurodevelopmental disorders, such as autism (ASD), is an area of active investigation. However, while C4 in SZ has been implicated in the context of synaptic pruning, little is known about its neuroinflammatory role. The subventricular zone (SVZ) is a region heavily involved in neurodevelopment and neuroimmune interactions through the lifespan; thus, it is a region wherein C4 may play a vital role in disease pathology. Using in situ hybridization with radioactive riboprobes and RNAscope, we identified robust astrocytic expression of C4 in the SVZ and in the septum pellucidum. C4 was also expressed in ependyma, neurons, and Ki67 + progenitor cells. Examination of mRNA levels showed elevated C4 in both ASD and SZ, with higher expression in SZ compared to controls. Targeted transcriptomic analysis of inflammatory pathways revealed a strong association of complement system genes with SZ, and to a lesser extent, ASD, as well as generalized immune dysregulation without a strong association with known infectious pathways. Analysis of differentially expressed genes (DEGs) showed that ASD DEGs were enriched in adaptive immune system functions such as Th cell differentiation, while SZ DEGs were enriched in innate immune system functions, including NF-κB and toll like receptor signaling. Moreover, the number of Ki67 + cells was significantly higher in ASD compared to SZ and controls. Taken together, these results support a role for C4 into inflammatory-neuroimmune dysregulation observed in SZ and ASD pathology., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Modulation of the endocannabinoid system (ECS) is a novel putative target for therapeutic intervention in depressive disorders. Altering concentrations of one of the principal endocannabinoids, N-arachidonoylethanolamine, also known as anandamide (AEA) can affect depressive-like behaviors through several mechanisms including anti-inflammatory, hormonal, and neural circuit alterations. Recently, isoflavonoids, a class of plant-derived compounds, have been of therapeutic interest given their ability to modulate the metabolism of the endogenous ligands of the ECS. To determine the therapeutic potential of isoflavonoids, we screened several candidate compounds (Genistein, Biochanin-A, and 7-hydroxyflavone) in silico to determine their binding properties with fatty acid amide hydrolase (FAAH), the primary degrative enzyme for AEA. We further validated the ability of these compounds to inhibit FAAH and determined their effects on depressive-like and locomotor behaviors in the forced swim test (FST) and open field test in male and female mice. We found that while genistein was the most potent FAAH inhibitor, 7-hydroxyflavone was most effective at reducing immobility time in the forced swim test. Finally, we measured blood corticosterone and prefrontal cortex AEA concentrations following the forced swim test and found that all tested compounds decreased corticosterone and increased AEA, demonstrating that isoflavonoids are promising therapeutic targets as FAAH inhibitors., (© 2022 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

We show that the sex of human experimenters affects mouse behaviors and responses following administration of the rapid-acting antidepressant ketamine and its bioactive metabolite (2R,6R)-hydroxynorketamine. Mice showed aversion to the scent of male experimenters, preference for the scent of female experimenters and increased stress susceptibility when handled by male experimenters. This human-male-scent-induced aversion and stress susceptibility was mediated by the activation of corticotropin-releasing factor (CRF) neurons in the entorhinal cortex that project to hippocampal area CA1. Exposure to the scent of male experimenters before ketamine administration activated CA1-projecting entorhinal cortex CRF neurons, and activation of this CRF pathway modulated in vivo and in vitro antidepressant-like effects of ketamine. A better understanding of the specific and quantitative contributions of the sex of human experimenters to study outcomes in rodents may improve replicability between studies and, as we have shown, reveal biological and pharmacological mechanisms., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The alkali-silica reaction can shorten concrete life due to expansive pressure build-up caused by reaction by-products, resulting in cracking. Understanding the role of the aggregate, as the main reactive component, is essential for understanding the underlying mechanisms of the alkali-silica reaction and thereby reducing, or even preventing, any potential damage. The present study aims to investigate the role of petrographic studies along with accelerated tests in predicting and determining the potential reactivity of aggregates, including granite, rhyodacite, limestone, and dolomite, with different geological characteristics in concrete. This study was performed under accelerated conditions in accordance with the ASTM C1260 and ASTM C1293 test methods. The extent of the alkali-silica reaction was assessed using a range of microanalysis techniques including optical microscopy, scanning electron microscopy, energy-dispersive X-ray analysis, and X-ray powder diffraction. The results showed that a calcium-rich aggregate with only a small quantity of siliceous component but with a higher porosity and water adsorption rate can lead to degradation due to the alkali-silica reaction, while dolomite aggregate, which is commonly considered a reactive aggregate, showed no considerable expansion during the conducted tests. The results also showed that rhyodacite samples, due to their glassy texture, the existence of strained quartz and quartz with undulatory extinction, as well as the presence of weathering minerals, have a higher alkali-reactivity potential than granite samples.

Understanding the underlying processes of biomineralization is crucial to a range of disciplines allowing us to quantify the effects of climate change on marine organisms, decipher the details of paleoclimate records and advance the development of biomimetic materials. Many biological minerals form via intermediate amorphous phases, which are hard to characterize due to their transient nature and a lack of long-range order. Here, using Monte Carlo simulations constrained by X-ray and neutron scattering data together with model building, we demonstrate a method for determining the structure of these intermediates with a study of amorphous calcium carbonate (ACC) which is a precursor in the bio-formation of crystalline calcium carbonates. We find that ACC consists of highly ordered anhydrous nano-domains of approx. 2 nm that can be described as nanocrystalline. These nano-domains are held together by an interstitial net-like matrix of water molecules which generate, on the mesoscale, a heterogeneous and gel-like structure of ACC. We probed the structural stability and dynamics of our model on the nanosecond timescale by molecular dynamics simulations. These simulations revealed a gel-like and glassy nature of ACC due to the water molecules and carbonate ions in the interstitial matrix featuring pronounced orientational and translational flexibility. This allows for viscous mobility with diffusion constants four to five orders of magnitude lower than those observed in solutions. Small and ultra-small angle neutron scattering indicates a hierarchically-ordered organization of ACC across length scales that allow us, based on our nano-domain model, to build a comprehensive picture of ACC formation by cluster assembly from solution. This contribution provides a new atomic-scale understanding of ACC and provides a framework for the general exploration of biomineralization and biomimetic processes., (© 2022. The Author(s).)

Objective: We aimed to understand the role of the transcriptional co-factor Yes-associated protein (Yap) in the molecular pathway underpinning the pathogenic transformation of synovial fibroblasts (SF) in rheumatoid arthritis (RA) to become invasive and cause joint destruction., Methods: Synovium from patients with RA and mice with antigen-induced arthritis (AIA) was analysed by immunostaining and qRT-PCR. SF were targeted using Pdgfrα-CreER and Gdf5-Cre mice, crossed with fluorescent reporters for cell tracing and Yap-flox mice for conditional Yap ablation. Fibroblast phenotypes were analysed by flow cytometry, and arthritis severity was assessed by histology. Yap activation was detected using Yap-Tead reporter cells and Yap-Snail interaction by proximity ligation assay. SF invasiveness was analysed using matrigel-coated transwells., Results: Yap, its binding partner Snail and downstream target connective tissue growth factor were upregulated in hyperplastic human RA and in mouse AIA synovium, with Yap detected in SF but not macrophages. Lineage tracing showed polyclonal expansion of Pdgfrα -expressing SF during AIA, with predominant expansion of the Gdf5 -lineage SF subpopulation descending from the embryonic joint interzone. Gdf5 -lineage SF showed increased expression of Yap and adopted an erosive phenotype (podoplanin+Thy-1 cell surface antigen-), invading cartilage and bone. Conditional ablation of Yap in Gdf5 -lineage cells or Pdgfrα -expressing fibroblasts ameliorated AIA. Interleukin (IL)-6, but not tumour necrosis factor alpha (TNF-α) or IL-1β, Jak-dependently activated Yap and induced Yap-Snail interaction. SF invasiveness induced by IL-6 stimulation or Snail overexpression was prevented by Yap knockdown, showing a critical role for Yap in SF transformation in RA., Conclusions: Our findings uncover the IL-6-Yap-Snail signalling axis in pathogenic SF in inflammatory arthritis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Importance: Pregnant patients over age 40 often have unique risk factors and potential complications before and during pregnancy that play a role in their counseling and management., Objective: To provide practitioners an overview on how to approach preconception evaluation and counseling, prenatal care, and management of associated comorbidities, as well as potential complications, in pregnant patients over age 40., Evidence Acquisition: Literature review was performed using OVID and PubMed, with further relevant information queried from guidelines of professional organizations., Results: Pregnant patients over age 40 should receive preconception evaluations by their obstetrician-gynecologist and other appropriate specialty care providers as they pertain to preexisting medical comorbidities. In the preconception period, attention should be given to managing and optimizing preexisting medical conditions and associated pharmacotherapeutics. Referral to specialists in assisted reproductive technologies or maternal-fetal medicine should be considered if indicated for appropriate evaluation and counseling. During pregnancy, accurate dating and counseling on aneuploidy screening, with consideration for early diabetes screening, should be performed in the first trimester. A detailed anatomy scan and fetal echocardiogram should be completed by 22 weeks' gestation, along with routine and high-risk (if indicated) prenatal care. Close attention should be given to the development of pregnancy-related complications associated with advancing age. Third-trimester fetal surveillance can be considered. Given that no contraindications exist, these patients should be encouraged to pursue a vaginal delivery with consideration for induction at 39 to 40 weeks' gestation., Conclusions and Relevance: Pregnancy rates are increasing in persons over age 40. As a result, preconception evaluation and counseling tailored to that demographic are essential. In addition to standard prenatal care, they should have early screening and diligent monitoring for pregnancy-related comorbidities associated with advancing age., Relevance Statement: With the increased pregnancy-associated comorbidities in patients over age 40, providers should be familiar with how to evaluate, counsel, and manage them during the preconception and pregnancy periods.

Leaf beetles (Coleoptera: Chrysomelidae) constitute a family of abundant, diverse, and ecologically important herbivorous insects, due to their high specificity with host plants, a close association with vegetation and a great sensitivity to microclimatic variation (factors that are modified gradually during the rainy and dry seasons). Therefore, the effects of seasonality (rainy and dry seasons) and microclimate on the community attributes of chrysomelids were evaluated in a semideciduous tropical forest fragment of northeastern Mexico. Monthly sampling was conducted, between March 2016 and February 2017, with an entomological sweep net in 18 plots of 20 × 20 m, randomly distributed from 320 to 480 m a.s.l. Seven microclimatic variables were simultaneously recorded during each of the samplings, using a portable weather station. In total, 216 samples were collected at the end of the study, of which 2,103 specimens, six subfamilies, 46 genera, and 71 species were obtained. The subfamily Galerucinae had the highest number of specimens and species in the study area, followed by Cassidinae. Seasonality caused significant changes in the abundance and number of leaf beetle species: highest richness was recorded in the rainy season, with 60 species, while the highest diversity (lowest dominance and highest H' index) was obtained in the dry season. Seasonal inventory completeness of leaf beetles approached (rainy season) or was higher (dry season) than 70%, while the faunistic similarity between seasons was 0.63%. The outlying mean index was significant in both seasons; of the seven microclimatic variables analyzed, only temperature, heat index, evapotranspiration and wind speed were significantly related to changes in abundance of Chrysomelidae. Association between microclimate and leaf beetles was higher in the dry season, with a difference in the value of importance of the abiotic variables. The results indicated that each species exhibited a different response pattern to the microclimate, depending on the season, which suggests that the species may exhibit modifications in their niche requirements according to abiotic conditions. However, the investigations must be replicated in other regions, in order to obtain a better characterization of the seasonal and microclimatic influence on the family Chrysomelidae., (José Norberto Lucio-García, Uriel Jeshua Sánchez-Reyes, Jorge Víctor Horta-Vega, Jesús Lumar Reyes-Muñoz, Shawn M. Clark, Santiago Niño-Maldonado.)

Aims: Indomethacin is used for the treatment of preterm labour, short cervices and idiopathic polyhydramnios during pregnancy. Few studies have described the pharmacokinetics (PK) of indomethacin during pregnancy. This study aimed to determine maternal and fetal PK of indomethacin during different trimesters of pregnancy using physiologically based PK (PBPK) modelling and simulations., Methods: Full PBPK simulations were performed in nonpregnant subjects and pregnant subjects from each trimester of pregnancy at steady state using Simcyp's healthy volunteers and pregnancy PBPK model, respectively. The fetal exposures were predicted using a fetoplacental pregnancy PBPK model. The models were verified by comparing PBPK-based predictions with observed PK profiles., Results: Predicted exposure (AUC 0-6h ) and clearance of indomethacin in nonpregnant women and pregnant women are similar to the clinical observations. AUC 0-6h of indomethacin is approximately 14, 24 and 32% lower, consistent with 18, 34 and 52% higher clearance in the first, second and third trimesters of pregnancy, respectively, compared to nonpregnant women. Predicted fetal plasma exposures increased by approximately 30% from the second trimester to the third trimester of pregnancy., Conclusion: A mechanistic PBPK model adequately described the maternal and the fetal PK of indomethacin during pregnancy. As the pregnancy progresses, a modest decrease (≤32%) in systemic exposures in pregnant women and a 33% increase in fetal exposures to indomethacin were predicted. Higher fetal exposures in the third trimester of pregnancy may pose safety risks to the fetus. Additional studies are warranted to understand the exposure-response relationship and provide appropriate dosing recommendations during pregnancy that consider both safety and efficacy., (© 2021 British Pharmacological Society.)

In Ethiopia, cancer accounts for about 5.8% of total national mortality, with an estimated annual incidence of cancer of approximately 60,960 cases and an annual mortality of over 44,000 persons. This is likely an underestimation. Survival rates for pediatric malignancies are likewise suboptimal although exact figures are unknown since a national cancer registry is unavailable. The World Health Organization (WHO) provides recommendations for the creation of cancer registries to track such data. Here we describe our pharmacist-led, pre-implementation assessment of introducing an enhanced national pediatric cancer registry in Ethiopia. Our assessment project had three specific aims around which the methods were designed: 1) characterization of the current spreadsheet-based tool across participating sites, including which variables were being collected, how these variables compared to standards set by the WHO, and a description of how the data were entered and its completeness; 2) assessment of the perceptions of an enhanced registry from hospital staff; and 3) evaluation of workflow gaps regarding documentation. The hospital staff and leadership have generally positive perceptions of an enhanced pediatric cancer registry, which were further improved by our interactions. The workflow assessment revealed several gaps, which were addressed systematically using a three-phase implementation science approach. The assessment also demonstrated that the existing spreadsheet-based tool was missing WHO-recommended variables and had inconsistent completion due to the workflow gaps. A pediatric oncology summary sheet will be implemented in upcoming trips in patient charts to better summarize the patients' journey starting from diagnosis. This document will be used by the data clerks in an enhanced-spreadsheet to have a more complete data set.

Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest.

Liposomal daunorubicin/cytarabine (CPX-351) gained FDA approval for secondary AML after demonstrating improved outcomes over daunorubicin and cytarabine (7 + 3). A number of study limitations prompted a comparison of safety/efficacy of CPX-351 against regimens containing a purine analogue and high-dose cytarabine (HIDAC). This retrospective study compared complete response rates with/without count recovery (CR/CRi) between HIDAC-based regimens and CPX-351 in 169 patients with newly diagnosed sAML. The CR/CRi rate was 62.7% in the HIDAC-based therapy arm vs. 47.9% in the CPX-351 arm ( p  = 0.002 [one-sided for non-inferiority]). Median time to absolute neutrophil and platelet count recovery was shorter after HIDAC-based therapy (18 and 23 days, respectively) compared to CPX-351 (36 and 38 days; p  < 0.001). Median overall survival was 9.8 months in the HIDAC-based group and 9.14 months in the CPX-351 group. 30-day mortality was greater with CPX-351 (8.5%) compared to HIDAC-based (1.3%; p  = 0.039). These results reveal comparable efficacy and favorable safety with HIDAC-based regimens.

Objectives: To examine the long-term adherence to serial imaging of patients with sporadic vestibular schwannoma and analyze factors associated with being lost to follow-up., Study Design: Retrospective chart review with telephone interview., Setting: Single tertiary care center., Methods: Patients with a sporadic vestibular schwannoma and started on observational surveillance management between January 2005 and December 2010 were included. Demographic data, tumor size, hearing and vestibular changes, and follow-up length were recorded. Patient factors were analyzed for association with being lost to follow-up., Results: In total, 122 patients were included with a median length of follow-up of 5 months (range, 0-146). After initial surveillance, 22.1% (n = 27) of patients had a change in management to either microsurgery or radiosurgery. Of the remaining 77.9% (n = 95), nearly half (44.2%, n = 42) never returned for a second visit, and all but 3 were eventually lost to follow-up. There was no association between sex, race, age at diagnosis, initial tumor size, insurance status, household income, or driving distance to hospital and being lost to follow-up. Of 26 interviewed patients initially lost to follow-up, 11 (42.3%) sought care at another institution, 5 (19.2%) chose to no longer receive care, 1 (3.8%) had transportation difficulties, and 9 (36.4%) had poor understanding of their diagnosis or instructions., Conclusions: The length of follow-up for patients undergoing surveillance of sporadic vestibular schwannoma varies widely, and patients are commonly lost to follow-up. Further efforts should be made to identify at-risk patients and provide adequate education to improve long-term surveillance., (© The Authors 2021.)

Human umbilical cord (hUC)- or bone marrow (hBM)-derived mesenchymal stromal cells (MSCs) were evaluated as an allogeneic source of cells for cartilage repair. We aimed to determine if they could enhance healing of chondral defects with or without the recruitment of endogenous cells. hMSCs were applied into a focal joint surface injury in knees of adult mice expressing tdTomato fluorescent protein in cells descending from Gdf5-expressing embryonic joint interzone cells. Three experimental groups were used: (i) hUC-MSCs, (ii) hBM-MSCs and (iii) PBS (vehicle) without cells. Cartilage repair was assessed after 8 weeks and tdTomato-expressing cells were detected by immunostaining. Plasma levels of pro-inflammatory mediators and other markers were measured by electrochemiluminescence. Both hUC-MSC ( n = 14, p = 0.009) and hBM-MSC ( n = 13, p = 0.006) treatment groups had significantly improved cartilage repair compared to controls ( n = 18). While hMSCs were not detectable in the repair tissue at 8 weeks post-implantation, increased endogenous Gdf5-lineage cells were detected in repair tissue of hUC-MSC-treated mice. This xenogeneic study indicates that hMSCs enhance intrinsic cartilage repair mechanisms in mice. Hence, hMSCs, particularly the more proliferative hUC-MSCs, could represent an attractive allogeneic cell population for treating patients with chondral defects and perhaps prevent the onset and progression of osteoarthritis.

Objective: Childhood maltreatment (CM) is a public health crisis that results in negative physical, mental health, and psychosocial (e.g., resource attainment) outcomes. Resource attainment is a critical outcome for marginalized populations, such as low-income African American women. This study addresses the gap in the literature regarding the association between CM and effectiveness of resource attainment and the potential mediating role of self-esteem in this association for African American women., Method: Data were gathered from a large public inner-city, university-affiliated health care system in the Southeastern United States. Participants selected were low-income African American women who have experienced intimate partner violence (IPV) and have attempted suicide in the prior year. The participants for this study completed the Childhood Trauma Questionnaire, the Beck Self-Esteem Scale, and the Effectiveness in Obtaining Resources Scale., Results: Mediation analyses using bootstrapping with 213 women revealed the powerful role self-esteem plays in explaining the link between CM and resource attainment in low-income African American women. Specifically, overall CM and four of its subtypes (emotional abuse, physical abuse, emotional neglect, and physical neglect) were all associated with decreased resource attainment via the effect of decreased self-esteem. Sexual abuse was the only subtype of CM not significantly associated with self-esteem nor effectiveness of resource attainment., Conclusion: This research highlights the importance of screening for CM, its subtypes, and resource attainment in this population and bolstering self-esteem through psychological interventions to increase women's capacity to effectively secure necessary community resources. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Objective: This study aimed to describe baseline characteristics of a cohort of pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and determine if these correlate with disease severity and perinatal outcomes., Study Design: This was a retrospective cohort trial conducted at the University of Texas Medical Branch Galveston, Texas. All pregnant women presented to our medical center, who were screened and tested positive for SARS-CoV-2 virus, were included. We stratified our study population in three groups: asymptomatic, symptomatic not requiring oxygen therapy, and patients requiring oxygen support to maintain oxygen saturation >94%. Relevant population characteristics, laboratory data, and maternal and neonatal outcomes were abstracted. A p -value <0.05 was considered statistically significant., Results: Between March and July 2020, 91 women tested positive for SARS-CoV-2 upon admission to our labor and delivery unit. Among these, 61.5% were asymptomatic, 34.1% were symptomatic, and 4.4% required oxygen support. Our population was mainly Hispanic (80.2%), multiparous (76.9%), obese (70.3%), and with a median age of 27 years. Median gestational age at symptom onset or diagnosis was 36 weeks. Significant differences were found between gestational age and disease severity. Maternal characteristics including age, body mass index (BMI), and presence of comorbid conditions did not appear to influence severity of SARS-CoV-2 infection. Significant laboratory findings associated with increasing disease severity included decreasing hemoglobin and white blood cell count, lymphopenia, and increasing levels of inflammatory markers including CRP, ferritin, and procalcitonin. Maternal and neonatal outcomes did not differ among groups. No SARS-CoV-2 was detected by polymerase chain reaction testing in neonates of mothers with COVID-19., Conclusion: Pregnant patients with COVID-19 infection are predominantly asymptomatic. Patients appear to be at increased risk for more severe infection requiring oxygen support later in pregnancy., Key Points: · The majority of pregnant patients with COVID-19 are asymptomatic and <1 in 20 require oxygen support.. · Women in the later stages of pregnancy may be at increased risk for severe infection.. · Anemia, leukopenia, CRP, ferritin, and procalcitonin are associated with increasing severity.., Competing Interests: None declared., (Thieme. All rights reserved.)

Hydroxynorketamines (HNKs) are formed in vivo after ( R , S )-ketamine (ketamine) administration. The 12 HNK stereoisomers are distinguished by the position of cyclohexyl ring hydroxylation (at the 4, 5, or 6 position) and their unique stereochemistry at two stereocenters. Although HNKs were initially classified as inactive metabolites because of their lack of anesthetic effects, more recent studies have begun to reveal their biologic activities. In particular, ( 2R , 6R )- and ( 2S 6 )-HNK exert antidepressant-relevant behavioral and physiologic effects in preclinical models, which led to a rapid increase in studies seeking to clarify the mechanisms by which HNKs exert their pharmacological effects. To date, the majority of HNK research has focused on the actions of ( 2R , 6R )-HNK because of its robust behavioral actions in tests of antidepressant effectiveness and its limited adverse effects. This review describes HNK pharmacokinetics and pharmacodynamics, as well as the putative cellular, molecular, and synaptic mechanisms thought to underlie their behavioral effects, both following their metabolism from ketamine and after direct administration in preclinical studies. Converging preclinical evidence indicates that HNKs modulate glutamatergic neurotransmission and downstream signaling pathways in several brain regions, including the hippocampus and prefrontal cortex. Effects on other neurotransmitter systems, as well as possible effects on neurotrophic and inflammatory processes, and energy metabolism, are also discussed. Additionally, the behavioral effects of HNKs and possible therapeutic applications are described, including the treatment of unipolar and bipolar depression, post-traumatic stress disorder, chronic pain, neuroinflammation, and other anti-inflammatory and analgesic uses. SIGNIFICANCE STATEMENT: Preclinical studies indicate that hydroxynorketamines (HNKs) exert antidepressant-relevant behavioral actions and may also have analgesic, anti-inflammatory, and other physiological effects that are relevant for the treatment of a variety of human diseases. This review details the pharmacokinetics and pharmacodynamics of the HNKs, as well as their behavioral actions, putative mechanisms of action, and potential therapeutic applications., Competing Interests: The following authors declare competing financial interests: R.M. and C.A.Z. are listed as co-inventors on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro- and hydroxylated metabolites of (R,S)-ketamine in the treatment of depression and neuropathic pain. P.Z., R.M., P.M., C.T., C.A.Z., and T.G. are listed as co-inventors on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. R.M., P.M., C.A.Z., and C.T. have assigned their patent rights to the United States government but will share a percentage of any royalties that may be received by the government. P.Z. and T.G. have assigned their patent rights to the University of Maryland Baltimore but will share a percentage of any royalties that may be received by the University of Maryland Baltimore. T.D.G. has received research funding from Allergan and Roche Pharmaceuticals and has served as a consultant for FSV7, LLC, during the preceding 3 years. All other authors declare no competing interests., (U.S. Government work not protected by U.S. copyright.)