Search

Remuneration issues are a substantial threat to the long-term stability of the pediatric nephrology workforce. It is uncertain whether the pediatric nephrology workforce will meet the growing needs of children with kidney disease without a substantial overhaul of the current reimbursement policies. In contrast to adult nephrology, the majority of pediatric nephrologists practice in an academic setting affiliated with a university and/or children's hospital. The pediatric nephrology service line is crucial to maintaining the financial health and wellness of a comprehensive children's hospital. However, in the current fee-for-service system, the clinical care for children with kidney disease is neither sufficiently valued, nor appropriately compensated. Current compensation models derived from the relative value unit (RVU) system contribute to the structural biases inherent in the current inequitable payment system. The perceived negative financial compensation is a significant driver of waning trainee interest in the field which is one of the least attractive specialties for students, with a significant proportion of training spots going unfilled each year and relatively stagnant growth rate as compared to the other pediatric subspecialties. This article reviews the current state of financial compensation issues plaguing the pediatric nephrology subspecialty. We further outline strategies for pediatric nephrologists, hospital administrators, and policy-makers to improve the landscape of financial reimbursement to pediatric subspecialists. A physician compensation model is proposed which aligns clinical activity with alternate metrics for current non-RVU producing activities that harmonizes hospital and personal mission statements.

Abstract Cannabinoid receptor activation has been proposed to trigger glutamate release from astrocytes located in cortical layer 2/3. Here, we measure the basal concentration of extracellular glutamate in layer 2/3 of mouse somatosensory cortex and find it to be 20–30 nM. We further examine the effect of cannabinoid receptor signaling on extracellular glutamate, and find no evidence for increased extracellular glutamate upon cannabinoid receptor agonist application.

Background: Symptoms in patients with systemic mastocytosis (SM) are associated with an increase in mast cell burden and release of mast cell–derived mediators. The most frequent presentation of SM is indolent SM (ISM), with moderate symptoms and prognosis. Basophil numbers in these patients are generally normal. However, when examining basophil activation in patients with ISM, we noted an abnormal response to N-formylmethione-leucyl-phenylalanine (fMLP). Objective: Our aim was to compare basophil responsiveness to fMLP and anti-IgE in healthy volunteers and patients with ISM and relate the findings to fMLP receptor (FPR) expression. Methods: Basophils isolated from peripheral blood of 15 patients with ISM and 14 healthy volunteers were stimulated with fMLP or anti-IgE. CD63 expression to assess basophil activation and expression of FPRs were assessed by flow cytometry. Results: Baseline expression of CD63 on basophils was similar between the healthy volunteers and patients with ISM. fMLP induced higher expression of CD63 on basophils from patients with ISM, whereas responses to anti-IgE were similar between groups. Basophils from patients with ISM also had higher fMLP1 receptor (FPR1) expression, wheresas FPR2 and FPR3 were not detected. fMLP blocked the binding of anti-FPR1 antibody to FPR1, consistent with the conclusion that fMLP signals through FPR1. Conclusions: Level of fMLP-induced basophil activation is higher in patients with ISM, which is associated with an increase in FPR1 expression. Further investigation is needed to determine why FPR1 expression is elevated, whether such expression might serve as an additional surrogate marker in the diagnosis of ISM, and whether enhanced responses of basophils to fMPL might have some relationship to unexplained episodes of mediator release.

Abstract The study aimed to determine the accuracy of diagnosing periodontal conditions using the developed web-based PocketPerio application and evaluate the user’s perspective on the use of PocketPerio. First, 22 third-year dental students (DS3) diagnosed ten cases without PocketPerio (control) and with PocketPerio (test) during a mock examination. Then, 105 DS3, 13 fourth-year dental students (DS4), and 32 senior second-year International Standing Program students (ISP2) used PocketPerio chairside. Statistical analysis was performed using a non-parametric paired two-tailed test of significance with the Wilcoxon matched-pairs signed rank test. The null hypothesis that PocketPerio did not increase the accuracy of periodontal diagnoses was rejected at α

Abstract The present study examined the role of age and sex in the outcomes of non-surgical periodontal therapy (NSPT). De-identified demographic and periodontal characteristics of patients who presented for baseline periodontal evaluation, NSPT, and periodontal re-evaluation were abstracted from electronic health records. Independent associations of age and sex with severe periodontitis defined as ≥ 5 mm clinical attachment loss (CAL) and ≥ 6 mm probing depth (PD) were determined using multinomial logistic regression. The null hypothesis was rejected at α

Porphyry-type Cu ± Au ± Mo deposits form in the upper (ca. 2–5 km deep) parts of large, long-lived magmatic-hydrothermal systems in which mineralising fluids are thought to be derived from mid-to shallow-crustal magma chambers. Increasingly, however, magmatic systems are viewed as consisting of mush with minor and transient lenses of magma, with mush being a variably packed framework of crystals with interstitial melt and magmatic volatile phase (MVP). In this context, questions remain as to the source (mainly depth) and mechanisms of transport and focussing of the vast volumes of fluids required for shallow level porphyry-type mineralisation. Even more problematic is a paucity of first-order textural evidence for the presence of mush in magmatic-hydrothermal systems, including those which host porphyry-type deposits. To address this, we have studied the aplitic porphyry cupola of the Saginaw Hill magmatic system, Tuscon, Arizona, United States, where magmatic-hydrothermal features are exceptionally well exposed, including a massive silica cap, quartz unidirectional solidification textures (USTs), stockworks of multiple generations of variably mineralised quartz veins and mineralised miarolitic cavities. From field-to micro-scale textural and geochemical studies, particularly observations of vermiform quartz between earlier generations of magmatic quartz and feldspar, we evidence the development of fluid pathways through mush at the magmatic-hydrothermal transition. These are shown to connect and provide fluids and ore constituents to the mineralised miarolitic cavities and early quartz vein stockworks. We suggest that this process should be considered in all new genetic, exploration and numerical models for porphyry and similar types of magmatic-hydrothermal ore-deposits.

ABSTRACTThe COVID-19 pandemic has completely disrupted and possibly permanently changed the way humans travel. In Puerto Rico, major travel restrictions to the island have persisted at different levels since March 2020, which heavily influenced residents’ travel behaviors. However, it remains unclear about how big the impact is and how inequitable it might be. The goal of this study is to evaluate COVID-19’s impacts on Puerto Rican’s travel behaviors by analyzing travel flows from Puerto Rico to the contiguous US with a modified gravity model. The roles of socioeconomic factors regarding the Puerto Rican travelers and COVID-19 factors regarding the destination US states have been assessed. COVID-19 was a strong deterring factor of travel at the beginning of the pandemic and also in the winter of 2020, but it did not keep Puerto Ricans from traveling during the summer 2020 when most travel restrictions were lifted. We found that the elderly population of Puerto Rico, despite being more vulnerable to COVID-19, were much more likely to travel during the pandemic. We also found that, during the holiday season in 2020, some socioeconomically disadvantaged populations were more likely to be traveling, a direct contradiction to their travel flows the year prior. These findings shed light on about how disproportionately affected populations behavior changed from pre-pandemic to after the pandemic started. With the continuance of the pandemic, this information is extremely valuable for future planning with respect to emergency management, travel regulation, and social benefit.

Abstract Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.

IntroductionCalcitonin gene-related peptide (CGRP) plays an important role in cerebral vasodilation, so here we aim to quantify the impact of CGRP monoclonal antibody (mAb) therapy on cerebral hemodynamics.MethodsIn 23 patients with chronic and episodic migraine, cerebral hemodynamic monitoring was performed (1) prior to and (2) 3-months into CGRP-mAb therapy. Transcranial Doppler monitored cerebral blood flow velocity (CBFv) in the middle cerebral artery (MCA) and posterior cerebral artery (PCA), from which cerebrovascular reactivity (CVR) and cerebral autoregulation (CA; Mx-index) were calculated.ResultsCA was similar off and on treatment, in the MCA (p = 0.42) and PCA (p = 0.72). CVR was also unaffected by treatment, in the MCA (p = 0.38) and PCA (p = 0.92). CBFv and blood pressure were also unaffected. The subgroup of clinical responders (>50% reduction in migraine frequency) exhibited a small reduction in MCA-CBFv (6.0 cm/s; IQR: 1.1–12.4; p = 0.007) and PCA-CBFv (8.9 cm/s; IQR: 6.9–10.3; p = 0.04).DiscussionDynamic measures of cerebrovascular physiology were preserved after 3 months of CGRP-mAb therapy, but a small reduction in CBFv was observed in patients who responded to treatment. Subgroup findings should be interpreted cautiously, but further investigation may clarify if CBFv is dependent on the degree of CGRP inhibition or may serve as a biomarker of drug sensitivity.

Abstract Background Although currently most widely used in mechanical ventilation and cardiopulmonary resuscitation, features of the carbon dioxide (CO2) waveform produced through capnometry have been shown to correlate with V/Q mismatch, dead space volume, type of breathing pattern, and small airway obstruction. This study applied feature engineering and machine learning techniques to capnography data collected by the N-Tidal™ device across four clinical studies to build a classifier that could distinguish CO2 recordings (capnograms) of patients with COPD from those without COPD. Methods Capnography data from four longitudinal observational studies (CBRS, GBRS, CBRS2 and ABRS) was analysed from 295 patients, generating a total of 88,186 capnograms. CO2 sensor data was processed using TidalSense’s regulated cloud platform, performing real-time geometric analysis on CO2 waveforms to generate 82 physiologic features per capnogram. These features were used to train machine learning classifiers to discriminate COPD from ‘non-COPD’ (a group that included healthy participants and those with other cardiorespiratory conditions); model performance was validated on independent test sets. Results The best machine learning model (XGBoost) performance provided a class-balanced AUROC of 0.985 ± 0.013, positive predictive value (PPV) of 0.914 ± 0.039 and sensitivity of 0.915 ± 0.066 for a diagnosis of COPD. The waveform features that are most important for driving classification are related to the alpha angle and expiratory plateau regions. These features correlated with spirometry readings, supporting their proposed properties as markers of COPD. Conclusion The N-Tidal™ device can be used to accurately diagnose COPD in near-real-time, lending support to future use in a clinical setting. Trial registration: Please see NCT03615365, NCT02814253, NCT04504838 and NCT03356288.

Influencer marketing spending in the United States was expected to surpass $6 billion in 2023. This marketing tactic poses a public health threat, as research suggests it has been utilized to undercut decades of public health progress—such as gains made against tobacco use among adolescents. Public health and public opinion researchers need practical tools to capture influential accounts on social media. Utilizing X (formerly Twitter) little cigar and cigarillo (LCC) data, we compared seven influential account detection metrics to help clarify our understanding of the functions of existing metrics and the nature of social media discussion of tobacco products. Results indicate that existing influential account detection metrics are non-harmonic and time-sensitive , capturing distinctly different users and categorically different user types. Our results also reveal that these metrics capture distinctly different conversations among influential social media accounts. Our findings suggest that public health and public opinion researchers hoping to conduct analyses of influential social media accounts need to understand each metric’s benefits and limitations and utilize more than one influential account detection metric to increase the likelihood of producing valid and reliable research.

Abstract Background Mental health literacy has implications for mental disorder recognition, help-seeking, and stigma reduction. Research on binge-eating disorder mental health literacy (BED MHL) is limited. To address this gap, our study examined BED MHL in a community sample. Method Two hundred and thirty-five participants completed an online survey. Participants read a vignette depicting a female character with BED then completed a questionnaire to assess five components of BED MHL (problem recognition, perceived causes, beliefs about treatment, expected helpfulness of interventions, and expected prognosis). Results About half of participants correctly identified BED as the character’s main problem (58.7%). The most frequently selected cause of the problem was psychological factors (46.8%) and a majority indicated that the character should seek professional help (91.9%). When provided a list of possible interventions, participants endorsed psychologist the most (77.9%). Conclusions Compared to previous studies, our findings suggest that current BED MHL among members of the public is better, but further improvements are needed. Initiatives to increase knowledge and awareness about the symptoms, causes, and treatments for BED may improve symptom recognition, help-seeking, and reduce stigma.

Abstract Porphyry-type deposits are a vital source of green technology metals such as copper and molybdenum. They typically form in subduction-related settings from large, long-lived magmatic systems. The most widely accepted model for their formation requires that mantle-derived magmas undergo an increase in volatiles and ore-forming constituents in mid- to lower crustal reservoirs over millions of years, however, this is mostly based on observations from shallow, sporadically exposed parts of porphyry systems. To examine this paradigm, we have evaluated the timeframe and geochemical signatures of magmatism in a ~ 8 km palaeodepth cross-section through plutonic and volcanic rocks of the classic Yerington magmatic system, Nevada. We show that the magmas in the upper parts of the system (< 8 km) underwent a major and rapid change in chemistry over a period of

Emerging infectious diseases threaten wildlife populations. Without well monitored wildlife systems, it is challenging to determine accurate population and ecosystem losses following disease emergence. North American temperate bats present a unique opportunity for studying the broad impacts of wildlife disease emergence, as their federal monitoring programs were prioritized in the USA throughout the 20th century and they are currently threatened by the invasive fungal pathogen, Pseudogymnoascus destructans (Pd), which causes white-nose syndrome. Here we provide a long-term dataset for capture records of Eptesicus fuscus (big brown bat) across the eastern USA, spanning 16 years before and 14 years after Pd invasion into North America. These data represent 30,496 E. fuscus captures across 3,567 unique sites. We encourage the use of this dataset for quantifying impacts of wildlife disease and other threats to wildlife (e.g., climate change) with the incorporation of other available data. We welcome additional data contributions for E. fuscus captures across North and Central America as well as the inclusion of other variables into the dataset that contribute to the quantification of wildlife health.

ObjectiveExperiences of relational bullying (RB) in adolescence are associated with the development of disordered eating. This association may be related to heightened shame resulting from perceived social inferiority, low social rank, and/or negative evaluation by others. Self-compassion may act as a protective factor against the influence of RB on shame and disordered eating. In the current study, we investigated whether shame mediated the relationship between recalled RB and current disordered eating in a sample of young adults. Then, using conditional process analysis, we examined whether the observed mediation was moderated by self-compassion.MethodParticipants were 359 young adults (aged 17–25) who completed online self-report measures of recalled RB experiences and current disordered eating, shame, and self-compassion.ResultsExperiences of RB were positively related to current shame and disordered eating, and negatively related to current self-compassion, with small-to-medium effect sizes. The association between RB and disordered eating was partially mediated by shame, and this mediation was moderated by self-compassion.DiscussionOur results suggest that young adults with lower self-compassion are more likely to demonstrate a relationship between recalled RB and disordered eating through the mechanism of shame. These findings have important implications for both anti-bullying awareness and eating disorder prevention programs.

Visitors to zoos can have positive, neutral, or negative relationships with zoo animals. This makes human–animal interactions (HAIs) an essential component of welfare and an important consideration in species selection for zoo exhibits and in enclosure designs. We measured the effect of visitors on reptiles by comparing open and closed periods during the lockdowns in response to the COVID-19 pandemic in the UK in a low-resolution dataset for thirteen species of reptiles and a high-resolution dataset focussing on just one of these. Scan sampling on thirteen reptile species (two chelonians and eleven squamates) showed species-specific differences in response to the presence/absence of visitors, with most taxa being only weakly affected. High-resolution scan sampling via video footage of an off-show and on-show enclosure was carried out for tokay geckos (Gekko gecko) over the open and closed periods. In this part of the study, tokay geckos were significantly more visible during zoo closure than when visitors were present on-exhibit, but there was no change in off-show animals, indicating the effect of visitors as opposed to other factors, such as seasonality, which applied equally to both on- and off-show animals. The high-resolution study showed that a significant effect was present for tokay geckos, even though the low-resolution suggested that they were more weakly affected than other taxa. Our results indicate that, for cryptic species such as this, more intensive sampling may be required to properly understand visitor effects. Our data do not allow the interpretation of effects on welfare but show that such assessments require a species-specific approach.

Maintaining Gymnophiona in captivity provides opportunities to study the behaviour and life-history of this poorly known Order, and to investigate and provide species-appropriate welfare guidelines, which are currently lacking. This study focuses on the terrestrial caecilian Herpele squalostoma to investigate its sensitivity to disturbances associated with routine husbandry needed for monitoring and maintaining adequate wellbeing in captivity. Fossorial caecilians gradually pollute their environment in captivity with waste products, and substrate must be replaced at intervals; doing so disturbs the animals directly and via destruction of burrow networks. As inappetence is frequently associated with stress in amphibians, the percentage consumption of offered food types, river shrimp (Palaemon varians) and brown crickets (Gryllus assimilis), was measured as an indicator of putative stress following three routine substrate changes up to 297 days post-substrate change. Mean daily variation in substrate temperatures were also recorded in order to account for environmental influences on food consumption, along with nitrogenous waste in tank substrate prior to a substrate change and fresh top soil in order to understand the trade-off between dealing with waste accumulation and disturbing animals. We found a significant negative effect of substrate disturbance on food intake, but no significant effect of prey type. Variations in daily soil temperatures did not have a significant effect on food intake, but mean substrate temperature did. Additionally, substrate nitrogenous waste testing indicated little difference between fresh and tank substrate. In conclusion, this study provides a basis from which to develop further welfare assessment for this and other rarely kept and rarely observed terrestrial caecilian species.

Abstract The immunosuppressive agents sirolimus and everolimus are sensitive CYP3A4 substrates with narrow therapeutic index. Ritonavir is a strong CYP3A inhibitor. A phase 1 study was conducted to evaluate the pharmacokinetics, safety, and tolerability of the co‐administration of sirolimus or everolimus with the ritonavir‐containing 3D regimen of the direct‐acting antiviral agents ombitasvir, ritonavir‐boosted paritaprevir, and dasabuvir in healthy subjects. This study had two independent arms, each with a two‐period, single‐sequence, crossover study design. A single dose of sirolimus 2 mg (N = 12) or everolimus 0.75 mg (N = 12) was administered in Period 1. In Period 2, multiple doses of the 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily and dasabuvir 250 mg twice daily) were administered for 34 or 28 days, with a single dose of sirolimus 0.5 mg or everolimus 0.75 mg co‐administered on Day 15. Following co‐administration with the 3D regimen, the sirolimus dose‐normalized maximum observed blood concentration (Cmax) and area under the blood concentration–time curve from time zero to infinity (AUCinf) increased to 6.4‐fold and 38‐fold, respectively. Following co‐administration with the 3D regimen, the everolimus Cmax and AUCinf increased to 4.7‐fold and 27‐fold, respectively. Sirolimus and everolimus half‐lives increased from 96 to 249 h, and 42 to 118 h, respectively. There were no major safety or tolerability issues in this study. The ritonavir‐containing 3D regimen resulted in a significant increase in sirolimus or everolimus exposure, consistent with the known strong inhibitory effect of ritonavir on CYP3A requiring dose and/or frequency modification when co‐administered with each other.

The mechanistic target of rapamycin (mTOR) functions in two distinct complexes: mTORC1, and mTORC2. mTORC1 has been implicated in the pathogenesis of flaviviruses including dengue, where it contributes to the establishment of a pro-viral autophagic state. Activation of mTORC2 occurs upon infection with some viruses, but its functional role in viral pathogenesis remains poorly understood. In this study, we explore the consequences of a physical protein-protein interaction between dengue non-structural protein 5 (NS5) and host cell mTOR proteins during infection. Using shRNA to differentially target mTORC1 and mTORC2 complexes, we show that mTORC2 is required for optimal dengue replication. Furthermore, we show that mTORC2 is activated during viral replication, and that mTORC2 counteracts virus-induced apoptosis, promoting the survival of infected cells. This work reveals a novel mechanism by which the dengue flavivirus can promote cell survival to maximize viral replication.

This study compared the resource use of juvenile zoo-living Chinese crocodile lizards, Shinisaurus crocodilurus crocodilurus across three observation windows, spanning nine months, accounting for time of day and lizard age, and under consistent environmental conditions. Lizards showed a significant difference in proportionate resource use, quantified using a modified spread of participation indices between the second and final sampling period, such that with increasing age, resources were more equally utilised. The time of day did not have a significant effect on resource use. Lizards in this study significantly increased their use of water bodies and branches outside the bask zone and decreased their use of the land areas within the bask zones over time. Resource use data suggests the importance of providing enclosures which cater to ontogenetic shifts in captive individuals or within mixed age groupings.

Background Despite evidence supporting the safety of breast implants, some women associate their implants with adverse health effects and have called this syndrome “breast implant illness.” We sought to characterize breast implant illness symptoms and to report how implant removal affects their symptoms. Methods An anonymous 20 question survey was administered to the Facebook group: “UTAH Breast Implant Illness” to characterize the symptoms these women attributed to their breast implants. Several questions allowed us to evaluate how implant removal affected women’s symptoms. Results Of the 182 respondents, 97% report that implants negatively affect their health and 95% identify these symptoms with breast implant illness. Ninety-six percent of respondents had implants placed for cosmetic reasons and 51% had silicone implants. The most common symptoms associated with breast implant illness are brain fog (95%), fatigue (92%), joint pain (80%), and hair loss (74%). Sixty percent of respondents learned about breast implant illness from family/friends and/or social media platforms (56%), 40% of respondents had their implants removed, and 97% report relief of their symptoms post-removal (23% complete, 74% partial). Following explantation, there was a significant improvement in all but one reported symptom. An association was found between the number of symptoms reported prior to explantation and the number of symptoms resolving following explantation. Conclusions Breast implant illness is a syndrome characterized by fatigue, decreased focus, hair loss, and joint pain after the placement of breast implants. Nearly all patients report improvement of symptoms after implant removal. Significant efforts should be made to better understand breast implant illness and its etiology.

NMDA receptors (NMDARs) are crucial for glutamatergic synaptic signaling in the mammalian central nervous system. When activated by glutamate and glycine/D-serine, the NMDAR ion channel can open, but current flux is further regulated by voltage-dependent block conferred by extracellular Mg2+ ions. The unique biophysical property of ligand- and voltage-dependence positions NMDARs as synaptic coincidence detectors, controlling a major source of synaptic Ca2+ influx. We measured synaptic currents in layer 2/3 neurons after stimulation in layer 4 of somatosensory cortex and found measurable NMDAR currents at all voltages tested. This NMDAR current did not require concurrent AMPAR depolarization. In physiological ionic conditions, the NMDAR current response at negative potentials was enhanced relative to ionic conditions typically used in slice experiments. NMDAR activity was also seen in synaptic recordings from hippocampal CA1 neurons, indicating a general property of NMDAR signaling. Using a fluorescent Ca2+ indicator, we measured responses to stimulation in layer 4 at individual synaptic sites, and Ca2+ influx could be detected even with AMPARs blocked. In current clamp recordings, we found that resting membrane potential was hyperpolarized by ∼7 mV and AP firing threshold depolarized by ∼4 mV in traditional compared to physiological ionic concentrations, and that NMDARs contribute to EPSPs at resting membrane potentials. These measurements demonstrate that, even in the presence of extracellular Mg2+ and absence of postsynaptic depolarization, NMDARs contribute to synaptic currents and Ca2+ influx.

Aim:Children with cutaneous or systemic mastocytosis may experience severe manifestations of mast cell mediator release including anaphylaxis. The perceived risk for adverse vaccine reactions creates concern among parents and pediatricians regarding modification of the routine vaccine schedule for safety.Materials and Methods:Using the National Institutes of Health (NIH) Biomedical Translational Research Information System and Clinical Research Information System, we conducted a retrospective chart review of 94 children ≤18 years of age, evaluated at NIH with mastocytosis. Based on the recommended childhood immunization schedule, we estimated that these 94 patients received approximately 2,136 vaccinations. Post vaccination reactions were determined as expected or unexpected according to the centers for disease control (CDC) parameters for vaccine-associated events.Results:Eighty-four patients (89.4%) had no reports of moderate-severe post-vaccination reactions. Eleven reactions after vaccination were reported in 10 of 94 patients (10.6%), of which four patients had unexpected reactions (4.3%). Unexpected reactions included facial swelling, flushing and exacerbation of skin lesions which are not reported as possible vaccine reactions by the CDC. One patient was treated for anaphylaxis 2 hours post-varicella vaccine administration. Five patients with a history of anaphylaxis and a mean tryptase level of 115 ng/mL did not report vaccine-induced reactions.Conclusion:Children with mastocytosis in this study did not experience a higher rate of adverse vaccine reactions compared to the general population. Anaphylaxis to other causes was not a risk factor for an untoward vaccine response. In patients that experience a severe postvaccination reaction such as anaphylaxis, a modified schedule with single vaccine administration is a safer approach.

Mastocytosis is a hematologic neoplasm characterized by expansion and focal accumulation of neoplastic mast cells (MC) in diverse organs, including the skin, bone marrow (BM), spleen, liver, and gastrointestinal tract. The World Health Organization classification divides the disease into prognostically distinct variants of cutaneous mastocytosis (CM) and systemic mastocytosis (SM). Although this classification remains valid, recent developments in the field and the advent of new diagnostic and prognostic parameters created a need to update and refine definitions and diagnostic criteria in MC neoplasms. In addition, MC activation syndromes (MCAS) and genetic features predisposing to SM and MCAS have been identified. To discuss these developments and refinements in the classification, we organized a Working Conference comprised of experts from Europe and the United States in August 2020. This article reports on outcomes from this conference. Of particular note, we propose adjustments in the classification of CM and SM, refinements in diagnostic criteria of SM variants, including smoldering SM and BM mastocytosis (BMM), and updated criteria for MCAS and other conditions involving MC. CD30 expression in MC now qualifies as a minor SM criterion, and BMM is now defined by SM criteria, absence of skin lesions and absence of B- and C-findings. A basal serum tryptase level exceeding 20 ng/mL remains a minor SM criterion, with recognition that hereditary alpha-tryptasemia and various myeloid neoplasms may also cause elevations in tryptase. Our updated proposal will support diagnostic evaluations and prognostication in daily practice and the conduct of clinical trials in MC disorders.

The ability to place perfectly aligned vertical nanowires at chosen positions on a silicon substrate is an important challenge in device fabrication. Here, the authors propose a mechanism to explain self-catalyzed III-V nanowire growth on silicon, providing valuable insights for growing high yield nanowire arrays.

The Xist lncRNA mediates X chromosome inactivation (XCI). Here we show that Spen, an Xist-binding repressor protein essential for XCI , binds to ancient retroviral RNA, performing a surveillance role to recruit chromatin silencing machinery to these parasitic loci. Spen loss activates a subset of endogenous retroviral (ERV) elements in mouse embryonic stem cells, with gain of chromatin accessibility, active histone modifications, and ERV RNA transcription. Spen binds directly to ERV RNAs that show structural similarity to the A-repeat of Xist, a region critical for Xist-mediated gene silencing. ERV RNA and Xist A-repeat bind the RRM domains of Spen in a competitive manner. Insertion of an ERV into an A-repeat deficient Xist rescues binding of Xist RNA to Spen and results in strictly local gene silencing in cis. These results suggest that Xist may coopt transposable element RNA-protein interactions to repurpose powerful antiviral chromatin silencing machinery for sex chromosome dosage compensation.

Persistent dysregulation of IL-6 production and signaling have been implicated in the pathology of various cancers. In systemic mastocytosis, increased serum levels of IL-6 associate with disease severity and progression, although the mechanisms involved are not well understood. Since systemic mastocytosis often associates with the presence in hematopoietic cells of a somatic gain-of-function variant in KIT, D816V-KIT, we examined its potential role in IL-6 upregulation. Bone marrow mononuclear cultures from patients with greater D816V allelic burden released increased amounts of IL-6 which correlated with the percentage of mast cells in the cultures. Intracellular IL-6 staining by flow cytometry and immunofluorescence was primarily associated with mast cells and suggested a higher percentage of IL-6 positive mast cells in patients with higher D816V allelic burden. Furthermore, mast cell lines expressing D816V-KIT, but not those expressing normal KIT or other KIT variants, produced constitutively high IL-6 amounts at the message and protein levels. We further demonstrate that aberrant KIT activity and signaling are critical for the induction of IL-6 and involve STAT5 and PI3K pathways but not STAT3 or STAT4. Activation of STAT5A and STAT5B downstream of D816V-KIT was mediated by JAK2 but also by MEK/ERK1/2, which not only promoted STAT5 phosphorylation but also its long-term transcription. Our study thus supports a role for mast cells and D816V-KIT activity in IL-6 dysregulation in mastocytosis and provides insights into the intracellular mechanisms. The findings contribute to a better understanding of the physiopathology of mastocytosis and suggest the importance of therapeutic targeting of these pathways.

Previous studies infecting global IL-4Rα−/−, IL-4−/−, and IL-13−/−mice on a BALB/c background with the visceralizing parasite Leishmania donovani have shown that the T helper 2 cytokines, IL-4, and IL-13, play influential but not completely overlapping roles in controlling primary infection. Subsequently, using macrophage/neutrophil-specific IL-4Rα deficient BALB/c mice, we demonstrated that macrophage/neutrophil unresponsiveness to IL-4 and IL-13 did not have a detrimental effect during L. donovani infection. Here we expand on these findings and show that CD4+ T cell-(Lckcre), as well as pan T cell-(iLckcre) specific IL-4Rα deficient mice, on a BALB/c background, unlike global IL-4Rα deficient mice, are also not adversely affected in terms of resistance to primary infection with L. donovani. Our analysis suggested only a transient and tissue specific impact on disease course due to lack of IL-4Rα on T cells, limited to a reduced hepatic parasite burden at day 30 post-infection. Consequently, the protective role(s) demonstrated for IL-4 and IL-13 during L. donovani infection are mediated by IL-4Rα-responsive cell(s) other than macrophages, neutrophils and T cells.

Agrobacterium-mediated transformation is a core technology for basic plant science and agricultural biotechnology. Improving transformation frequency is a major goal for plant transgenesis. We previously showed that T-DNA insertions in some histone genes decreased transformation susceptibility, whereas overexpression of several Arabidopsis H2A and H4 isoforms increased transformation. Overexpression of several histone H2B and H3 isoforms had little effect on transformation frequency. However, overexpression of histone H3-11 (HTR11) enhanced transformation. HTR11 is a unique H3 variant that lacks lysine at positions 9 and 27. The modification status of these lysine residues in canonical H3 proteins plays a critical role in epigenetic determination of gene expression. We mutated histone H3-4 (HTR4), a canonical H3.3 protein that does not increase transformation when overexpressed, by replacing either or both K9 and K27 with the amino acids in HTR11 (either K9I, K27Q, or both). Overexpression of HTR4 with the K27Q but not the K9I substitution enhanced transformation. HTR4K27Q was incorporated into chromatin, and HTR4K27Q overexpression lines exhibited deregulated expression of H3K27me3-enriched genes. These results demonstrate that mutation of K27 in H3.3 is sufficient to perturb H3K27me3-dependent expression in plants as in animals and suggest a distinct epigenetic role for histone HTR11. Further, these observations implicate manipulation of H3K27me3-dependent gene expression as a novel strategy to increase transformation susceptibility.

Given the tenuous relationship Christians have had with Jews over the centuries, not to mention division among Christianity on points of doctrine and practice, a contemporary examination of the Sabbath could be an opportunity to bring Jews and Christians into further dialogue with each other, not on the basis of a shared written text, but rather the living texts of religious experience. However, a review of the literature reveals a scarcity of empirical research on the Sabbath, especially how religious professionals practice Sabbath as exemplars in their spheres of influence. In this study, I, therefore, offer a comparative description of my findings with respect to two practical theological studies I conducted on Shabbat/Sabbath practice, one with American pulpit rabbis and the other Seventh-day Adventist pastors. As a practical theological project, I offer a theological reflection of the data, followed by implications for theological (re)construction and revised praxis for the Church and Jewish-Christian relations.

Leishmaniasis is a vector-borne parasitic disease that has been neglected in priority for control and eradication of malaria, tuberculosis, and HIV/AIDS. Collectively, over one seventh of the world’s population is at risk of being infected with 0.7–1.2 million new infections reported annually. Clinical manifestations range from self-healing cutaneous lesions to fatal visceral disease. The first anti-leishmanial drugs were introduced in the 1950′s and, despite several shortcomings, remain the mainstay for treatment. Regardless of this and the steady increase in infections over the years, particularly among populations of low economic status, research on leishmaniasis remains under funded. This review looks at the drugs currently in clinical use and how they interact with the host immune response. Employing chemoimmunotherapeutic approaches may be one viable alternative to improve the efficacy of novel/existing drugs and extend their lifespan in clinical use.

Miltefosine (Milt) is the only oral treatment for visceral leishmaniasis (VL) but its use is associated with adverse effects, e.g., teratogenicity, vomiting, diarrhoea. Understanding how its chemical structure induces cytotoxicity, whilst not compromising its anti-parasitic efficacy, could identify more effective compounds. Therefore, we systemically modified the compound’s head, tail and linker tested the in vitro activity of three alkylphosphocholines (APC) series against Leishmania donovani strains with different sensitivities to antimony. The analogue, APC12, with an alkyl carbon chain of 12 atoms, was also tested for anti-leishmanial in vivo activity in a murine VL model. All APCs produced had anti-leishmanial activity in the micromolar range (IC50 and IC90, 0.46– > 82.21 µM and 4.14–739.89 µM; 0.01– > 8.02 µM and 0.09–72.18 µM, respectively, against promastigotes and intracellular amastigotes). The analogue, APC12 was the most active, was 4–10 fold more effective than the parent Milt molecule (APC16), irrespective of the strain’s sensitivity to antimony. Intravenous administration of 40 mg/kg APC12 to L. donovani infected BALB/c mice reduced liver and spleen parasite burdens by 60 ± 11% and 60 ± 19%, respectively, while oral administration reduced parasite load in the bone marrow by 54 ± 34%. These studies confirm that it is possible to alter the Milt structure and produce more active anti-leishmanial compounds.

In the present density functional theory (DFT) research, nine different molecules, each with different combinations of A (triel) and E (divalent metal) elements, were reacted to effect methane C–H activation. The compounds modeled herein incorporated the triels A = B, Al, or Ga and the divalent metals E = Be, Mg, or Zn. The results show that changes in the divalent metal have a much bigger impact on the thermodynamics and methane activation barriers than changes in the triels. The activating molecules that contained beryllium were most likely to have the potential for activating methane, as their free energies of reaction and free energy barriers were close to reasonable experimental values (i.e., ΔG close to thermoneutral, ΔG‡ ~30 kcal/mol). In contrast, the molecules that contained larger elements such as Zn and Ga had much higher ΔG‡. The addition of various substituents to the A–E complexes did not seem to affect thermodynamics but had some effect on the kinetics when substituted closer to the active site.

Oral chemotherapy represents a major patient-centric advancement in therapy convenience. However, ownership of safe and correct administration of these agents requires significant patient education. To address this challenge, an in-person pharmacist-led oral chemotherapy education clinic in gastrointestinal oncology patients within an academic medical center was created and assessed. In this pilot program, a medication-specific quiz was administered to patients before and after education performed by a pharmacist to assess patient understanding of their new oral chemotherapy. A five-question satisfaction survey was also administered at the conclusion of the pharmacist clinic visit. Primary outcome was the percentage difference between pre-and post-education quiz scores. Secondary outcomes included patient satisfaction, time to treatment initiation, and number of pharmacist interventions. Frequencies and medians were used to describe categorical and continuous variables, respectively. Of the 18 patients analyzed, 50% were male and median age was 59.5 years. Approximately 28% had colon cancer, and 61% were treated with capecitabine. The median post-education scores improved from a pre-education score of 75% to 100%. Overall, seventeen of the eighteen patients responded with “strongly agree” to all satisfaction survey statements. An in-person oncology pharmacist-led oral chemotherapy education session demonstrated an improvement in patients’ understanding of their new oral chemotherapy treatment.

This longitudinal study aimed at showing the effect of early social-emotional/behavioural problems and competencies on vocabulary development in toddlers. The participants were 60 native Finnish-speaking healthy children (30 boys and 30 girls). Parental reports on the Brief Infant-Toddler Social and Emotional Assessment (BITSEA) were gathered at the children’s age of 18 months. The Problem Total and Competence Total, as well as externalizing, internalizing and dysregulation problem domain, scores were calculated. Vocabulary development was assessed by a certified speech and language therapist at ages 24 and 30 months using the Receptive and Expressive One-Word Picture Vocabulary Tests (ROWPVT-4 and EOWPVT-4). Compared to boys, girls obtained higher Competence Total scores and scored considerably higher in all the vocabulary measures. With regard to the relationships between early social-emotional/behavioural problems and vocabulary measures, Problem Total scores correlated negatively with receptive vocabulary scores at 24 months and expressive vocabulary scores at 30 months. Further analyses indicated that particularly externalizing problems were associated with slower vocabulary development. By contrast, Competence Total scores correlated positively with expressive vocabulary at 30 months. The same analyses were carried out separately for boys and girls. Mostly, the separate findings were in line with the results for the whole group of children.