Square Parametric Excitation: A Digital Resonant Method for the Quadrupole Ion Trap.

Digital ion trap technology is an alternate method for driving quadrupole ion traps and mass filters using variable frequency, fixed amplitude RF square waves in place of variable amplitude, fixed frequency RF sine waves. This technique offers some advantages such as an increase in the high mass analysis range by varying frequency and lower overall voltage requirements. Here, we present a complex square waveform developed for resonant parametric excitation in a quadrupole linear ion trap. Unlike traditional resonance methods, the driving RF square wave and auxiliary square wave are coupled using the same digital circuitry without the need for transformer coupling. In this work, we use this complex waveform to selectively excite the first order parametric resonances of ion motion. The square parametric excitation method presented here employs a simple and repetitive circuit design consisting of a low-voltage waveform generator followed by a series of high-voltage MOSFET switches. This design allows for resonance methods to be easily implemented in the all-digital quadrupole. The complex square waveform can perform the same useful functions as sine wave auxiliary signals, such as selective mass elimination and mass isolation. We also demonstrate that the mass resolution performance and S/N of our digital mass spectrometer is improved by applying the complex square waveform during ion ejection.

Speckle-free coherent imaging through deep turbulence.

We develop and validate a model-based iterative reconstruction framework for digitally correcting coherent images corrupted by deep turbulence. In general, this framework is applicable to coherent-imaging approaches that gain access to the complex-optical field; however, we demonstrate our approach with multi-shot digital holography data. To test our image correction framework, we generate calibrated deep-turbulence conditions from our laboratory testbed. Using the resulting data, we demonstrate groundbreaking performance in terms of speckle-free image correction in deep-turbulence conditions.

Leaning in and moving forward: a call to action and review of diversity initiatives in SAGES.

BACKGROUND: Diversity, equity, and inclusion have been an intentional focus for SAGES well before the COVID-19 pandemic and the coincident societal recognition of social injustices and racism. Longstanding inequities within our society, healthcare, and the surgery profession have come to light in the aftermath of events that rose to attention around the time of Covid. In so doing, they have brought into focus disparities, injustices, and inequalities that have long been present in the field of surgery, selectively affecting the most vulnerable. METHODS: This White paper examines the current state of diversity within the field of surgery and SAGES (Society of American Gastrointestinal and Endoscopic Surgeons) approach and effort to pave the way forward to meaningful change. We delineate the imperative for diversity, equity, and inclusion for all. By all, we mean to be inclusive of the diversity of gender and sexual orientation, race, ethnicity, geography, sex, and disability in the field of surgery. RESULTS: SAGES is an organization that lives at the intersection of education and innovation. It has a vital role in assisting the surgical profession in addressing these issues and needs and being a force alongside others for sustained and necessary change. SAGES can only realize these goals through a commitment across all aspects of the organization to embed diversity, equity, and inclusion into our very fabric. CONCLUSION: True diversity, equity, and inclusion within a surgical organization is vital for its longevity, growth, relevance, and impact. Unfortunately, the absence of DEI limits opportunity, robs the organization of collective intelligence in an environment in which its presence is critical, contributes to health inequities, and impoverishes all within the society and its value to all with whom it interfaces. SAGES is an organization that lives at the intersection of education and innovation. It has a vital role in assisting the surgical profession in addressing these issues and needs and being a force alongside others for sustained and necessary change. SAGES can only realize these goals through a commitment across all aspects of the organization to embed diversity, equity, and inclusion into our very fabric. Strategies like those highlighted in this White Paper, may be within our grasp and we can learn yet more if we remain in a place of humility and teachability in the future.

RNA Isolation from Human Stem Cell-Derived Retinal Organoids.

RNA isolation is an essential first step for many types of molecular analyses, including reverse transcription PCR (RT-PCR)/quantitative RT-PCR (qRT-PCR), Northern blotting, microarrays, and RNA-sequencing. While many RNA purification methods have been reported, it can be challenging to extract sufficient quantity, and suitable quality, of RNA from very small amounts of tissue and/or samples containing low numbers of cells. Here we outline a total RNA isolation method that reproducibly yields high-quality RNA from human stem cell-derived retinal organoids for downstream transcriptomic analysis.

Adult-born granule cells modulate CA2 network activity during retrieval of developmental memories of the mother.

Adult-born granule cells (abGCs) project to the CA2 region of the hippocampus, but it remains unknown how this circuit affects behavioral function. Here, we show that abGC input to the CA2 of adult mice is involved in the retrieval of remote developmental memories of the mother. Ablation of abGCs impaired the ability to discriminate between a caregiving mother and a novel mother, and this ability returned after abGCs were regenerated. Chemogenetic inhibition of projections from abGCs to the CA2 also temporarily prevented the retrieval of remote mother memories. These findings were observed when abGCs were inhibited at 4-6 weeks old, but not when they were inhibited at 10-12 weeks old. We also found that abGCs are necessary for differentiating features of CA2 network activity, including theta-gamma coupling and sharp wave ripples, in response to novel versus familiar social stimuli. Taken together, these findings suggest that abGCs are necessary for neuronal oscillations associated with discriminating between social stimuli, thus enabling retrieval of remote developmental memories of the mother by their adult offspring.

Activation of Hepatocyte Growth Factor/MET Signaling as a Mechanism of Acquired Resistance to a Novel YAP1/TEAD Small Molecule Inhibitor.

Many tumor types harbor alterations in the Hippo pathway, including mesothelioma, where a high percentage of cases are considered YAP1/TEAD dependent. Identification of autopalmitoylation sites in the hydrophobic palmitate pocket of TEADs, which may be necessary for YAP1 protein interactions, has enabled modern drug discovery platforms to generate compounds that allosterically inhibit YAP1/TEAD complex formation and transcriptional activity. We report the discovery and characterization of a novel YAP1/TEAD inhibitor MRK-A from an aryl ether chemical series demonstrating potent and specific inhibition of YAP1/TEAD activity. In vivo, MRK-A showed a favorable tolerability profile in mice and demonstrated pharmacokinetics suitable for twice daily oral dosing in preclinical efficacy studies. Importantly, monotherapeutic targeting of YAP1/TEAD in preclinical models generated regressions in a mesothelioma CDX model; however, rapid resistance to therapy was observed. RNA-sequencing of resistant tumors revealed mRNA expression changes correlated with the resistance state and a marked increase of hepatocyte growth factor (HGF) expression. In vitro, exogenous HGF was able to fully rescue cytostasis induced by MRK-A in mesothelioma cell lines. In addition, co-administration of small molecule inhibitors of the MET receptor tyrosine kinase suppressed the resistance generating effect of HGF on MRK-A induced growth inhibition. In this work, we report the structure and characterization of MRK-A, demonstrating potent and specific inhibition of YAP1/TAZ-TEAD-mediated transcriptional responses, with potential implications for treating malignancies driven by altered Hippo signaling, including factors resulting in acquired drug resistance.

Broad proteomics analysis of seeding-induced aggregation of α-synuclein in M83 neurons reveals remodeling of proteostasis mechanisms that might contribute to Parkinson's disease pathogenesis.

Aggregation of misfolded α-synuclein (α-syn) is a key characteristic feature of Parkinson's disease (PD) and related synucleinopathies. The nature of these aggregates and their contribution to cellular dysfunction is still not clearly elucidated. We employed mass spectrometry-based total and phospho-proteomics to characterize the underlying molecular and biological changes due to α-syn aggregation using the M83 mouse primary neuronal model of PD. We identified gross changes in the proteome that coincided with the formation of large Lewy body-like α-syn aggregates in these neurons. We used protein-protein interaction (PPI)-based network analysis to identify key protein clusters modulating specific biological pathways that may be dysregulated and identified several mechanisms that regulate protein homeostasis (proteostasis). The observed changes in the proteome may include both homeostatic compensation and dysregulation due to α-syn aggregation and a greater understanding of both processes and their role in α-syn-related proteostasis may lead to improved therapeutic options for patients with PD and related disorders.

Genetic Predisposition to Sarcoma: What Should Clinicians Know?

OPINION STATEMENT: Pathogenic germline variants in the setting of several associated cancer predisposition syndromes (CPS) may lead to the development of sarcoma. We would consider testing for a CPS in patients with a strong family history of cancer, multiple primary malignancies, and/or pediatric/adolescent/young adult patients diagnosed with other malignancies strongly associated with CPS. When a CPS is diagnosed in a patient with sarcoma, additional treatment considerations and imaging options for those patients are required. This applies particularly to the use of radiation therapy, ionizing radiation with diagnostic imaging, and the use of alkylating chemotherapy. As data and guidelines are currently lacking for many of these scenarios, we have adopted a shared decision-making process with patients and their families. If the best chance for cure in a patient with CPS requires utilization of radiation therapy or alkylating chemotherapy, we discuss the risks with the patient but do not omit these modalities. However, if there are treatment options that yield equivalent survival rates, yet avoid these modalities, we elect for those options. Considering staging imaging and post-therapy evaluation for sarcoma recurrence, we avoid surveillance techniques that utilize ionizing radiation when possible but do not completely omit them when their use is indicated.

A comparison of dementia diagnoses and cognitive function measures in Medicare claims and the Minimum Data Set.

BACKGROUND: Gold standard dementia assessments are rarely available in large real-world datasets, leaving researchers to choose among methods with imperfect but acceptable accuracy to identify nursing home (NH) residents with dementia. In healthcare claims, options include claims-based diagnosis algorithms, diagnosis indicators, and cognitive function measures in the Minimum Data Set (MDS), but few studies have compared these. We evaluated the proportion of NH residents identified with possible dementia and concordance of these three. METHODS: Using a 20% random sample of 2018-2019 Medicare beneficiaries, we identified MDS admission assessments for non-skilled NH stays among individuals with continuous enrollment in Medicare Parts A, B, and D. Dementia was identified using: (1) Chronic Conditions Warehouse (CCW) claims-based algorithm for Alzheimer's disease and non-Alzheimer's dementia; (2) MDS active diagnosis indicators for Alzheimer's disease and non-Alzheimer's dementias; and (3) the MDS Cognitive Function Scale (CFS) (at least mild cognitive impairment). We compared the proportion of admissions with evidence of possible dementia using each criterion and calculated the sensitivity, specificity, and agreement of the CCW claims definition and MDS indicators for identifying any impairment on the CFS. RESULTS: Among 346,013 non-SNF NH admissions between 2018 and 2019, 57.2% met criteria for at least one definition (44.7% CFS, 40.7% CCW algorithm, 26.0% MDS indicators). The MDS CFS uniquely identified the greatest proportion with evidence of dementia. The CCW claims algorithm had 63.7% sensitivity and 78.1% specificity for identifying any cognitive impairment on the CFS. Active diagnosis indicators from the MDS had lower sensitivity (47.0%), but higher specificity (91.0%). CONCLUSIONS: Claims- and MDS-based methods for identifying NH residents with possible dementia have only partial overlap in the cohorts they identify, and neither is an obvious gold standard. Future studies should seek to determine whether additional functional assessments from the MDS or prescriptions can improve identification of possible dementia in this population.

Perception of uncontrollable mortality risk is associated with food insecurity and reduced economic effort among resource-insecure college students during COVID-19.

In the framework of the uncontrollable mortality risk hypothesis, resource scarcity intersects with mortality risk, shaping resource allocation strategies with enduring impacts on human health and wellbeing. Despite rising economic and food insecurity among US college students, little is known about how these insecurities relate to mortality risk, or how scarcity and mortality risk interact to shape college students' resource allocation strategies. We examine perceptions of resource scarcity and mortality risk and their associations with food insecurity and resource allocation strategies among economically insecure college students during COVID-19 lockdowns. Participants were recruited through an economic crisis response center at a major public university in the United States. A total of 118 participants completed an online Qualtrics survey assessing sociodemographic characteristics, perceptions of mortality risk and resource availability, food security, economic effort, and time perspective; a subset (n = 51) also participated in a telephone interview assessing psychological distress. In general, participants reported more environmental adversity and economic effort during COVID-19 lockdowns compared to before. Students experiencing higher levels of uncontrollable (and not controllable) mortality risk report lower levels of economic effort, and the association was strongest among students perceiving the fewest resources. We also found significant associations between uncontrollable mortality risk and food insecurity. Our results highlight uncontrollable mortality risk's influence on human well-being. Public health efforts should target the experiences and root structural causes of uncontrollable mortality risk, which among economically insecure college students increasingly involves food insecurity.

Social media influences National Park visitation.

Visitation to National Parks in the United States increased by more than 25% since 2010, rising from roughly 70 to 90 million annual visitors. Anecdotes suggest that this increase was driven by the advent of social media in the early-to-mid 2010s, generating a new form of exposure for parks, and has led to concerns about overcrowding and degradation of environmental quality. However, there is little empirical evidence on the role of social media in influencing recreation decisions. Here, I construct a dataset on social media exposure (SME) for each National Park and relate that exposure to changes in visitation over the last two decades. High SME parks see visitation increase by 16 to 22% relative to parks with less exposure, which comes with a concomitant increase in revenue. Low SME parks have no, or negative, changes in visitation. These estimates account for unobserved park heterogeneity and are based on an instrumental variables strategy that predicts exposure with a park's online popularity prior to the social media era. Additional analysis suggests that recent social media posts that include media attachments increase visitation, while posts with negative sentiment reduce visitation. These results provide insight for the National Park Service-which faces more than $22 billion in deferred maintenance costs and is considering policy options to manage demand-as well as for management of recreation on other public lands.

Erratum: Why do people who stutter attend stuttering support groups?

No abstract available.

Spatial Heterogeneity of the Respiratory Health Impacts of Wildfire Smoke PM2.5 in California.

Wildfire smoke fine particles (PM2.5) are a growing public health threat as wildfire events become more common and intense under climate change, especially in the Western United States. Studies assessing the association between wildfire PM2.5 exposure and health typically summarize the effects over the study area. However, health responses to wildfire PM2.5 may vary spatially. We evaluated spatially-varying respiratory acute care utilization risks associated with short-term exposure to wildfire PM2.5 and explored community characteristics possibly driving spatial heterogeneity. Using ensemble-modeled daily wildfire PM2.5, we defined a wildfire smoke day to have wildfire-specific PM2.5 concentration ≥15 µg/m3. We included daily respiratory emergency department visits and unplanned hospitalizations in 1,396 California ZIP Code Tabulation Areas (ZCTAs) and 15 census-derived community characteristics. Employing a case-crossover design and conditional logistic regression, we observed increased odds of respiratory acute care utilization on wildfire smoke days at the state level (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 1.05, 1.07). Across air basins, ORs ranged from 0.88 to 1.57, with the highest effect estimate in San Diego. A within-community matching design and spatial Bayesian hierarchical model also revealed spatial heterogeneity in ZCTA-level rate differences. For example, communities with a higher percentage of Black or Pacific Islander residents had stronger wildfire PM2.5-outcome relationships, while more air conditioning and tree canopy attenuated associations. We found an important heterogeneity in wildfire smoke-related health impacts across air basins, counties, and ZCTAs, and we identified characteristics of vulnerable communities, providing evidence to guide policy development and resource allocation.

Comparison of the analytical sensitivity of COVID-19 rapid antigen tests in Australia and Canada.

Rapid testing has become an indispensable strategy to identify the most infectious individuals and prevent the transmission of SARS-CoV-2 in vulnerable populations. As such, COVID-19 rapid antigen tests (RATs) are being manufactured faster than ever yet lack relevant comparative analyses required to inform on absolute analytical sensitivity and performance, limiting end-user ability to accurately compare brands for decision making. To date, more than 1000 different COVID-19 RATs are commercially available in the world, most of which detect the viral nucleocapsid protein (NP). Here, we examine and compare the analytical sensitivity of 26 RATs that are readily available in Canada and/or Australia using two NP reference materials (RMs) - a fluorescent NP-GFP expressed in bacterial cells and NCAP-1 produced in a mammalian expression system. Both RMs generate highly comparable results within each RAT, indicating minimal bias due to differing expression systems and final buffer compositions. However, we demonstrate orders of magnitude differences in analytical sensitivities among distinct RATs, and find little correlation with the median tissue culture infectious dose (TCID50) assay values reported by manufacturers. In addition, two COVID-19/Influenza A&B combination RATs were evaluated with influenza A NP-GFP. Finally, important logistics considerations are discussed regarding the robustness, ease of international shipping and safe use of these reference proteins. Taken together, our data highlight the need for and practicality of readily available, reliable reference proteins for end-users that will ensure that manufacturers maintain batch-to-batch quality and accuracy of RATs. They will aid international public health and government agencies, as well as health and aged care facilities to reliably benchmark and select the best RATs to curb transmission of future SARS-CoV-2 and influenza outbreaks.

German and Italian validation of the Dyadic Coping Inventory-Sexual Minority Stress (DCI-SMS) scale.

Lesbian, gay, bisexual, and transgender individuals (hereafter people with minoritized sexual orientation and/or gender identities) have limited legal rights and access to resources because of their marginalized status in society. These limitations are associated with notable health disparities and increase experiences of minority stress. For those in a romantic relationship, being able to communicate and cope with one's partner-dyadic coping-can help buffer stress' deleterious effects on well-being. Given the promise of understanding how dyadic coping can mitigate experiences of sexual minority stress, the Dyadic Coping Inventory-Sexual Minority Stress (DCI-SMS) was recently created and validated with those living in the United States to assess how partners cope with sexual minority stress. Answering a global call to expand psychological science beyond a U.S. centric perspective, the purpose of this study was to validate the DCI-SMS in German and Italian using samples from Austria, Germany, Switzerland, and Italy, respectively. Confirmatory factor analysis results, along with tests of convergent and discriminant validity, and measurement invariance, suggest that the DCI-SMS is a valid measure of stress communication and dyadic coping behaviors for those in a same-gender relationship in the countries sampled. Important future directions include examining its efficacy in other countries, such as those with more adverse sociopolitical climates for people with minoritized sexual orientation and/or gender identities in a same-gender relationship. Limitations and future directions for research and clinical practice are presented. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Assessing the long-term priorities of pancreaticoduodenectomy survivors.

BACKGROUND: This study assessed the long-term quality of life (QOL) and priorities of pancreaticoduodenectomy (PD) survivors. METHODS: Survivors were surveyed via internet-based support groups. The relative importance of longevity, experience, costs, and QOL were assessed. RESULTS: The PD cohort (n = 247, 35%) was 60 ± 12 years, 71% female, and 93% white. With moderate agreement, patients ranked survival most important, followed by functional and emotional well-being; costs and experience were least important (W = 35.7%, p < 0.001). Well-being improved throughout survivorship (P-QOL: 39 ± 12 at ≤3 mo vs 43 ± 12 at >10 y, p = 0.170; M-QOL: 38 ± 13 at ≤3 mo vs 44 ± 16 at >10 y; p = 0.015) but remained below the general population (p < 0.001). PD patients with benign diagnoses ranked functional independence as most important (2.00 ± 1.13 vs 2.63 ± 1.19, p < 0.001, W = 41.1%); PD patients with malignant diagnoses regarded overall survival most important (2.10 ± 1.20 vs 1.82 ± 1.22, p < 0.16, W = 35.1%). The mean rank order of priorities remained concordant between short-term (<1 year) and long-term (>5 years) survivors. CONCLUSION: PD survivors experience long-term mental and physical health impairments, underscoring the importance of functional and emotional support. Survivors place paramount importance on overall survival, functional independence, and emotional well-being. Cancer survivors prioritize longevity, while survivors of chronic benign conditions prioritize functional independence.

PD-1 regulates ILC3-driven intestinal immunity and homeostasis.

Interleukin-(IL) 22 production by intestinal group 3 innate lymphoid cells (ILC3) is critical to maintain gut homeostasis. However, IL-22 needs to be tightly controlled; reduced IL-22 expression is associated with intestinal epithelial barrier defect while its overexpression promotes tumor development. Here, using a single-cell ribonucleic acid sequencing approach, we identified a core set of genes associated with increased IL-22 production by ILC3. Among these genes, programmed cell death 1 (PD-1), extensively studied in the context of cancer and chronic infection, was constitutively expressed on a subset of ILC3. These cells, found in the crypt of the small intestine and colon, displayed superior capacity to produce IL-22. PD-1 expression on ILC3 was dependent on the microbiota and was induced during inflammation in response to IL-23 but, conversely, was reduced in the presence of Notch ligand. PD-1+ ILC3 exhibited distinct metabolic activity with increased glycolytic, lipid, and polyamine synthesis associated with augmented proliferation compared with their PD-1- counterparts. Further, PD-1+ ILC3 showed increased expression of mitochondrial antioxidant proteins which enable the cells to maintain their levels of reactive oxygen species. Loss of PD-1 signaling in ILC3 led to reduced IL-22 production in a cell-intrinsic manner. During inflammation, PD-1 expression was increased on natural cytotoxicity receptor (NCR)- ILC3 while deficiency in PD-1 expression resulted in increased susceptibility to experimental colitis and failure to maintain gut barrier integrity. Collectively, our findings uncover a new function of the PD-1 and highlight the role of PD-1 signaling in the maintenance of gut homeostasis mediated by ILC3 in mice.