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Background & Aims: Metabolic-dysfunction associated steatohepatitis (MASH) is associated with obesity and diabetes, and is linked to liver fibrosis and cardiovascular disease. Identification of patients who have MASH is challenging and the development of non-invasive strategies to diagnose and follow this condition is an important unmet need. Recent studies in mouse and humans have identified that significant changes occur in liver macrophage composition during MASH progression; namely, resident Kupffer cells decrease in number while recruited monocyte-derived macrophages increase. Methods: We developed peptide radiotracers targeted to C–C motif chemokine receptor 2 (CCR2) and CD163 to conduct positron emission tomography (PET) imaging of recruited vs. resident macrophages, respectively. Mice were placed on a MASH-inducing diet and non-invasive PET imaging of the liver was performed with tissue confirmation studies using flow cytometry and immunofluorescence. Statistical analyses were conducted using Student’s t tests, Pearson correlational analysis, and linear regression. Results: Using a mouse model of MASH, we found that the liver uptake of both CCR2 and CD163 radiotracers detected an increase in recruited cells and a decrease in resident macrophages. These findings correlated well with tissue macrophage content assessed by flow cytometry with an r value of 0.77 (p = 0.002) and 0.78 (p = 0.001) for CCR2 and CD163, respectively. Serial imaging with these radiotracers at several time points during MASH progression and regression revealed good correlation between liver macrophage composition and PET signal intensity. Conclusion: We demonstrate that novel PET radiotracers targeting CCR2 and CD163 can be used to image macrophage composition in MASH. Non-invasive molecular imaging of inflammation has the potential for diagnosis and monitoring of disease activity in humans with MASH. Impact and implications:: Macrophage-mediated inflammation contributes to MASH progression and fibrosis; however, liver biopsy is currently the only tool to assess this response. Thus, the development of non-invasive imaging modalities to identify and follow inflammatory activation is an area of need for patient care. In this study, we leverage molecular imaging using PET radiotracers to follow changes in macrophage composition that are related to MASH disease activity. The results in our preclinical model provide important proof of concept evidence that this approach can be used to diagnose MASH and to follow disease activity in response to intervention. Ongoing studies will evaluate the utility of this modality in humans with MASH.

Abstract Iron-sulfur clusters are essential for life and defects in their biosynthesis lead to human diseases. The mechanism of cluster assembly and delivery to cytosolic and nuclear client proteins via the cytosolic iron-sulfur cluster assembly (CIA) pathway is not well understood. Here we report cryo-EM structures of the HEAT-repeat protein Met18 from Saccharomyces cerevisiae, a key component of the CIA targeting complex (CTC) that identifies cytosolic and nuclear client proteins and delivers a mature iron-sulfur cluster. We find that in the absence of other CTC proteins, Met18 adopts tetrameric and hexameric states. Using mass photometry and negative stain EM, we show that upon the addition of Cia2, these higher order oligomeric states of Met18 disassemble. We also use pulldown assays to identify residues of critical importance for Cia2 binding and recognition of the Leu1 client, many of which are buried when Met18 oligomerizes. Our structures show conformations of Met18 that have not been previously observed in any Met18 homolog, lending support to the idea that a highly flexible Met18 may be key to how the CTC is able to deliver iron-sulfur clusters to client proteins of various sizes and shapes, i.e. Met18 conforms to the dimensions needed.

The ongoing COVID-19 pandemic is causing significant morbidity and mortality across the US. In this ecological study, we identified county-level variables associated with the COVID-19 case-fatality rate (CFR) using publicly available datasets and a negative binomial generalized linear model. Variables associated with decreased CFR included a greater number of hospitals per 10,000 people, banning religious gatherings, a higher percentage of people living in mobile homes, and a higher percentage of uninsured people. Variables associated with increased CFR included a higher percentage of the population over age 65, a higher percentage of Black or African Americans, a higher asthma prevalence, and a greater number of hospitals in a county. By identifying factors that are associated with COVID-19 CFR in US counties, we hope to help officials target public health interventions and healthcare resources to locations that are at increased risk of COVID-19 fatalities.

We prove that an integral domain D is pseudo-Dedekind if and only if it satisfies a certain "Gauss's lemma for power series": c (f g) v = c (f) v c (g) v for all power series f and g over D in any (possibly infinite) number of indeterminates, where c (f) v denotes the v-closure of the content of f. We generalize this fact via semistar operations, coefficient rings with zero divisors, and fractional (semi)regular contents. Along the way, we prove several other new facts about (semistar) power series content formulas, generalizing as above on known results about Prüfer (v-multiplication) domains, (completely) integrally closed domains, and (generalized) GCD domains. [ABSTRACT FROM AUTHOR]

Introduction: This study explores using Neural Ordinary Differential Equations (NODEs) to analyze hormone dynamics in the hypothalamicpituitary-adrenal (HPA) axis during Trier Social Stress Tests (TSST) to classify patients with Major Depressive Disorder (MDD).Methods: Data from TSST were used, measuring plasma ACTH and cortisol concentrations. NODE models replicated hormone changes without prior knowledge of the stressor. The derived vector fields from NODEs were input into a Convolutional Neural Network (CNN) for patient classification, validated through cross-validation (CV) procedures.Results: NODE models effectively captured system dynamics, embedding stress effects in the vector fields. The classification procedure yielded promising results, with the 1x1 CV achieving an AUROC score that correctly identified 83% of Atypical MDD patients and 53% of healthy controls. The 2x2 CV produced similar outcomes, supporting model robustness.Discussion: Our results demonstrate the potential of combining NODEs and CNNs to classify patients based on disease state, providing a preliminary step towards further research using the HPA axis stress response as an objective biomarker for MDD.

Abstract Introduction This study aimed to characterize patient-reported outcomes from social media conversations in the gout community. The impact of management strategy differences on the community’s emotional states was explored. Methods We analyzed two social media sources using a variety of natural language processing techniques. We isolated conversations with a high probability of discussing disease management (score > 0.99). These conversations were stratified by management type: proactive or reactive. The polarity (positivity/negativity) of language and emotions conveyed in statements shared by community members was assessed by management type. Results Among the statements related to management, reactive management (e.g., urgent care) was mentioned in 0.5% of statements, and proactive management (e.g., primary care) was mentioned in 0.6% of statements. Reactive management statements had a significantly larger proportion of negative words (59%) than did proactive management statements (44%); “fear” occurred more frequently with reactive statements, whereas “trust” predominated in proactive statements. Allopurinol was the most common medication in proactive management statements, whereas reactive management had significantly higher counts of prednisone/steroid mentions. Conclusions A unique aspect of examining gout-related social media conversations is the ability to better understand the intersection of clinical management and emotional impacts in the gout community. The effect of social media statements was significantly stratified by management type for gout community members, where proactive management statements were characterized by more positive language than reactive management statements. These results suggest that proactive disease management may result in more positive mental and emotional experiences in patients with gout.

Summary: Background: Understanding formation of the human tissue resident memory T cell (TRM) repertoire requires longitudinal access to human non-lymphoid tissues. Methods: By applying flow cytometry and next generation sequencing to serial blood, lymphoid tissue, and gut samples from 16 intestinal transplantation (ITx) patients, we assessed the origin, distribution, and specificity of human TRMs at phenotypic and clonal levels. Findings: Donor age ≥1 year and blood T cell macrochimerism (peak level ≥4%) were associated with delayed establishment of stable recipient TRM repertoires in the transplanted ileum. T cell receptor (TCR) overlap between paired gut and blood repertoires from ITx patients was significantly greater than that in healthy controls, demonstrating increased gut-blood crosstalk after ITx. Crosstalk with the circulating pool remained high for years of follow-up. TCR sequences identifiable in pre-Tx recipient gut but not those in lymphoid tissues alone were more likely to populate post-Tx ileal allografts. Clones detected in both pre-Tx gut and lymphoid tissue had distinct transcriptional profiles from those identifiable in only one tissue. Recipient T cells were distributed widely throughout the gut, including allograft and native colon, which had substantial repertoire overlap. Both alloreactive and microbe-reactive recipient T cells persisted in transplanted ileum, contributing to the TRM repertoire. Interpretation: Our studies reveal human intestinal TRM repertoire establishment from the circulation, preferentially involving lymphoid tissue counterparts of recipient intestinal T cell clones, including TRMs. We have described the temporal and spatial dynamics of this active crosstalk between the circulating pool and the intestinal TRM pool. Funding: This study was funded by the National Institute of Allergy and Infectious Diseases (NIAID) P01 grant AI106697.

"Unique factorization" was central to the initial development of ideal theory. We update this topic with several new results concerning notions of "unique ideal factorization rings" with zero divisors. Along the way, we obtain new characterizations of several well-known kinds of rings in terms of their ideal factorization properties and examine when monoid rings satisfy various kinds of "unique ideal factorization." Our results include necessary and sufficient conditions for a monoid ring R [ S ] with S cancellative to be a π-ring, a higher-dimensional generalization of Hardy and Shores's classic characterization of when R [ S ] is a general Zerlegung Primideale ring. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and accounts for ∼84% of all lung cancer cases. NSCLC remains one of the leading causes of cancer-associated death, with a 5-year survival rate less than 25%. This type of cancer begins with healthy cells that change and start growing out of control, leading to the formation of lesions or tumors. Understanding the dynamics of how the tumor microenvironment promotes cancer initiation and progression that leads to cancer metastasis is crucial to help identify new molecular therapies. 3D primary cell tumor models have received renewed recognition due to their ability to better mimic the complexity of in vivo tumors and as a potential bridge between traditional 2D culture and in vivo studies. Vast improvements in 3D cell culture technologies make them much more cost effective and efficient largely because of the use of a cell-repellent surfaces and a novel angle plate adaptor technology. To exploit this technology, we accessed the Natural Products Library (NPL) at UF Scripps, which consists of crude extracts, partially purified fractions, and pure natural products (NPs). NPs generally are not very well represented in most drug discovery libraries and thus provide new insights to discover leads that could potentially emerge as novel molecular therapies. Herein we describe how we combined these technologies for 3D screening in 1536 well format using a panel of ten NSCLC cells lines (5 wild type and 5 mutant) against ∼1280 selected members of the NPL. After further evaluation, the selected active hits were prioritized to be screened against all 10 NSCLC cell lines as concentration response curves to determine the efficacy and selectivity of the compounds between wild type and mutant 3D cell models. Here, we demonstrate the methods needed for automated 3D screening using microbial NPs, exemplified by crude extracts, partially purified fractions, and pure NPs, that may lead to future use targeting human cancer.

We study the factorization of ideals of a commutative ring, in the context of the U-factorization framework introduced by Fletcher. This leads to several "U-factorability" properties weaker than unique U-factorization. We characterize these notions, determine the implications between them, and give several examples to illustrate the differences. For example, we show that a ring is a general ZPI-ring if and only if its monoid of ideals has unique factorization in the sense of Fletcher. We also examine how these "U-factorability" properties behave with respect to several ring-theoretic constructions. [ABSTRACT FROM AUTHOR]

Background: Lung cancer (LC) care is resource and cost intensive. We launched a Multidisciplinary LC Clinic (MDC), where patients with a new LC diagnosis received concurrent oncology consultation, resulting in improved time to LC assessment and treatment. Here, we evaluate the impact of MDC on health resource utilization, patient and caregiver costs, and secondary patient benefits. Methods: We retrospectively analyzed patients in a rapid assessment clinic with a new LC diagnosis pre-MDC (September 2016–February 2017) and post-MDC implementation (February 2017–December 2018). Data are reported as means; unpaired t-tests and ANOVA were used to assess for significance. We also conducted a cost analysis. Resource utilization, out-of-pocket costs, procedure-related costs, and indirect costs were evaluated from the societal perspective and presented in 2019 Canadian dollars (CAD); multi-way worst/best case and threshold sensitivity analyses were conducted. Results: We reviewed 428 patients (78 traditional model, 350 MDC). Patients in the MDC model required significantly fewer oncology visits from LC diagnosis to first LC treatment (1.62 vs. 2.68, p < 0.001), which was significant for patients with stage 1, 3, and 4 disease. Compared with the traditional model, there was no change in mean biopsies/patient (1.32 traditional vs. 1.17 MDC, p = 0.18) or staging investigations/patient (2.24 traditional vs. 2.02 MDC, p = 0.20). Post-MDC, there was an increase in invasive mediastinal staging for patients with stage 2/3 LC (15.0% vs. 60.0%, p < 0.001). Over 22 months, MDC resulted in savings of CAD 48,389 including CAD 24,167 CAD in direct patient out-of-pocket expenses. For the threshold analyses, MDC was estimated to cost CAD 25,708 per quality-adjusted life year (QALY), considered to be below current willingness to pay thresholds (at CAD 80,000 per QALY). MDC also facilitated oncology assessment for 29 non-LC patients. Conclusions: An MDC led to a reduction in patient visits and direct patient and caregiver costs.

In order for mathematical models to make credible contributions, it is essential for them to be verified and validated. Currently, verification and validation (V&V) of these models does not meet the expectations of the system biology and systems pharmacology communities. Partially as a result of this shortfall, systemic V&V of existing models currently requires a lot of time and effort. In order to facilitate systemic V&V of chosen hypothalamic-pituitary-adrenal (HPA) axis models, we have developed a computational framework named VeVaPy—taking care to follow the recommended best practices regarding the development of mathematical models. VeVaPy includes four functional modules coded in Python, and the source code is publicly available. We demonstrate that VeVaPy can help us efficiently verify and validate the five HPA axis models we have chosen. Supplied with new and independent data, VeVaPy outputs objective V&V benchmarks for each model. We believe that VeVaPy will help future researchers with basic modeling and programming experience to efficiently verify and validate mathematical models from the fields of systems biology and systems pharmacology.

Colpocephaly is a form of congenital ventriculomegaly characterized by enlarged occipital horns of the lateral ventricles with associated neurologic abnormalities. The diagnosis of colpocephaly is typically made in infancy. Its diagnosis in adulthood without associated clinical symptoms is exceptionally rare. We report a case of colpocephaly diagnosed incidentally in an adult without neurologic abnormalities in the emergency department. To our knowledge, this is only the ninth reported case in an asymptomatic adult and the first to be described in the emergency medicine literature.

Identifying misconceptions in student learning is a valuable practice for evaluating student learning gains and directing educational interventions. By accurately identifying students’ knowledge and misconceptions about microbiology concepts, instructors can design effective classroom practices centered on student understanding. Following the development of ASM’s Curriculum Guidelines in 2012, we developed a concept inventory, the Microbiology for Health Sciences Concept Inventory (MHSCI), that measures learning gains and identifies student misconceptions in health sciences microbiology classrooms. The 23-question MHSCI was delivered to a wide variety of students at multiple institution types. Psychometric analysis identified that the MHSCI instrument is both discriminatory and reliable in measuring student learning gains. The MHSCI results correlated with course outcomes, showing the value of using the instrument alongside course level assessments to measure student learning. The MHSCI is a reliable and efficient way to measure student learning in microbiology and can be used both as a faculty development tool and an effective student assessment tool.

People with sickle cell disease (SCD) suffer from numerous acute complications that can result in multiple hospitalizations and emergency department (ED) and outpatient care visits. Priapism, a prolonged unwanted erection of the penis not due to sexual stimulation, is a serious complication among males with SCD. Variations in estimates of prevalence make it difficult to accurately assess the burden of this complication of SCD. We analyzed data from the Nationwide Emergency Department Sample (NEDS), a product of the Healthcare Cost and Utilization Project, for the years 2006 through 2010 to measure the numbers of ED visits and to examine patterns of subsequent hospitalizations associated with priapism among male patients with SCD. We find that among ED visits associated with males with SCD, those prompted by priapism are more likely to result in hospitalization than are those associated with pain.

Background: RRx-001 is a novel NO and hypoxia mediated anticancer agent with epigenetic activity. In the first-in-human, Phase I trial, 5/5 patients who progressed on RRx-001 treatment were resensitized to previously refractory therapy, hinting at a generalized resensitization effect. Aims: A randomized open-label multi-part, multi-center phase II trial of RRx-001 versus regorafenib (ROCKET) has commenced to explore the resensitization and/or ‘episensitization’ potential in irinotecan refractory tumors and its impact on overall survival. Methods: Patients with irinotecan-refractory metastatic colorectal cancer with an ECOG PS 0–1 who progressed on oxaliplatin-, and irinotecan-based regimens with or without bevacizumab, cetuximab or panitumumab are randomized 2:1 to receive RRx-001 16.5mg/m2 IV 1x/week or regorafenib 160mg orally 21 of 28 days until progression or unacceptable toxicity followed by treatment with refractory irinotecan-based therapies. Results: To date, 26 patients have been randomized with 18 patients evaluable for resensitization. Post RRx-001 patients demonstrated marked decreases in CEA in 12/13 patients as compared to 5 patients receiving regorafenib who were too systemically unwell to proceed to subsequent treatment. Progression free survival (ongoing) for RRx-001+irinotecan is 4.9 months compared 1.8 months on Regorafenib+irinotecan. Conclusion: Early results in the ROCKET study suggest that RRx-001-mediated resensitization to previously refractory therapies may have a generalized effect, independent of KRAS or p53 status. These early results are intriguing, suggesting improved QOL and overall survival over currently approved therapy in the chemotherapy refractory colorectal cancer.

This paper describes recent process modifications made to enhance the performance of interline and electron-multiplying charge-coupled-device (EMCCD) image sensors. By use of MeV ion implantation, quantum efficiency in the NIR region of the spectrum was increased by 2×, and image smear was reduced by 6 dB. By reducing the depth of the shallow photodiode (PD) implants, the photodiode-to-vertical-charge-coupled-device (VCCD) transfer gate voltage required for no-lag operation was reduced by 3 V, and the electronic shutter voltage was reduced by 9 V. The thinner, surface pinning layer also resulted in a reduction of smear by 4 dB in the blue portion of the visible spectrum. For EMCCDs, gain aging was eliminated by providing an oxide-only dielectric under its multiplication phase, while retaining the oxide-nitride-oxide (ONO) gate dielectrics elsewhere in the device.

Este artículo explora los esfuerzos realizados para fomentar el mercado y aplicar técnicas de ingeniería constitucional como medios para el cambio liberal en el Irak de posguerra. Al identificar los intereses, tácticas de coerción e ideas previamente asumidas acerca del entorno político en el que se han aplicado estos proyectos, se identifica su culpabilidad en la generación de la situación actual. El articulo profundiza además en como las narrativas contemporáneas de la transición global y de su carácter novedoso articularon una visión del régimen iraquí como fuente de esfuerzos de transformación. Sugiero que esta visión, y los proyectos de revolución y transición forzadas que se basaron en ella, era más atractiva por su lógica interna que por una apreciación realista de la situación en Irak. En ultima instancia, los resultados de los proyectos de neoliberalismo revolucionario y transición en Irak requerirán que hagamos algo mas que señalar los fallos de EE.UU. al implementarlos o las carencias culturales de los iraquíes; estos deberían hacernos considerar las limitaciones de fomentar el mercado y la metodología de transición como técnicas para comprender y actuar sobre el mundo político.

In April 2020, in light of COVID-19-related blood shortages, the US Food and Drug Administration (FDA) reduced the deferral period for men who have sex with men (MSM) from its previous duration of 1 year to 3 months.Although originally born out of necessity, the decades-old restrictions on MSM donors have been mitigated by significant advancements in HIV screening, treatment, and public education. The severity of the ongoing COVID-19 pandemic-and the urgent need for safe blood products to respond to such crises-demands an immediate reconsideration of the 3-month deferral policy for MSM.We review historical HIV testing and transmission evidence, discuss the ethical ramifications of the current deferral period, and examine the issue of noncompliance with donor deferral rules. We also propose an eligibility screening format that involves an individual risk-based screening protocol and, unlike current FDA guidelines, does not effectively exclude donors on the basis of gender identity or sexual orientation. Our policy proposal would allow historically marginalized community members to participate with dignity in the blood donation process without compromising blood donation and transfusion safety outcomes.