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Abstract Background Cover cropping is an agricultural practice that uses secondary crops to support the growth of primary crops through various mechanisms including erosion control, weed suppression, nutrient management, and enhanced biodiversity. Cover crops may elicit some of these ecosystem services through chemical interactions with the soil microbiome via root exudation, or the release of plant metabolites from roots. Phytohormones are one metabolite type exuded by plants that activate the rhizosphere microbiome, yet managing this chemical interaction remains an untapped mechanism for optimizing plant-soil-microbiome interactions. Currently, there is limited understanding on the diversity of cover crop phytohormone root exudation patterns and our aim was to understand how phytochemical signals selectively enrich specific microbial taxa and functionalities in agricultural soils. Results Here, we link variability in cover crop root exudate composition to changes in soil microbiome functionality. Exudate chemical profiles from 4 cover crop species (Sorghum bicolor, Vicia villosa, Brassica napus, and Secale cereal) were used as the chemical inputs to decipher microbial responses. These distinct exudate profiles, along with a no exudate control, were amended to agricultural soil microcosms with microbial responses tracked over time using metabolomes and genome-resolved metatranscriptomes. Our findings illustrated microbial metabolic patterns were unique in response to cover crop exudate inputs over time, particularly by sorghum and cereal rye amended microcosms. In these microcosms, we identify novel microbial members (at the genera and family level) who produced IAA and GA4 over time. Additionally, we identified cover crop exudates exclusively enriched for bacterial nitrite oxidizers, while control microcosms were discriminated for nitrogen transport, mineralization, and assimilation, highlighting distinct changes in microbial nitrogen cycling in response to chemical inputs. Conclusions We highlight that root exudate amendments alter microbial community function (i.e., N cycling) and microbial phytohormone metabolisms, particularly in response to root exudates isolated from cereal rye and sorghum plants. Additionally, we constructed a soil microbial genomic catalog of microorganisms responding to commonly used cover crops, a public resource for agriculturally relevant microbes. Many of our exudate-stimulated microorganisms are representatives from poorly characterized or novel taxa, revealing the yet to be discovered metabolic reservoir harbored in agricultural soils. Our findings emphasize the tractability of high-resolution multi-omics approaches to investigate processes relevant for agricultural soils, opening the possibility of targeting specific soil biogeochemical outcomes through biological precision agricultural practices that use cover crops and the microbiome as levers for enhanced crop production. Video Abstract

Abstract Biofilms are a concern for spaceflight missions, given their propensity for biofouling systems and their potential threat to astronaut health. Herein, we describe a random positioning machine-based method for growing fluorescent protein-expressing streptococcal biofilms under simulated microgravity. Biofilms can be subsequently imaged by confocal microscopy without further manipulation, minimizing disruption of architecture. This methodology could be adaptable to other bacteria, potentially standardizing biofilm growth and study under simulated microgravity.

Abstract Alcohol use is an independent risk factor for the development of bacterial pneumonia due, in part, to impaired mucus-facilitated clearance, macrophage phagocytosis, and recruitment of neutrophils. Alcohol consumption is also known to reduce peripheral natural killer (NK) cell numbers and compromise NK cell cytolytic activity, especially NK cells with a mature phenotype. However, the role of innate lymphocytes, such as NK cells during host defense against alcohol-associated bacterial pneumonia is essentially unknown. We have previously shown that indole supplementation mitigates increases in pulmonary bacterial burden and improves pulmonary NK cell recruitment in alcohol-fed mice, which were dependent on aryl hydrocarbon receptor (AhR) signaling. Employing a binge-on-chronic alcohol-feeding model we sought to define the role and interaction of indole and NK cells during pulmonary host defense against alcohol-associated pneumonia. We demonstrate that alcohol dysregulates NK cell effector function and pulmonary recruitment via alterations in two key signaling pathways. We found that alcohol increases transforming growth factor beta (TGF-β) signaling while suppressing AhR signaling. We further demonstrated that NK cells isolated from alcohol-fed mice have a reduced ability to kill Klebsiella pneumoniae. NK cell migratory capacity to chemokines was also significantly altered by alcohol, as NK cells isolated from alcohol-fed mice exhibited preferential migration in response to CXCR3 chemokines but exhibited reduced migration in response to CCR2, CXCR4, and CX3CR1 chemokines. Together this data suggests that alcohol disrupts NK cell-specific TGF-β and AhR signaling pathways leading to decreased pulmonary recruitment and cytolytic activity thereby increasing susceptibility to alcohol-associated bacterial pneumonia.

ABSTRACT: Objective: To evaluate the impact of the COVID-19 pandemic on the psychosocial functioning of individuals with cleft lip and/or palate (CL/P). Methods: Patients with CL/P ≥ 6 years old were prospectively recruited from the Cleft and Craniofacial Clinic of a tertiary children's hospital. From July-October 2021, eligible patients (or their parent/guardian) were sent a survey regarding their psychosocial functioning before and after the start of the pandemic. Main Outcome Measure: The difference between prepandemic and intrapandemic patient-reported outcome scores. Results: Thirty-six patients (20 female, age: 15.9 ± 9.8 years) responded. Most had cleft lip and palate (77.8%), responded online (69.4%), interacted remotely via both voice- and video-conferencing (62.9%), and wore masks routinely (77.1%). Similar numbers of patients responded independently (27.8%), responded with the help of a parent/guardian (36.1%), or had a parent/guardian respond on their behalf (36.1%). General social-emotional well-being (p = 0.004, rrb = 0.659) and satisfaction with facial appearance (p = 0.044, rrb = 0.610) significantly improved after the start of the pandemic. Compared to their general intrapandemic social-emotional well-being scores, patients reported higher scores while wearing a mask (rrb = 0.827) and lower scores while interacting remotely (rrb = 0.605), although all were still significantly improved compared to their prepandemic scores (p ≤ 0.010). Patients also reported significant improvement in social functioning while wearing a mask (p = 0.036, rrb = 0.519), whereas they did not when considering their general intrapandemic feelings/experiences (p = 0.269, rrb = 0.211). Conclusion: Patients with CL/P demonstrated significant improvement in overall social-emotional well-being, satisfaction with facial appearance, and social functioning after the start of the COVID-19 pandemic, particularly when wearing a mask.

Abstract Background Dietary supplement (DS) use is common and increasing among older adults, though much data available on use frequencies are from surveys and performed cross-sectionally. This paper sought to assess the frequency and pattern of dietary supplement use among older adults over time. Methods A secondary analysis of data from the AAA LongROAD study, a longitudinal prospective cohort study of older adult drivers, using data from baseline and the first two years of follow up included a total of 2990 drivers aged 65–79 years recruited at five study sites across the US from July 2015 to March 2017. Participants underwent baseline and annual evaluations, which included a “brown bag” medication review. DS were identified and categorized according to type and key components. Prevalence and pattern of DS use over time and relationship to demographics were measured with frequency and Chi squared analyses. Results 84% of participants took at least one dietary supplement during the 2-year study period, and 55% of participants continually reported use. DS accounted for approximately 30% of the total pharmacologic-pill burden in all years. Participants who were White non-Hispanic, female, 75–79 years of age at baseline, and on more non-supplement medications took significantly more dietary supplements (P

Abstract Background Inflammatory bowel disease (IBD) affects over 3 million Americans and has a relapsing and remitting course with up to 30% of patients experiencing exacerbations each year despite the availability of immune targeted therapies. An urgent need exists to develop adjunctive treatment approaches to better manage IBD symptoms and disease activity. Circadian disruption is associated with increased disease activity and may be an important modifiable treatment target for IBD. Morning light treatment, which advances and stabilizes circadian timing, may have the potential to improve IBD symptoms and disease activity, but no studies have explored these potential therapeutic benefits in IBD. Therefore, in this study, we aim to test the effectiveness of morning light treatment for patients with IBD. Methods We will recruit sixty-eight individuals with biopsy-proven IBD and clinical symptoms and randomize them to 4-weeks of morning light treatment or 4-weeks of treatment as usual (TAU), with equivalent study contact. Patient-reported outcomes (IBD-related quality of life, mood, sleep), clinician-rated disease severity, and a biomarker of gastrointestinal inflammation (fecal calprotectin) will be assessed before and after treatment. Our primary objective will be to test the effect of morning light treatment versus TAU on IBD-related quality of life and our secondary objectives will be to test the effects on clinician-rated disease activity, depression, and sleep quality. We will also explore the effect of morning light treatment versus TAU on a biomarker of gastrointestinal inflammation (fecal calprotectin), and the potential moderating effects of steroid use, restless leg syndrome, and biological sex. Discussion Morning light treatment may be an acceptable, feasible, and effective adjunctive treatment for individuals with active IBD suffering from impaired health-related quality of life. Trial registration The study protocol was registered on ClinicalTrials.gov as NCT06094608 on October 23, 2023, before recruitment began on February 1, 2024.

This Review summarizes a range of analytical techniques that can be used to detect, quantify, and/or distinguish between isotopes of iodine (e.g., long-lived 129I, short-lived 131I, stable 127I). One reason this is of interest is that understanding potential radioiodine release from nuclear processes is crucial to prevent environmental contamination and to protect human health as it can incorporate into the thyroid leading to cancer. It is also of interest for evaluating iodine retention performances of next-generation iodine off-gas capture materials and long-term waste forms for immobilizing radioiodine for disposal in geologic repositories. Depending upon the form of iodine (e.g., molecules, elemental, and ionic) and the matter state (i.e., solid, liquid, and gaseous), the available options can vary. In addition, several other key parameters vary between the methods discussed herein, including the destructive vs nondestructive nature of the measurement process (including in situ vs ex situ measurement options), the analytical data collection times, and the amount of sample required for analysis.

Abstract Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies remains challenging in part due to the lack of faithful preclinical in vitro models. Here we establish twelve patient-derived WT cell lines and demonstrate that these models faithfully recapitulate WT biology using genomic and transcriptomic techniques. We then perform loss-of-function screens to identify the nuclear export gene, XPO1, as a vulnerability. We find that the FDA approved XPO1 inhibitor, KPT-330, suppresses TRIP13 expression, which is required for survival. We further identify synergy between KPT-330 and doxorubicin, a chemotherapy used in high-risk FHWT. Taken together, we identify XPO1 inhibition with KPT-330 as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.

Introduction Pharmacists focusing on psychotropic medication management and practicing across a wide variety of healthcare settings have significantly improved patient-level outcomes. The Systematic Literature Review Committee of the American Association of Psychiatric Pharmacists was tasked with compiling a comprehensive database of primary literature highlighting the impact of psychiatric pharmacists on patient-level outcomes. Methods A systematic search of literature published from January 1, 1961, to December 31, 2022, was conducted using PubMed and search terms based on a prior American Association of Psychiatric Pharmacists literature review. Publications describing patient-level outcome results associated with pharmacist provision of care in psychiatric/neurologic settings and/or in relation to psychotropic medications were included. The search excluded articles for which there was no pharmacist intervention, no psychiatric disorder treatment, no clinical outcomes, no original research, no access to full text, and/or no English-language version. Results A total of 4270 articles were reviewed via PubMed, with 4072 articles excluded based on title, abstract, and/or full text in the initial pass and 208 articles selected for inclusion. A secondary full-text review excluded 11 additional articles, and 5 excluded articles were ultimately included based on a secondary review, for a final total of 202 articles meeting the inclusion criteria. A comprehensive database of these articles was compiled, including details on their study designs and outcomes. Discussion The articles included in the final database had a wide range of heterogeneity. While the overall impact of psychiatric pharmacists was positive, the study variability highlights the need for future publications to have more consistent, standardized outcomes with stronger study designs.

OBJECTIVES:. Interhospital transfer of patients with acute respiratory failure (ARF) is relevant in the current landscape of critical care delivery. However, current transfer practices for patients with ARF are highly variable, poorly formalized, and lack evidence. We aim to synthesize the existing evidence, identify knowledge gaps, and highlight persisting questions related to interhospital transfer of patients with ARF. DATA SOURCES:. Ovid Medline, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Embase, CINAHL Plus, and American Psychological Association. STUDY SELECTION:. We included studies that evaluated or described hospital transfers of adult (age > 18) patients with ARF between January 2020 and 2024 conducted in the United States. Using predetermined search terms and strategies, a total of 3369 articles were found across all databases. After deduplication, 1748 abstracts were screened by authors with 45 articles that advanced to full-text review. This yielded 16 studies that fit our inclusion criteria. DATA EXTRACTION:. The studies were reviewed in accordance to Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews by three authors. DATA SYNTHESIS:. Included studies were mostly retrospective analyses of heterogeneous patients with various etiologies and severity of ARF. Overall, transferred patients were younger, had high severity of illness, and were more likely to have commercial insurance compared with nontransferred cohorts. There is a paucity of data examining why patients get transferred. Studies that retrospectively evaluated outcomes between transferred and nontransferred cohorts found no differences in mortality, although transferred patients have a longer length of stay. There is limited evidence to suggest that patients transferred early in their course have improved outcomes. CONCLUSIONS:. Our scoping review highlights the sparse evidence and the urgent need for further research into understanding the complexity behind ARF transfers. Future studies should focus on defining best practices to inform clinical decision-making and improve downstream outcomes.

Summary: Here, we show that a NOT gated cell therapy (Tmod) can exploit antigens such as epidermal growth factor receptor (EGFR) and human leukocyte antigen-E (HLA-E) which are widely expressed on cancer cells. Noncancerous cells—despite high expression of these antigens—are protected from cytotoxicity by the action of an inhibitory receptor (“blocker”) via a mechanism that involves blocker modulation of CAR surface expression. The blocker is triggered by the product of a polymorphic HLA allele (e.g., HLA-A∗02) deleted in a significant subset of solid tumors via loss of heterozygosity. Moreover, Tmod constructs that target mouse homologs of EGFR or HLA-E for activation, and a mouse-equivalent of HLA-A∗02 for inhibition, protect mice from toxicity caused by the CAR alone. The blocker also controls graft vs. host response in allogeneic T cells in vitro, consistent with the use of Tmod cells for off-the-shelf therapy without additional gene-editing.

Viruses are infectious agents that cause various diseases worldwide. The recent COVID-19 pandemic has shown the need for rapid and reliable tests to confirm viral infections, aiming at the rapid isolation, treatment, and identification of high-incidence regions. Rapid antigen tests based on lateral flow immunochromatography have proven to be very useful. However, they are not accurate in patients with low viral loadings. The gold standard test is RT-PCR, which identifies parts of the viral genome by detecting specific DNA or RNA sequences. RT-PCR or similar tests such as RT-LAMP involve several steps for sample preparation and amplification of target sequences, require trained personnel to be performed, and can be time-consuming and expensive, limiting their point-of-care application. Biosensors are promising analytical devices for detecting nucleic acids, mainly RNA from viruses, offering advantages such as rapid results, high sensitivity, and low cost compared with the RT-PCR test since the amplification of target sequences is not necessary. Recently, several biosensors have been developed to detect RNA viruses without sequence amplification. Here, we present a review on the design and technology of amplification-free biosensors for the detection of viral RNA as an alternative for diagnosing infectious diseases. The challenges and advances for the point-of-care electrochemical, electrical, and optical biosensors will be addressed.

Patent Foramen Ovale (PFO) is a common congenital atrial septal defect present in 20%–35% of the general population. Although generally considered a benign anatomic variant, a PFO may facilitate passage of a thrombus from the venous to arterial circulation, thereby resulting in cryptogenic stroke or systemic embolization. A PFO is detected in nearly one half of patients presenting with cryptogenic stroke and often considered the most likely etiology when other causes have been excluded. In this review, we discuss the contemporary role of transcatheter closure of PFO in the treatment of cryptogenic stroke, including devices currently available for commercial use in the United States (Amplatzer PFOTM Occluder and GoreTM Cardioform Septal Occluder) and a novel suture-mediated device (NobleStitchTM EL) under clinical investigation. To provide the best care for cryptogenic stroke patients, practitioners should be familiar with the indications for PFO closure and corresponding treatment options.

As doenças cardiovasculares lideram a causa de mortalidade no mundo. O eletrocardiograma é uma das formas de obter o diagnóstico relacionado a doenças cardíacas. O exame consiste no registro da atividade elétrica do músculo cardíaco por meio de eletrodos posicionados nos braços, pernas e tórax do indivíduo. Neste trabalho estudamos o modelo de McSharry, que é capaz de reproduzir os sinais característicos do eletrocardiograma usando três equações diferenciais acopladas. Adicionando ao modelo um ruído e um termo senoidal, verificamos que essas modificações permitem alterar a característica do sinal de eletrocardiograma. Mostramos que é possível gerar sinais semelhantes àqueles que caracterizam anomalias no sistema cardiovascular. Utilizamos exames reais reportados pela Sociedade de Cardiologia do Estado do Rio de Janeiro para comparar com os resultados das simulações.

Abstract Background Given significant risks associated with long-term prescription opioid use, there is a need for non-pharmacological interventions for treating chronic pain. Activating patients to manage chronic pain has the potential to improve health outcomes. The ACTIVATE study was designed to evaluate the effectiveness of a 4-session patient activation intervention in primary care for patients on long-term opioid therapy. Methods The two-arm, pragmatic, randomized trial was conducted in two primary care clinics in an integrated health system from June 2015—August 2018. Consenting participants were randomized to the intervention (n = 189) or usual care (n = 187). Participants completed online and interviewer-administered surveys at baseline, 6- and 12- months follow-up. Prescription opioid use was extracted from the EHR. The primary outcome was patient activation assessed by the Patient Activation Measure (PAM). Secondary outcomes included mood, function, overall health, non-pharmacologic pain management strategies, and patient portal use. We conducted a repeated measure analysis and reported between-group differences at 12 months. Results At 12 months, the intervention and usual care arms had similar PAM scores. However, compared to usual care at 12 months, the intervention arm demonstrated: less moderate/severe depression (odds ratio [OR] = 0.40, 95%CI 0.18–0.87); higher overall health (OR = 3.14, 95%CI 1.64–6.01); greater use of the patient portal’s health/wellness resources (OR = 2.50, 95%CI 1.42–4.40) and lab/immunization history (OR = 2.70, 95%CI 1.29–5.65); and greater use of meditation (OR = 2.72; 95%CI 1.61–4.58) and exercise/physical therapy (OR = 2.24, 95%CI 1.29–3.88). At 12 months, the intervention arm had a higher physical health measure (mean difference 1.63; 95%CI: 0.27–2.98). Conclusion This trial evaluated the effectiveness of a primary care intervention in improving patient activation and patient-reported outcomes among adults with chronic pain on long-term opioid therapy. Despite a lack of improvement in patient activation, a brief intervention in primary care can improve outcomes such as depression, overall health, non-pharmacologic pain management, and engagement with the health system. Trial Registration The study was registered on 10/27/14 on ClinicalTrials.gov (NCT02290223).

Abstract Staphylococcus aureus colonizes the nares of approximately 30% of humans, a risk factor for opportunistic infections. To gain insight into S. aureus virulence potential in the spaceflight environment, we analyzed RNA-Seq, cellular proteomics, and metabolomics data from the “Biological Research in Canisters-23” (BRIC-23) GeneLab spaceflight experiment, a mission designed to measure the response of S. aureus to growth in low earth orbit on the international space station. This experiment used Biological Research in Canisters-Petri Dish Fixation Units (BRIC-PDFUs) to grow asynchronous ground control and spaceflight cultures of S. aureus for 48 h. RNAIII, the effector of the Accessory Gene Regulator (Agr) quorum sensing system, was the most highly upregulated gene transcript in spaceflight relative to ground controls. The agr operon gene transcripts were also highly upregulated during spaceflight, followed by genes encoding phenol-soluble modulins and secreted proteases, which are positively regulated by Agr. Upregulated spaceflight genes/proteins also had functions related to urease activity, type VII-like Ess secretion, and copper transport. We also performed secretome analysis of BRIC-23 culture supernatants, which revealed that spaceflight samples had increased abundance of secreted virulence factors, including Agr-regulated proteases (SspA, SspB), staphylococcal nuclease (Nuc), and EsxA (secreted by the Ess system). These data also indicated that S. aureus metabolism is altered in spaceflight conditions relative to the ground controls. Collectively, these data suggest that S. aureus experiences increased quorum sensing and altered expression of virulence factors in response to the spaceflight environment that may impact its pathogenic potential.

Abstract Despite the increasing availability of tandem mass spectrometry (MS/MS) community spectral libraries for untargeted metabolomics over the past decade, the majority of acquired MS/MS spectra remain uninterpreted. To further aid in interpreting unannotated spectra, we created a nearest neighbor suspect spectral library, consisting of 87,916 annotated MS/MS spectra derived from hundreds of millions of MS/MS spectra originating from published untargeted metabolomics experiments. Entries in this library, or “suspects,” were derived from unannotated spectra that could be linked in a molecular network to an annotated spectrum. Annotations were propagated to unknowns based on structural relationships to reference molecules using MS/MS-based spectrum alignment. We demonstrate the broad relevance of the nearest neighbor suspect spectral library through representative examples of propagation-based annotation of acylcarnitines, bacterial and plant natural products, and drug metabolism. Our results also highlight how the library can help to better understand an Alzheimer’s brain phenotype. The nearest neighbor suspect spectral library is openly available for download or for data analysis through the GNPS platform to help investigators hypothesize candidate structures for unknown MS/MS spectra in untargeted metabolomics data.

Introduction: Transgender and nonbinary (TGNB) individuals are highly stigmatized members of society and are significantly at higher risk of having mood or anxiety-related disorders compared to non-TGNB individuals. Methods: In this retrospective cohort study, antidepressant prescribing data were collected from TGNB adults diagnosed with gender dysphoria (GD) and mood or anxiety-related disorder between January 2005 and October 2021. The primary outcome was to compare the number of active outpatient antidepressant prescriptions at the time of GD diagnosis between gender identities. The secondary outcomes were to compare antidepressant class utilization between gender identities as well as the prevalence of concurrent mood or anxiety-related disorder diagnoses between gender identities. Results: Of 131 patients who met inclusion criteria, there was no significant difference in number of active antidepressant prescriptions between gender identities at the time of the GD diagnosis (p = .357). However, transgender females were prescribed bupropion at significantly higher rates than other gender identities (p = .046). Approximately 38% of patients did not have an active antidepressant prescription at the time of GD diagnosis despite concurrent mood or anxiety-related diagnoses. The prevalence of generalized anxiety disorder was significantly greater among transgender males (p = .044). Discussion: Although the number of active antidepressant prescriptions between gender identities were similar in this study, we found 38% of patients were not prescribed any antidepressants at time of GD and mood or anxiety-related disorders. This serendipitous finding elucidates a potential gap in mental health care among transgender adults.

The coronavirus disease 2019 (COVID-19) pandemic significantly impacted pharmacy students’ education and well-being. The primary aim of this study was to evaluate the effects of the pandemic on students’ perceived stress by comparing third- and fourth-year students from the pre-pandemic Class of 2019 with mid-pandemic Class of 2021 at two public institutions. Secondary aims were to evaluate the pandemic effects on students’ academic and professional development skills and practice readiness. The Perceived Stress Scale (PSS) and the Brief Coping Orientation to Problems Experienced (COPE) scale were used to measure student well-being. Students’ self-rated problem-solving, time management, and study skills were used to measure their academic and professional development; practice readiness was measured using students’ self-rated confidence levels. PSS scores were significantly higher in mid-pandemic than pre-pandemic students, and the Brief COPE avoidant coping subscale differed between pre-pandemic and mid-pandemic students. No differences were found in any academic and professional development skills between the pre- and mid-pandemic students, and there were significant improvements in student confidence levels for practice readiness among the mid-pandemic students. In conclusion, the pandemic appeared to affect students’ stress and avoidant coping mechanism but had variable effects on academic and professional development and practice readiness.

BackgroundDespite the availability of various dietary assessment tools, there is a need for a tool aligned with the needs of lifestyle medicine (LM) physicians. Such a tool would be brief, aimed at use in a clinical setting, and focused on a “food as medicine” approach consistent with recommendations for a diet based predominately on whole plant foods. The objective of this study is to describe the development and initial pilot testing of a brief, dietary screener to assess the proportion of whole, unrefined plant foods and water relative to total food and beverage intake.MethodsA multidisciplinary study team led the screener development, providing input on the design and food/beverage items included, and existing published dietary assessment tools were reviewed for relevance. Feedback was solicited from LM practitioners in the form of a cross-sectional survey that captured information on medical practice, barriers, and needs in assessing patients’ diets, in addition to an opportunity to complete the screener and provide feedback on its utility. The study team assessed feedback and revised the screener accordingly, which included seeking and incorporating feedback on additional food items to be included from subject matter experts in specific cultural and ethnic groups in the United States. The final screener was submitted for professional design, and scoring was developed.ResultsOf 539 total participants, the majority reported assessing diet either informally (62%) or formally (26%) during patient encounters, and 73% reported discussing diet with all or most of their patients. Participants also reported facing barriers (80%) to assessing diet. Eighty-eight percent believed the screener was quick enough to use in a clinical setting, and 68% reported they would use it.ConclusionThe ACLM Diet Screener was developed through iterative review and pilot testing. The screener is a brief, 27-item diet assessment tool that can be successfully used in clinical settings to track patient dietary intakes, guide clinical conversations, and support nutrition prescriptions. Pilot testing of the screener found strong alignment with clinician needs for assessing a patient’s intake of whole plant food and water relative to the overall diet. Future research will involve pilot testing the screener in clinical interventions and conducting a validation study to establish construct validity.

Summary: The gastrointestinal (GI) tract is innervated by intrinsic neurons of the enteric nervous system (ENS) and extrinsic neurons of the central nervous system and peripheral ganglia. The GI tract also harbors a diverse microbiome, but interactions between the ENS and the microbiome remain poorly understood. Here, we activate choline acetyltransferase (ChAT)-expressing or tyrosine hydroxylase (TH)-expressing gut-associated neurons in mice to determine effects on intestinal microbial communities and their metabolites as well as on host physiology. The resulting multi-omics datasets support broad roles for discrete peripheral neuronal subtypes in shaping microbiome structure, including modulating bile acid profiles and fungal colonization. Physiologically, activation of either ChAT+ or TH+ neurons increases fecal output, while only ChAT+ activation results in increased colonic contractility and diarrhea-like fluid secretion. These findings suggest that specific subsets of peripherally activated neurons differentially regulate the gut microbiome and GI physiology in mice without involvement of signals from the brain.

Background Distal transradial access (dTRA) is an alternative to conventional forearm transradial access (fTRA) for coronary angiography (CAG). Differences in healing of the radial artery (RA) in the forearm have not been evaluated between these 2 access strategies. We sought to compare the mean difference in forearm RA intimal‐medial thickening (IMT) in patients randomized to dTRA versus fTRA. Methods and Results In this single‐center randomized clinical trial, 64 patients undergoing nonemergent CAG were randomized (1:1) to dTRA versus fTRA. Ultra–high‐resolution (55‐MHz) vascular ultrasound of the forearm and distal RA was performed pre‐CAG and at 90 days. The primary end point was the mean change in forearm RA IMT. Secondary end points included procedural characteristics, vascular injury, RA occlusion, and ipsilateral hand pain and function. Baseline demographics and clinical characteristics, mean forearm RA IMT, and procedural specifics were similar between the dTRA and fTRA cohorts. There was no difference in mean change in forearm RA IMT between the 2 cohorts (0.07 versus 0.07 mm; P=0.37). No RA occlusions or signs of major vascular injury were observed at 90 days. Ipsilateral hand pain and function (Borg pain scale score: 12 versus 11; P=0.24; Disabilities of the Arm, Shoulders, and Hand scale score: 6 versus 8; P=0.46) were comparable. Conclusions Following CAG, dTRA was associated with no differences in mean change of forearm RA IMT, hand pain, and function versus fTRA for CAG. Further investigation is warranted to elucidate mechanisms and predictors of RA healing and identify effective strategies to preserving RA integrity for repeated procedures. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04801901.

Background: The beneficial properties of wine by-products include actions that help prevent and treat cardiovascular conditions such as hypertension, primarily due to their antioxidant effects. Novel pharmacotherapies are being developed to treat arterial hypertension, including investigations into natural products exhibiting biological activity, necessitating rigorous evaluation of their efficacy and safety. This study aimed to identify and quantify phenolic compounds in Syrah (Vitis vinifera) grapes grown in the Brazilian Cerrado and their presence in winemaking by-products. It also examined the effects of grape pomace on blood pressure. Methods: Fresh grapes, pomace, and lees, were subjected to spectrophotometric determination of total phenolic compounds, followed by identification and quantification using HPLC-DAD-ESI-MSn. Normotensive male rats (Wistar) and spontaneously hypertensive rats (SHR) received grape pomace-enriched (150 or 300 mg/kg/day, 14 days) or standard chow. Indirect arterial pressure was assessed, while vascular reactivity was evaluated in mesenteric resistance arteries. Results: Pomace samples exhibited higher total phenolic compound concentrations than grapes or lees. Seven derivatives of hydroxycinnamic acids and twenty-one flavonols were identified. Quercetin-3-glucoside and ethyl caffeate were the most abundant phenolic compounds. Grape pomace-enriched chow demonstrated a dose-dependent hypotensive effect in rats. Conclusion: the abundance of flavonols and hydroxycinnamic acids, combined with their hypotensive effects, underscores the therapeutic potential of fine wine-making by-products produced in the Brazilian Cerrado.

Understanding the relationship between the intake of sugars and diet quality can inform public health recommendations. This systematic review synthesized recent literature on associations between sugar intake and diet quality in generally healthy populations aged 2 years or older. We searched databases from 2010 to 2022 for studies of any design examining associations between quantified sugar intake in the daily diet and dietary indexes (DIs) or micronutrient intakes. Different sugar types and diet quality measures were analyzed separately. We converted DI results to Pearson’s r correlations and grouped indexes with or without a free or added sugar component to facilitate cross-study comparisons. Meta-analysis was deemed inappropriate. From 13,869 screened records, we included 27 cross-sectional studies. NUQUEST risk of bias ratings were neutral (n = 18 studies) or poor (n = 9), and strength of evidence by the GRADE approach was very low due to study design. Most studies reported negative associations for added and free sugars with diet quality indexes (r ranging from −0.13 to −0.42) and nutrients of public health concern (fiber, vitamin D, calcium, potassium), while associations with total sugars were mixed. Due to cross-sectional study designs, the clinical relevance of these findings is unclear. Prospective studies are needed to minimize confounding and inform causal relationships.

Abstract Background The murine CBA/J mouse model widely supports immunology and enteric pathogen research. This model has illuminated Salmonella interactions with the gut microbiome since pathogen proliferation does not require disruptive pretreatment of the native microbiota, nor does it become systemic, thereby representing an analog to gastroenteritis disease progression in humans. Despite the value to broad research communities, microbiota in CBA/J mice are not represented in current murine microbiome genome catalogs. Results Here we present the first microbial and viral genomic catalog of the CBA/J murine gut microbiome. Using fecal microbial communities from untreated and Salmonella-infected, highly inflamed mice, we performed genomic reconstruction to determine the impacts on gut microbiome membership and functional potential. From high depth whole community sequencing (~ 42.4 Gbps/sample), we reconstructed 2281 bacterial and 4516 viral draft genomes. Salmonella challenge significantly altered gut membership in CBA/J mice, revealing 30 genera and 98 species that were conditionally rare and unsampled in non-inflamed mice. Additionally, inflamed communities were depleted in microbial genes that modulate host anti-inflammatory pathways and enriched in genes for respiratory energy generation. Our findings suggest decreases in butyrate concentrations during Salmonella infection corresponded to reductions in the relative abundance in members of the Alistipes. Strain-level comparison of CBA/J microbial genomes to prominent murine gut microbiome databases identified newly sampled lineages in this resource, while comparisons to human gut microbiomes extended the host relevance of dominant CBA/J inflammation-resistant strains. Conclusions This CBA/J microbiome database provides the first genomic sampling of relevant, uncultivated microorganisms within the gut from this widely used laboratory model. Using this resource, we curated a functional, strain-resolved view on how Salmonella remodels intact murine gut communities, advancing pathobiome understanding beyond inferences from prior amplicon-based approaches. Salmonella-induced inflammation suppressed Alistipes and other dominant members, while rarer commensals like Lactobacillus and Enterococcus endure. The rare and novel species sampled across this inflammation gradient advance the utility of this microbiome resource to benefit the broad research needs of the CBA/J scientific community, and those using murine models for understanding the impact of inflammation on the gut microbiome more generally. Video Abstract

Abstract Activating point mutations in Anaplastic Lymphoma Kinase (ALK) have positioned ALK as the only mutated oncogene tractable for targeted therapy in neuroblastoma. Cells with these mutations respond to lorlatinib in pre-clinical studies, providing the rationale for a first-in-child Phase 1 trial (NCT03107988) in patients with ALK-driven neuroblastoma. To track evolutionary dynamics and heterogeneity of tumors, and to detect early emergence of lorlatinib resistance, we collected serial circulating tumor DNA samples from patients enrolled on this trial. Here we report the discovery of off-target resistance mutations in 11 patients (27%), predominantly in the RAS-MAPK pathway. We also identify newly acquired secondary compound ALK mutations in 6 (15%) patients, all acquired at disease progression. Functional cellular and biochemical assays and computational studies elucidate lorlatinib resistance mechanisms. Our results establish the clinical utility of serial circulating tumor DNA sampling to track response and progression and to discover acquired resistance mechanisms that can be leveraged to develop therapeutic strategies to overcome lorlatinib resistance.

ABSTRACTWhile wetlands are major sources of biogenic methane (CH4), our understanding of resident microbial metabolism is incomplete, which compromises the prediction of CH4 emissions under ongoing climate change. Here, we employed genome-resolved multi-omics to expand our understanding of methanogenesis in the thawing permafrost peatland of Stordalen Mire in Arctic Sweden. In quadrupling the genomic representation of the site’s methanogens and examining their encoded metabolism, we revealed that nearly 20% of the metagenome-assembled genomes (MAGs) encoded the potential for methylotrophic methanogenesis. Further, 27% of the transcriptionally active methanogens expressed methylotrophic genes; for Methanosarcinales and Methanobacteriales MAGs, these data indicated the use of methylated oxygen compounds (e.g., methanol), while for Methanomassiliicoccales, they primarily implicated methyl sulfides and methylamines. In addition to methanogenic methylotrophy, >1,700 bacterial MAGs across 19 phyla encoded anaerobic methylotrophic potential, with expression across 12 phyla. Metabolomic analyses revealed the presence of diverse methylated compounds in the Mire, including some known methylotrophic substrates. Active methylotrophy was observed across all stages of a permafrost thaw gradient in Stordalen, with the most frozen non-methanogenic palsa found to host bacterial methylotrophy and the partially thawed bog and fully thawed fen seen to house both methanogenic and bacterial methylotrophic activities. Methanogenesis across increasing permafrost thaw is thus revised from the sole dominance of hydrogenotrophic production and the appearance of acetoclastic at full thaw to consider the co-occurrence of methylotrophy throughout. Collectively, these findings indicate that methanogenic and bacterial methylotrophy may be an important and previously underappreciated component of carbon cycling and emissions in these rapidly changing wetland habitats.IMPORTANCEWetlands are the biggest natural source of atmospheric methane (CH4) emissions, yet we have an incomplete understanding of the suite of microbial metabolism that results in CH4 formation. Specifically, methanogenesis from methylated compounds is excluded from all ecosystem models used to predict wetland contributions to the global CH4 budget. Though recent studies have shown methylotrophic methanogenesis to be active across wetlands, the broad climatic importance of the metabolism remains critically understudied. Further, some methylotrophic bacteria are known to produce methanogenic by-products like acetate, increasing the complexity of the microbial methylotrophic metabolic network. Prior studies of Stordalen Mire have suggested that methylotrophic methanogenesis is irrelevant in situ and have not emphasized the bacterial capacity for metabolism, both of which we countered in this study. The importance of our findings lies in the significant advancement toward unraveling the broader impact of methylotrophs in wetland methanogenesis and, consequently, their contribution to the terrestrial global carbon cycle.

Summary: Aging increases the risk of age-related diseases, imposing substantial healthcare and personal costs. Targeting fundamental aging mechanisms pharmacologically can promote healthy aging and reduce this disease susceptibility. In this work, we employed transcriptome-based drug screening to identify compounds emulating transcriptional signatures of long-lived genetic interventions. We discovered compound 60 (Cmpd60), a selective histone deacetylase 1 and 2 (HDAC1/2) inhibitor, mimicking diverse longevity interventions. In extensive molecular, phenotypic, and bioinformatic assessments using various cell and aged mouse models, we found Cmpd60 treatment to improve age-related phenotypes in multiple organs. Cmpd60 reduces renal epithelial-mesenchymal transition and fibrosis in kidney, diminishes dementia-related gene expression in brain, and enhances cardiac contractility and relaxation for the heart. In sum, our two-week HDAC1/2 inhibitor treatment in aged mice establishes a multi-tissue, healthy aging intervention in mammals, holding promise for therapeutic translation to promote healthy aging in humans.

Recurrent patellar instability is a rare complication after patellofemoral arthroplasty (PFA) and usually involves a traumatic injury. Medial patellofemoral ligament (MPFL) reconstruction after arthroplasty is a complicated and technically challenging surgical procedure because the lack of patellar bone stock due to resurfacing significantly increases the risk of patellar fracture. We present our surgical technique for revision MPFL reconstruction for recurrent instability after PFA. This technical note describes the use of 1.8-mm all-suture anchors for revision MPFL reconstruction in patients with decreased patellar bone stock after PFA. This technique reduces the risk of patellar fracture without compromising the integrity of the MPFL graft.

Objectives: This study was designed to understand the experience and needs surrounding advance care planning (ACP) discussions for surrogate decision-makers of persons with advanced dementia (PWAD). Methods: Semi-structured qualitative interviews based on end-of-life communication models with a convenience sample of 17 clinicians, and 15 surrogates of PWAD. We used a hybrid approach of deductive and inductive thematic analysis. Results: Two main themes emerged. 1)Deficits in communication: Often surrogates did not fully comprehend the disease trajectory or medical treatments, like the likelihood of pneumonia and use of mechanical ventilation, nor concepts related to ACP, particularly legal documents and orders such as Do Not Hospitalize, which made decision-making challenging as perceived by clinicians. 2)Decision-making conflicts: Clinicians perceived a disconnect between surrogates' understanding of their loved one's preferences and knowing how or when to operationalize them. Conclusions: Significant gaps in knowledge surrounding disease trajectory and complications, such as pneumonia, and aspects of ACP, exist. These gaps create decision-making challenges for surrogates and clinicians alike. Innovation: This study assessed both clinicians and surrogate decision-makers' perspectives on communication and decision-making concerning care preferences, goals, and ACP. The study findings from a national cohort can inform decision-support interventions for clinicians and surrogate decision-makers of PWAD.

ABSTRACTPediatric patients with high-risk neuroblastoma often relapse with chemotherapy-resistant, incurable disease. Relapsed neuroblastomas harbor chemo-resistant mesenchymal tumor cells and increased expression/activity of the transcriptional co-regulator, the Yes-Associated Protein (YAP). Patients with relapsed neuroblastoma are often treated with immunotherapy such as the anti-GD2 antibody, dinutuximab, in combination with chemotherapy. We have previously shown that YAP mediates both chemotherapy and MEK inhibitor resistance in relapsed RAS mutated neuroblastoma and so posited that YAP might also be involved in anti-GD2 antibody resistance. We now show that YAP genetic inhibition significantly enhances sensitivity of mesenchymal neuroblastomas to dinutuximab and gamma delta (γδ) T cells both in vitro and in vivo. Mechanistically, YAP inhibition induces increased GD2 cell surface expression through upregulation of ST8SIA1, the gene encoding GD3 synthase and the rate-limiting enzyme in GD2 biosynthesis. The mechanism of ST8SIA1 suppression by YAP is independent of PRRX1 expression, a mesenchymal master transcription factor, suggesting YAP may be the downstream effector of mesenchymal GD2 resistance. These results therefore identify YAP as a therapeutic target to augment GD2 immunotherapy responses in patients with neuroblastoma.

Locally advanced cholangiocarcinoma has a poor prognosis, with long-term survival only for patients where complete surgical resection is achieved. Median overall survival with chemotherapy alone is less than 1 year. Novel strategies combining conventional chemotherapy and radiotherapy followed by targeted agents can lead to durable treatment responses and are applicable to cholangiocarcinoma management. Pediatric cholangiocarcinoma is exceedingly rare, with an estimate of 15–22 cases reported in the last 40 years. As such, no standard therapeutic regimen exists. We present a case of a 16-year-old previously healthy patient with unresectable cholangiocarcinoma whose tumor genetic sequencing revealed a novel, actionable neuregulin-1 (NRG1) gene translocation. The patient underwent standard systemic chemotherapy with gemcitabine and cisplatin followed by hypofractionated proton radiation therapy for local control. The patient then started an oral pan-ERBB (erythroblastic B receptor tyrosine kinases including ErbB1/EGFR, ErbB2/HER2, ErbB3/HER3, ErbB4/HER4) family inhibitor as a maintenance medication, remaining with stable disease and excellent quality of life for over 2 years. This case highlights a novel NRG1 fusion in a rare clinical entity that provided an opportunity to utilize a multimodal therapeutic strategy in the pediatric setting.

Abstract Objective To assess the efficacy of liraglutide 3.0 mg, a glucagon‐like peptide‐1 (GLP‐1) receptor agonist, for binge eating disorder (BED). Methods Adults with a body mass index (BMI) ≥ 27 kg/m2 enrolled in a pilot, 17‐week double‐blind, randomized controlled trial of liraglutide 3.0 mg/day for BED. The primary outcome was number of objective binge episodes (OBEs)/week. Binge remission, weight change, and psychosocial variables were secondary outcomes. Mixed effect models were used for continuous variables, and generalized estimating equations were used for remission rates. Results Participants (n = 27) were 44.2 ± 10.6 years; BMI = 37.9 ± 11.8 kg/m2; 63% women; and 59% White and 41% Black. At baseline, the liraglutide group (n = 13) reported 4.7 ± 0.7 OBEs/week, compared with 3.0 ± 0.7 OBEs/week for the placebo group, p = 0.07. At week 17, OBEs/week decreased by 4.0 ± 0.6 in liraglutide participants and by 2.5 ± 0.5 in placebo participants (p = 0.37, mean difference = 1.2, 95% confidence interval 1.3, 2.0). BED remission rates of 44% and 36%, respectively, did not differ. Percent weight loss was significantly greater in the liraglutide versus the placebo group (5.2 ± 1.0% vs. 0.9 ± 0.7%, p = 0.005). Conclusion Participants in both groups reported reductions in OBEs, with the liraglutide group showing clinically meaningful weight loss. A pharmacy medication dispensing error was a significant limitation of this study. Further research on liraglutide and other GLP‐1 agonists for BED is warranted.

Introduction: Despite the high prevalence of those with mental illnesses, there is a critical shortage of psychiatric providers in the United States. Psychiatric pharmacists are valuable members of the health care team who meet patient care needs, especially those practicing with prescriptive authority (PA). Methods: A cross-sectional electronic survey was administered to Board Certified Psychiatric Pharmacists (BCPPs) and non-BCPP members of the College of Psychiatric and Neurologic Pharmacists. The objective of this study was to compare demographic and practice characteristics between respondents with and without PA. Results: Of the 334 respondents, 155 (46.4%) reported having PA. Those with PA, including those with Veterans Affairs (VA) affiliated PA, had fewer mean number of years of licensure than those without PA (P =.008 and P =.007, respectively). The majority with PA practiced in outpatient settings (53.5%). Respondents with PA (including those with VA-affiliated PA) were more likely to have their positions funded by practice sites (P

Malignant human B cells express autocrine prolactin (PRL), which has the potential to engage the long isoform and intermediate form of the PRL receptor to promote proliferation and/or survival.

Srinath, Xie et al. analyze plasma metabolites present in patients with cerebral cavernous angiomas. Cholic acid and hypoxanthine are found in those with Cavernous Angioma disease whilst arachidonic and linoleic acids are found in Cavernous Angioma patients with symptomatic hemorrhage.

Desferrioxamine B (DFO) is the clinical standard chelator for preparing zirconium-89 labeled antibodies. In the current study, the stabilities of a zirconium-89 labeled panitumumab (PAN; Vectibix®) with three different chelators (DFO, DFO*, and DOTA) were compared. PAN is an anti-HER1/EGFR monoclonal antibody approved by the FDA for the treatment of HER1-expressing colorectal cancers and was used as the model antibody for this study. DFO/DFO* conjugates of PAN were directly radiolabeled with zirconium-89 at room temperature to produce [89Zr]Zr-DFO/DFO*-PAN conjugates following a well-established procedure. A zirconium-89 labeled DOTA-PAN conjugate was prepared by an indirect radiolabeling method. A cyclooctyne-linked DOTA chelator (BCN-DOTA-GA) was first radiolabeled with zirconium-89 at 90 °C under a two-step basic pH adjustment method followed by conjugation with PAN-tetrazene at 37 °C to produce a labeled conjugate, BCN-[89Zr]Zr-DOTA-GA-PAN. High reproducibility of the radiolabeling was observed via this two-step basic pH adjustment. The overall radiochemical yield was 40–50% (n = 12, decay uncorrected) with a radiochemical purity of >95% in 2 h synthesis time. All three conjugates were stable in whole human serum for up to 7 days at 37 °C. The kinetic inertness of the conjugates was assessed against the EDTA challenge. BCN-[89Zr]Zr-DOTA-GA-PAN exhibited excellent inertness followed by [89Zr]Zr-DFO*-PAN. [89Zr]Zr-DFO-PAN displayed the lowest level of inertness.

ABSTRACT Despite the promise of the gut microbiome to predict human health, few studies expose the molecular-scale processes underpinning such forecasts. We mined over 200,000 gut-derived genomes from cultivated and uncultivated microbial lineages to inventory the gut microorganisms and their gene content that control trimethylamine-induced cardiovascular disease. We assigned an atherosclerotic profile to the 6,341 microbial genomes that encoded metabolisms associated with heart disease, creating the Methylated Amine Gene Inventory of Catabolism database (MAGICdb). From microbiome gene expression data sets, we demonstrate that MAGICdb enhanced the recovery of disease-relevant genes and identified the most active microorganisms, unveiling future therapeutic targets. From the feces of healthy and diseased subjects, we show that MAGICdb predicted cardiovascular disease status as effectively as traditional lipid blood tests. This functional microbiome catalog is a public, exploitable resource, designed to enable a new era of microbiota-based therapeutics and diagnostics. IMPORTANCE One of the most-cited examples of the gut microbiome modulating human disease is the microbial metabolism of quaternary amines from protein-rich foods. By-products of this microbial processing promote atherosclerotic heart disease, a leading cause of human mortality globally. Our research addresses current knowledge gaps in our understanding of this microbial metabolism by holistically inventorying the microorganisms and expressed genes catalyzing critical atherosclerosis-promoting and -ameliorating reactions in the human gut. This led to the creation of an open-access resource, the Methylated Amine Gene Inventory of Catabolism database, the first systematic inventory of gut methylated amine metabolism. More importantly, using this resource we deliver here, we show for the first time that these gut microbial genes can predict human disease, paving the way for microbiota-inspired diagnostics and interventions.

ABSTRACT Staphylococcus aureus nitric oxide synthase (saNOS) contributes to oxidative stress resistance, antibiotic tolerance, virulence, and modulation of aerobic and nitrate-based cellular respiration. Despite its involvement in these essential processes, the genetic regulation of nos expression has not been well characterized. 5′ rapid amplification of cDNA ends on nos RNA isolated from S. aureus UAMS-1 (USA200 strain) and AH1263 (USA300 strain) revealed that the nos transcriptional start site mapped to an adenine nucleotide in the predicted Shine-Dalgarno site located 11 bp upstream of the nos ATG start codon, suggesting that the nos transcript may have a leaderless organization or may be subject to processing. The SrrAB two-component system (TCS) was previously identified as a positive regulator of nos RNA levels, and experiments using a β-galactosidase reporter plasmid confirmed that SrrAB is a positive regulator of nos promoter activity. In addition, the quorum-sensing system Agr was identified as a negative regulator of low-oxygen nos expression in UAMS-1, with activity epistatic to SrrAB. Involvement of Agr was strain dependent, as nos expression remained unchanged in an AH1263 agr mutant, which has higher Agr activity compared to UAMS-1. Furthermore, nos promoter activity and RNA levels were significantly stronger in AH1263 relative to UAMS-1 during late-exponential low-oxygen growth, when nos expression is maximal. Global regulators Rex and MgrA were also implicated as negative regulators of low-oxygen nos promoter activity in UAMS-1. Collectively, these results provide new insight into factors that control nos expression. IMPORTANCE Bacterial nitric oxide synthase (bNOS) has recently emerged in several species as a key player in resistance to stresses commonly encountered during infection. Although Staphylococcus aureus (sa)NOS has been suggested to be a promising drug target in S. aureus, an obstacle to this in practice is the existence of mammalian NOS, whose oxygenase domain is like bacterial NOS. Increased understanding of the nos regulatory network in S. aureus could allow targeting of saNOS through its regulators, bypassing the issue of also inhibiting mammalian NOS. Furthermore, the observed strain-dependent differences in S. aureus nos regulation presented in this study reinforce the importance of studying bacterial NOS regulation and function at both the strain and species levels.

IntroductionThis study focuses on the impact of the COVID-19 pandemic on international students' overall experiences.MethodWe interviewed 22 international students from 11 countries and 17 universities in the US who participated in a large longitudinal study that aims to understand the physical and emotional wellbeing of young adults during the COVID-19 pandemic. Guided by Bronfenbrenner's ecological model, the findings suggested that students were impacted by the COVID-19 pandemic at interpersonal, institutional, political, and personal levels.ResultsThe results showed that the pandemic exacerbated existing stressors such as the lack of social support from family, various visa regulations, competitive and limited job opportunities, discrimination and xenophobia, particularly toward students from Asia, and financial burdens. Additionally, the findings highlighted students' perceived loss of the “American dream” and the uneven return on investment due to the pandemic.DiscussionThis study reveals the importance of US higher education institutions in supporting international students during the pandemic, particularly in terms of their sense of belonging. Recommendations for institutions drawn from the findings are proposed to better support international students during times of COVID-19 and beyond.

Although river ecosystems constitute a small fraction of Earth’s total area, they are critical modulators of microbially and virally orchestrated global biogeochemical cycles. However, most studies either use data that is not spatially resolved or is collected at timepoints that do not reflect the short life cycles of microorganisms. To address this gap, we assessed how viral and microbial communities change over a 48-hour period by sampling surface water and pore water compartments of the wastewater-impacted River Erpe in Germany. We sampled every 3 hours resulting in 32 samples for which we obtained metagenomes along with geochemical and metabolite measurements. From our metagenomes, we identified 6,500 viral and 1,033 microbial metagenome assembled genomes (MAGs) and found distinct community membership and abundance associated with each river compartment (e.g., Competibacteraceae in surfacewater and Sulfurimonadaceae in pore water). We show that 17% of our viral MAGs clustered to viruses from other ecosystems like wastewater treatment plants and rivers. Our results also indicated that 70% of the viral community was persistent in surface waters, whereas only 13% were persistent in the pore waters taken from the hyporheic zone. Finally, we predicted linkages between 73 viral genomes and 38 microbial genomes. These putatively linked hosts included members of the Competibacteraceae, which we suggest are potential contributors to river carbon and nitrogen cycling via denitrification and nitrogen fixation. Together, these findings demonstrate that members of the surface water microbiome from this urban river are stable over multiple diurnal cycles. These temporal insights raise important considerations for ecosystem models attempting to constrain dynamics of river biogeochemical cycles.

Memristors (abbreviation of memory and resistor), introduced as the fourth fundamental electrical circuit element, remember the electric charge that flowed through it. These nonlinear elements are considered as a class of two terminal resistive devices and offers a lot of possible applications in various areas. In this article, we review the dynamical behaviour of some electrical circuits with memristors. Initially, we show that a simple circuit with a capacitor and an inductor connected to a memristor exhibits periodic and chaotic attractors. After that, we show that the known Chua circuit, with a nonlinear resistance, can generate bifurcations and chaos. Substituting the nonlinear resistance by a memristor, the modified Chua circuit exhibits coexistence of attractors. Another known circuit, the Colpitts, is made of a combination of capacitors and inductors containing a bipolar junction transistor. We show that the modified Colpitts circuit, created by substituting the transistor by a memristor, presents multistability and coexistence of many attractors.

This research article reports results of a study centered on an undergraduate instructor who facilitated a practice- based field experience with undergraduate preservice teachers (n=125) in an urban museum setting, working with middle school students with a public museum school. In addition to exploring this practice-based field experience, we also examined ways the setting functioned as a third space for teaching and learning. Also discussed are some of the changes the instructor made to maximize student learning in this third space. Results indicate that implementing practice-based learning in undergraduate education serves to extend and support teaching and learning. Moreover, practice-based learning experiences provide additional learning opportunities, including connecting undergraduates’ chosen careers with professionals working in the field. The outcomes of this study also indicate that when implementing and facilitating practice-based learning opportunities there are some pedagogical shifts instructors will need to make, including increasing one’s flexibility and adaptability as well as intentionally utilizing the additional third space(s) as text and teacher, when and where possible.

Abstract Background Pulmonary vascular abnormalities pose a risk for severe life-threatening hemodynamic disturbances following surgical repair of congenital cardiac communications (CCCs). In the distal lung, small airways and vessels share a common microenvironment, where biological crosstalks take place. Because respiratory cells infected by viruses express a number of molecules with potential impact on airway and vascular remodeling, we decided to test the hypothesis that CCC patients carrying viral genomes in the airways might be at a higher risk for pulmonary (and systemic) hemodynamic disturbances postoperatively. Methods Sixty patients were prospectively enrolled (age 11 [7–16] months, median with interquartile range). Preoperative pulmonary/systemic mean arterial pressure ratio (PAP/SAP) was 0.78 (0.63–0.88). The presence or absence of genetic material for respiratory viruses in nasopharyngeal and tracheal aspirates was investigated preoperatively in the absence of respiratory symptoms using real-time polymerase chain reaction (kit for detection of 19 pathogens). Post-cardiopulmonary bypass (CPB) inflammatory reaction was analyzed by measuring serum levels of 36 inflammatory proteins (immunoblotting) 4 h after its termination. Postoperative hemodynamics was assessed using continuous recording of PAP and SAP with calculation of PAP/SAP ratio. Results Viral genomes were detected in nasopharynx and the trachea in 64% and 38% of patients, respectively. Rhinovirus was the most prevalent agent. The presence of viral genomes in the trachea was associated with an upward shift of postoperative PAP curve (p = 0.011) with a PAP/SAP of 0.44 (0.36–0.50) in patients who were positive versus 0.34 (0.30–0.45) in those who were negative (p = 0.008). The presence or absence of viral genomes in nasopharynx did not help predict postoperative hemodynamics. Postoperative PAP/SAP was positively correlated with post-CPB levels of interleukin-1 receptor antagonist (p = 0.026), macrophage migration inhibitory factor (p = 0.019) and monocyte chemoattractant protein-1 (p = 0.031), particularly in patients with virus-positive tracheal aspirates. Conclusions Patients with CCCs carrying respiratory viral genomes in lower airways are at a higher risk for postoperative pulmonary hypertension, thus deserving special attention and care. Preoperative exposure to respiratory viruses and post-CPB inflammatory reaction seem to play a combined role in determining the postoperative behavior of the pulmonary circulation.

Abstract Glioblastoma is a prevalent malignant brain tumor and despite clinical intervention, tumor recurrence is frequent and usually fatal. Genomic investigations have provided a greater understanding of molecular heterogeneity in glioblastoma, yet there are still no curative treatments, and the prognosis has remained unchanged. The aggressive nature of glioblastoma is attributed to the heterogeneity in tumor cell subpopulations and aberrant microvascular proliferation. Ganglioside-directed immunotherapy and membrane lipid therapy have shown efficacy in the treatment of glioblastoma. To truly harness these novel therapeutics and develop a regimen that improves clinical outcome, a greater understanding of the altered lipidomic profiles within the glioblastoma tumor microenvironment is urgently needed. In this work, high resolution mass spectrometry imaging was utilized to investigate lipid heterogeneity in human glioblastoma samples. Data presented offers the first insight into the histology-specific accumulation of lipids involved in cell metabolism and signaling. Cardiolipins, phosphatidylinositol, ceramide-1-phosphate, and gangliosides, including the glioblastoma stem cell marker, GD3, were shown to differentially accumulate in tumor and endothelial cell subpopulations. Conversely, a reduction in sphingomyelins and sulfatides were detected in tumor cell regions. Cellular accumulation for each lipid class was dependent upon their fatty acid residue composition, highlighting the importance of understanding lipid structure–function relationships. Discriminating ions were identified and correlated to histopathology and Ki67 proliferation index. These results identified multiple lipids within the glioblastoma microenvironment that warrant further investigation for the development of predictive biomarkers and lipid-based therapeutics.

Abstract The current study utilized eye-tracking to investigate the effects of intersensory redundancy and language on infant visual attention and detection of a change in prosody in audiovisual speech. Twelve-month-old monolingual English-learning infants viewed either synchronous (redundant) or asynchronous (non-redundant) presentations of a woman speaking in native or non-native speech. Halfway through each trial, the speaker changed prosody from infant-directed speech (IDS) to adult-directed speech (ADS) or vice versa. Infants focused more on the mouth of the speaker on IDS trials compared to ADS trials regardless of language or intersensory redundancy. Additionally, infants demonstrated greater detection of prosody changes from IDS speech to ADS speech in native speech. Planned comparisons indicated that infants detected prosody changes across a broader range of conditions during redundant stimulus presentations. These findings shed light on the influence of language and prosody on infant attention and highlight the complexity of audiovisual speech processing in infancy.