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Objective Blindness is a feared complication of giant cell arteritis (GCA). However, the spectrum of pathologic orbital imaging findings on magnetic resonance imaging (MRI) in GCA is not well understood. In this study, we assess inflammatory changes of intraorbital structures on black blood MRI (BB-MRI) in patients with GCA compared to age-matched controls. Methods In this multicenter case-control study, 106 subjects underwent BB-MRI. Fifty-six patients with clinically or histologically diagnosed GCA and 50 age-matched controls without clinical or laboratory evidence of vasculitis were included. All individuals were imaged on a 3-T MR scanner with a post-contrast compressed-sensing (CS) T1-weighted sampling perfection with application-optimized contrasts using different flip angle evolution (SPACE) BB-MRI sequence. Imaging results were correlated with available clinical symptoms. Results Eighteen of 56 GCA patients (32%) showed inflammatory changes of at least one of the intraorbital structures. The most common finding was enhancement of at least one of the optic nerve sheaths (N = 13, 72%). Vessel wall enhancement of the ophthalmic artery was unilateral in 8 and bilateral in 3 patients. Enhancement of the optic nerve was observed in one patient. There was no significant correlation between imaging features of inflammation and clinically reported orbital symptoms (p = 0.10). None of the age-matched control patients showed any inflammatory changes of intraorbital structures. Conclusions BB-MRI revealed inflammatory findings in the orbits in up to 32% of patients with GCA. Optic nerve sheath enhancement was the most common intraorbital inflammatory change on BB-MRI. MRI findings were independent of clinically reported orbital symptoms. Key Points • Up to 32% of GCA patients shows signs of inflammation of intraorbital structures on BB-MRI. • Enhancement of the optic nerve sheath is the most common intraorbital finding in GCA patients on BB-MRI. • Features of inflammation of intraorbital structures are independent of clinically reported symptoms.

Few studies have comprehensively compared severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-induced and hybrid B- and T-cell responses in people with HIV (PWH) to those in comparable controls without HIV. We included 195 PWH and 246 comparable controls from the AGEhIV COVID-19 substudy. A positive nucleocapsid antibody (INgezim IgA/IgM/IgG) or self-reported PCR test defined prior SARS-CoV-2 infection. SARS-CoV-2 anti-spike (anti-S) IgG titers and anti-S IgG production by memory B cells were assessed. Neutralizing antibody titers were determined in a subset of participants. T-cell responses were assessed by gamma interferon (IFN-γ) release and activation-induced marker assay. We estimated mean differences in postvaccination immune responses (β) between levels of determinants. Anti-S IgG titers and anti-S IgG production by memory B cells were not different between PWH and controls. Prior SARS-CoV-2 infection (β = 0.77), receiving mRNA vaccine (β = 0.56), female sex (β = 0.24), fewer days between last vaccination and sampling (β = 0.07), and a CD4/CD8 ratio of

Enterohemorrhagic Escherichia coli (EHEC) is a major cause of severe bloody diarrhea, with potentially lethal complications, such as hemolytic uremic syndrome. In humans, EHEC colonizes the colon, which is also home to a diverse community of trillions of microbes known as the gut microbiota. Although these microbes and the metabolites that they produce represent an important component of EHEC's ecological niche, little is known about how EHEC senses and responds to the presence of gut microbiota metabolites. In this study, we used a combined RNA-Seq and Tn-Seq approach to characterize EHEC's response to metabolites from an in vitro culture of 33 human gut microbiota isolates (MET-1), previously demonstrated to effectively resolve recurrent Clostridioides difficile infection in human patients. Collectively, the results revealed that EHEC adjusts to growth in the presence of microbiota metabolites in two major ways: by altering its metabolism and by activating stress responses. Metabolic adaptations to the presence of microbiota metabolites included increased expression of systems for maintaining redox balance and decreased expression of biotin biosynthesis genes, reflecting the high levels of biotin released by the microbiota into the culture medium. In addition, numerous genes related to envelope and oxidative stress responses (including cpxP, spy, soxS, yhcN, and bhsA) were upregulated during EHEC growth in a medium containing microbiota metabolites. Together, these results provide insight into the molecular mechanisms by which pathogens adapt to the presence of competing microbes in the host environment, which ultimately may enable the development of therapies to enhance colonization resistance and prevent infection.

BackgroundRandomized controlled trials (RCTs) are essential for determining the safety and efficacy of healthcare interventions. However, both laypeople and clinicians often demonstrate experiment aversion: preferring to implement either of two interventions for everyone rather than comparing them to determine which is best. We studied whether clinician and layperson views of pragmatic RCTs for Covid-19 or other interventions became more positive early in the pandemic, which increased both the urgency and public discussion of RCTs.MethodsWe conducted several survey studies with laypeople (totaln=2,909) and two with clinicians (n=895;n=1,254) in 2020 and 2021. Participants read vignettes in which a hypothetical decision-maker who sought to improve health could choose to implement intervention A for all, implement intervention B for all, or experimentally compare A and B and implement the superior intervention. Participants rated and ranked the appropriateness of each decision.ResultsCompared to our pre-pandemic results, we found no decrease in laypeople’s aversion to non-Covid-19 experiments involving catheterization checklists and hypertension drugs. Nor were either laypeople or clinicians less averse to Covid-19 RCTs (concerning corticosteroid drugs, vaccines, intubation checklists, proning, school reopening, and mask protocols), on average. Across all vignettes and samples, levels of experiment aversion ranged from 28% to 57%, while levels of experiment appreciation (in which the RCT is rated higher than the participant’s highest-rated intervention) ranged from only 6% to 35%.ConclusionsAdvancing evidence-based medicine through pragmatic RCTs will require anticipating and addressing experiment aversion among both patients and healthcare professionals.

Fine needle aspiration (FNA) is an early step in the work-up of lymphadenopathy in people with HIV (PWH). We set out to characterize the FNA cytology in PWH and report on the time to lymphoma diagnosis through the FNA clinics in the public healthcare system in Johannesburg, South Africa.Retrospective review of laboratory database.A retrospective chart review of patients undergoing FNA through the department of cytopathology at the National Health Laboratory Service (NHLS) was undertaken. Results of FNAs performed between March and May 2018 were reviewed. Medical record chart abstraction included general demographics, HIV status, site and results of FNA, prior history of malignancy and other laboratory data.Five hundred and thirty-nine lymph node FNAs were performed on PWH. Pathological findings included tuberculosis 47% (252), inadequate sampling 14% (75), reactive adenopathy 13% (71), benign disease 12% (63), suspicious for lymphoproliferative neoplasm 8% (45), other malignancy 4% (21) and inflammation 2% ( n = 12). Only 53% (24) of lymphomas were confirmed by biopsy. Those not confirmed had a high mortality (57%) and loss to follow-up rate (29%) over the following year. The median diagnostic interval exceeded 8 weeks from time of FNA to lymphoma diagnosis.FNA is an important screening modality in this high HIV and tuberculosis (TB) burden region. Patients with cytology suggestive for lymphoma, but without biopsy confirmation, have a high mortality rate suggesting undiagnosed lymphoma. A better understanding of the barriers to appropriate diagnostic triage for lymphoma is needed.

PURPOSE Diagnosis of AIDS lymphoma in low-resource settings, like South Africa, is often delayed, leaving patients with limited treatment options. In tuberculosis (TB) endemic regions, overlapping signs and symptoms often lead to diagnostic delays. Assessment of plasma cell-free DNA (cfDNA) by next-generation sequencing (NGS) may expedite the diagnosis of lymphoma but requires high-quality cfDNA. METHODS People living with HIV with newly diagnosed aggressive B-cell lymphoma and those with newly diagnosed TB seeking care at Chris Hani Baragwanath Academic Hospital and its surrounding clinics, in Soweto, South Africa, were enrolled in this study. Each participant provided a whole blood specimen collected in cell-stabilizing tubes. Quantity and quality of plasma cfDNA were assessed. NGS of the immunoglobulin heavy chain was performed. RESULTS Nine HIV+ patients with untreated lymphoma and eight HIV+ patients with TB, but without lymphoma, were enrolled. All cfDNA quantity and quality metrics were similar between the two groups, except that cfDNA accounted for a larger fraction of recovered plasma DNA in patients with lymphoma. The concentration of cfDNA in plasma also trended higher in patients with lymphoma. NGS of immunoglobulin heavy chain showed robust amplification of DNA, with large amplicons (> 250 bp) being more readily detected in patients with lymphoma. Clonal sequences were detected in five of nine patients with lymphoma, and none of the patients with TB. CONCLUSION This proof-of-principle study demonstrates that whole blood collected for cfDNA in a low-resource setting is suitable for sophisticated sequencing analyses, including clonal immunoglobulin NGS. The detection of clonal sequences in more than half of patients with lymphoma shows promise as a diagnostic marker that may be explored in future studies.

Non-ability-based confidence is confidence in one’s ability that is not calibrated to actual ability. Here, we examine what psychological factors are associated with possessing more or less confidence relative to one’s ability and to what extent genetic and environmental processes contribute to these links. Using data from the Texas Twin Project ( N = 1,588 participants, aged 7–15 years), we apply a latent variable residual approach to calculate non-ability-based confidence as self-rated confidence net of ability on standardized cognitive tests. Non-ability-based confidence was modestly heritable (9%–28%) and strongly positively correlated with the need for cognition, mastery goal orientation, grit, openness, and emotional stability. These correlations were partly mediated by genetic factors (57% of the association on average). This widespread pattern of associations between non-ability-based confidence and several other measures of thinking, feeling, and acting suggest that non-ability-based confidence can be conceptualized as a personality attribute.

Objectives 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET/CT can be utilized in patients with giant cell arteritis (GCA), but pretest probability of established laboratory marker such as C-reactive protein (CRP) and white blood cell count (WBC) has not been defined yet. We aimed to elucidate the clinical utility of CRP and WBC for scheduling an [18F]FDG scan. Methods 18 treatment-naïve GCA patients and 14 GCA subjects with anti-inflammatory treatment (glucocorticoids or comparable drugs), who underwent [18F]FDG PET/CT and who had no other inflammatory disease at time of scan, were identified. A semi-quantitative analysis in 11 vessel segments was conducted, with averaged jugular vein, healthy liver and lung tissue (Target-to-background ratio [TBR]VJ/liver/lung) serving as background. Derived TBR were then correlated with CRP and WBC at time of PET using Spearman’s correlation. Results For all treatment-naïve patients, TBRVJ was 2.3±1.1 (95%CI, 2.2–2.5), TBRliver was 1.0±0.5 (95%CI, 0.9–1.0) and average TBRlung was 6.3±3.6 (95%CI, 5.8–6.8). No significant correlation was noted for either CRP (TBRVJ: R=–0.19; TBRliver: R=–0.03; TBRlung: R=–0.17; each P ≥ 0.44) or for WBC (TBRVJ: R=–0.40; TBRliver: R=–0.32; TBRlung: R=–0.37; each P ≥ 0.10). Similar results were recorded for patients under treatment at time of PET. Again, no significant correlation was reached for either CRP (TBRVJ: R=–0.17; TBRliver: R=–0.28; TBRlung: R=–0.09; each P ≥ 0.32) or WBC (TBRVJ: R=–0.06; TBRliver: R=–0.13; TBRlung: R=0.06; each P ≥ 0.65). Conclusions In GCA patients with and without anti-inflammatory treatment, CRP and WBC did not substantially correlate with TBR at time of scan. Given the rather limited pretest probability of those parameters, such laboratory values may have less diagnostic utility to order an [18F]FDG PET/CT.

To review the role of digital health technologies in behavioral health treatment and promotion for sexual and gender minorities (SGM).Digital technologies have advantages and limitations at multiple levels in addressing SGM's behavioral health needs. For patients, digital technologies improve convenience and may reduce stigma; however, privacy concerns in the home may limit their utilization. Providers also benefit from the convenience of these technologies; however, not all providers are comfortable delivering virtual care to SGM. For society, digital technologies reduce transportation-related costs and increase access to healthcare in an increasingly hostile political climate for SGM; however, these advantages are limited by technological access and anti-SGM policies. Digital technologies can improve the behavioral health of SGM at the patient, provider, and systemic levels. Further efforts are necessary to standardize provider training, improve SUD-specific care delivery, and increase quality and accessibility of these technologies.

Blindness is a feared complication of giant cell arteritis (GCA). However, the spectrum of pathologic orbital imaging findings on magnetic resonance imaging (MRI) in GCA is not well understood. In this study, we assess inflammatory changes of intraorbital structures on black blood MRI (BB-MRI) in patients with GCA compared to age-matched controls.In this multicenter case-control study, 106 subjects underwent BB-MRI. Fifty-six patients with clinically or histologically diagnosed GCA and 50 age-matched controls without clinical or laboratory evidence of vasculitis were included. All individuals were imaged on a 3-T MR scanner with a post-contrast compressed-sensing (CS) T1-weighted sampling perfection with application-optimized contrasts using different flip angle evolution (SPACE) BB-MRI sequence. Imaging results were correlated with available clinical symptoms.Eighteen of 56 GCA patients (32%) showed inflammatory changes of at least one of the intraorbital structures. The most common finding was enhancement of at least one of the optic nerve sheaths (N = 13, 72%). Vessel wall enhancement of the ophthalmic artery was unilateral in 8 and bilateral in 3 patients. Enhancement of the optic nerve was observed in one patient. There was no significant correlation between imaging features of inflammation and clinically reported orbital symptoms (p = 0.10). None of the age-matched control patients showed any inflammatory changes of intraorbital structures.BB-MRI revealed inflammatory findings in the orbits in up to 32% of patients with GCA. Optic nerve sheath enhancement was the most common intraorbital inflammatory change on BB-MRI. MRI findings were independent of clinically reported orbital symptoms.• Up to 32% of GCA patients shows signs of inflammation of intraorbital structures on BB-MRI. • Enhancement of the optic nerve sheath is the most common intraorbital finding in GCA patients on BB-MRI. • Features of inflammation of intraorbital structures are independent of clinically reported symptoms.

As a step towards the understanding of local electrophoretic deposition, particle trajectories are investigated in nonuniform electric field. Our hypothesis is that particles can be locally deposited in nonuniform fields. As an important process parameter, we also study the effect of solvent polarity. For the experiments, the particles are coated with suitable dispersants. The movement and deposition in polar as well as in nonpolar media and mixtures thereof in nonuniform dc electric fields are monitored by optical microscopy. We find that the average velocity of particles in pure cyclohexane increases linear with electric field strength in agreement with standard theory. Electrophoretic mobility and Zeta potential of the particles are calculated from this data. The particles deposit in a homogeneous layer on the electrode surface. The same findings are true for mixtures of 7.5 vol% to 30 vol% ethanol in cyclohexane as suspension media. In water, the particles move against the apparent electrostatic force at voltages below 3 V and do not deposit on either electrode. At voltages above 3 V dendritic structures are formed by cathodic electrophoretic deposition. We conclude that under suitable conditions, local deposition of particles is possible.

The gastrointestinal (GI) environment plays a critical role in shaping enteric infections. Host environmental factors create bottlenecks, restrictive events that reduce the genetic diversity of invading bacterial populations. However, the identity and impact of bottleneck events on bacterial infection are largely unknown. We used Citrobacter rodentium infection of mice, a model of human pathogenic Escherichia coli infections, to examine bacterial population dynamics and quantify bottlenecks to host colonization. Using Sequence Tag-based Analysis of Microbial Populations (STAMP) we characterized the founding population size (Nb') and relatedness of C. rodentium populations at relevant tissue sites during early- and peak-infection. We demonstrate that the GI environment severely restricts the colonizing population, with an average Nb' of only 12-43 lineages (of 2,000+ inoculated) identified regardless of time or biogeographic location. Passage through gastric acid and escape to the systemic circulation were identified as major bottlenecks during C. rodentium colonization. Manipulating such events by increasing gastric pH dramatically increased intestinal Nb'. Importantly, removal of the stomach acid barrier had downstream consequences on host systemic colonization, morbidity, and mortality. These findings highlight the capability of the host GI environment to limit early pathogen colonization, controlling the population of initial founders with consequences for downstream infection outcomes.

Management of neurogenic detrusor overactivity (NDO) remains a clinical priority to improve patients’ quality of life and prevent dramatic urological complications. Intradetrusor injection of onabotulinumtoxinA (BoNT/A1, botulinum neurotoxin A1) is approved as second therapeutic line in these patients, demonstrating a good efficacy. However, a loss of its efficacy over time has been described, with no clear understanding of the underlying mechanisms. This paper aims at shedding new light on BoNT/A1 secondary failure in NDO through functional and structural analysis. Three groups of patients (either non-NDO, NDO with no toxin history or toxin secondary failure) were investigated using an ex vivo bladder strip assay. Detrusor strips were tensed in organ baths and submitted to electrical field stimulation to generate contractions. Recombinant BoNT/A1 was then added at various concentrations and contractions recorded for 4 h. Histology exploring BoNT/A1 targets, fibrosis and neuronal markers was also used. Detrusor strips from patients with BoNT/A1 secondary failure displayed a smaller sensitivity to toxin ex vivo at 3 nM compared to the other groups. Histological evaluation demonstrated the presence of cleaved Synaptosomal-Associated Protein, 25 kDa (c-SNAP25) in the detrusor from the toxin-secondary failure population, indicating some remaining in vivo sensitivity to BoNT/A1 despite the therapeutic escape. Moreover, residual c-SNAP25 did not affect parasympathetic-driven contractions observed ex vivo. This study confirms the slightly lower efficacy of BoNT/A1 in the BoNT/A1 secondary failure NDO group, suggesting that the escape from BoNT/A1 efficacy in NDO occurs at least at the parasympathetic level and could imply compensatory mechanisms for detrusor contraction.

Pancreatic ductal adenocarcinoma (PDAC) harbors mutations in KRAS in greater than 90% of cases and is characterized by a dense, fibrotic stroma that fosters the formation of a hypoxic, nutrient-poor tumor microenvironment. Tumor cells counteract these stresses through the hyperactivation of multiple nutrient scavenging pathways, including macropinoytosis and macroautophagy. Whereas the role of the latter in the regulation of PDAC growth has been extensively studied, much less is known about the role of endoplasmic reticulum (ER)-specific autophagy (ERphagy), a homeostatic mechanism involving ER membrane remodeling which promotes the clearance of misfolded protein aggregates, thereby supporting proteostasis. Using an ERphagy reporter system, we found that pancreatic cancer cells display mutant KRas-dependent suppression of ERphagy both at baseline and in the context of nutrient deprivation, which was partially dependent on the ER-resident receptor CCPG1. Furthermore, direct perturbation of the 26S proteasome with bortezomib enhanced ERphagy, suggesting that the attenuated ERphagy capacity in pancreatic cancer cells may reflect a greater dependence on proteasomal activity for the maintenance of proteostasis. Significantly, the knockdown of CCPG1 but not other ERphagy receptors augmented the growth-suppressive effects of bortezomib in vitro, an effect likely caused by unresolved proteotoxic stress. Overall, our findings implicate CCPG1-mediated ERphagy in pancreatic cancer cell survival and identify a targetable cell-intrinsic vulnerability that can potentiate the cytotoxic effects of bortezomib, which alone is clinically ineffective in treating PDAC. Citation Format: Sandra L. Vogt, Dafna Bar-Sagi. Investigating the role of ERphagy in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B060.

ImportanceAdult sexual assault (SA) survivors experience numerous emergent health problems, yet few seek emergency medical care. Quantifying the number and types of survivors presenting to US emergency departments (EDs) after SA can inform health care delivery strategies to reduce survivor morbidity and mortality.ObjectiveTo quantify ED use and factors that influenced seeking ED care for adult SA from 2006 through 2019.Design, Setting, and ParticipantsThis cross-sectional study used SA data from the Nationwide Emergency Department Sample from 2006 through 2019, which includes more than 35.8 million observations of US ED visits from 989 hospitals, a 20% stratified sample of hospital-based EDs. The study also used the Federal Bureau of Investigation’s Uniform Crime Reporting Program, which includes annual crime data from more than 18 000 law enforcement agencies representing more than 300 million US inhabitants. The study sample included any adult aged 18 to 65 years with an ED visit in the Nationwide Emergency Department Sample coded as SA. The data were analyzed between January 2020 and June 2022.Main Outcomes and MeasuresAnnual SA-related ED visits, subsequent hospital admissions, and associated patient-related factors (age, sex, race and ethnicity, income quartile, and insurance) were analyzed using descriptive statistics.ResultsData were from 120 to 143 million weighted ED visits reported annually from 2006 through 2019. Sexual assault–related ED visits increased more than 1533.0% from 3607 in 2006 to 55 296 in 2019. Concurrently, admission rates for these visits declined from 12.6% to 4.3%. Female, younger, and lower-income individuals were more likely to present to the ED after SA. Older and Medicaid-insured patients were more likely to be admitted. Overall, the rate of ED visits for SA outpaced law enforcement reporting.Conclusions and RelevanceThis cross-sectional study found that US adult SA ED visits increased from 2006 through 2019 and highlighted the populations who access emergency care most frequently and who more likely need inpatient care. These data can inform policies and the programming needed to support this vulnerable population.

Intracellular bacterial pathogens have evolved sophisticated infection strategies, including the release and secretion of virulence factors to interfere with host cell functions and to perturb immune responses. ForSalmonella entericaserovar Typhimurium (S. Typhimurium), the type III secretion systems encoded onSalmonellapathogenicity islands (SPI) 1 and 2 mediates invasion of the bacterium into innate immune cells and regulates bacterial replication and survival within the hostile environment of the host, respectively. Here, we explore the temporal and strain-specific dual perspective response of both the host and pathogen during cellular infection via quantitative proteomics. We report time- and pathogenicity island-specific expression and secretion of infection-associated proteins (i.e., SL1344_1263, SL1344_3112, SL1344_1563, and YnhG) and regulated immune response proteins in macrophage, including Cd86, Cd40, Casp4, C3, IL-1α, and Cd69). Through intracellular macrophage andin vivomurine models of infection, we reveal a role in virulence for three of the bacterial proteins (SL1344_1263, SL1344_1563, and YnhG), defining their importance as novel T3SS effectors. We characterize the temporal intra- and extracellular production of the effectors and identify their interaction networks in host cells, representing inhibitory and stimulatory pathways mounted by invading bacterial pathogens.Author SummaryThe relationship between a host and pathogen is intricate, and regulation of the host immune response correlates with the progressive timing of infection and tailored responses to the pathogen. Relying on detection and quantification of protein-level changes using mass spectrometry-based proteomics, we explore the production of known and novel effectors bySalmonelladuring intracellular survival within macrophage. Our results portray a role for these effectors in bacterial virulence using anin vivomurine model of infection, and we define a dynamic network of interaction between the effectors and host proteins. These interactions reveal opportunity for drug design to disrupt modulation of the host by the invading bacterium as a new strategy for combatting infection. Our approach is dynamic and universal, with the power to alter therapeutic discovery against infectious diseases.

The high prevalence of psychiatric conditions and the concomitant increase in need for mental illness have posed a challenge across the USA. Patients continue to encounter many barriers to accessing care with only 43% receiving treatment. This situation is even more challenging for LGBT individuals, who experience higher rates of some mental health conditions, with an increased risk of suicidality, due to stressors such as discrimination and trauma. Simultaneously, LGBT individuals face specific barriers at the individual level, clinician level, and systemic level. Telepsychiatry has emerged as an approach that can help overcome some of the challenges faced by LGBT individuals when it comes to healthcare access. This paper examines the ways in which telepsychiatry can overcome the aforementioned barriers and provides recommendations to enhance the quality of telepsychiatry services for LGBT patients. Recommendations include improving medical education, enhancing health-force training on cultural competency, and expanding culturally affirming telehealth programs.

Despite the staggering physical, economic, and societal costs of mental health conditions in the United States, there continues to be a significant gap in mental health service, as access lags behind the demand for them. The uneven distribution of mental health service providers contributes to this gap, making it necessary to incorporate novel approaches to the delivery of mental health services. Telepsychiatry has proven to be one of the more innovative approaches for improving access to mental health services. This article focuses on six challenges that have historically impeded larger-scale adoption of telepsychiatry: limited training, limitations of existing research, security and technology issues, clinical practice challenges, licensure, and reimbursement restrictions. The article discusses recent developments, ongoing advances, and future directions to overcoming these barriers. [ Psychiatr Ann . 2019;49(2):82–88.]

Purpose of review Neutrophils priming has been long studied in vitro. Recent studies describe it in vivo. In pathophysiological conditions, complex, heterogeneous characteristics of priming are described in the last few years. Recent findings Priming can occur systemically when insults such as sepsis or trauma result in an array of circulating mediators and circulating primed neutrophils seem to exert detrimental effects either directly, or indirectly by interacting with other cells, thereby contributing to the development of organ dysfunction. Local priming of neutrophils augments their ability to clear infection, but may also lead to local bystander tissue injury, for example, in the inflamed joint. The complexity, heterogeneity and dynamic nature of inflammatory responses and the accessibility of cells from local sites make neutrophil priming challenging to study in human disease; however, recent advances have made significant progress to this field. Summary Herein, we summarize the literature regarding neutrophil priming in selected conditions. In some diseases and in the setting of specific genetic influences, the priming repertoire seems to be restricted, with only some neutrophil functions upregulated. A greater understanding of the nature of neutrophil priming and its role in human disease is required before this process becomes tractable to therapeutic intervention.

Alcohol hangover refers to the combination of negative mental and physical symptoms that can be experienced after an episode of alcohol consumption, typically emerging as blood alcohol concentration (BAC) approaches zero. Hangover has been associated with heavy drinking and may be relevant in the transition to alcohol use disorder (AUD). Our aim was to examine hangover prevalence and associated symptoms following intravenous alcohol self-administration (IV-ASA), and to identify possible predictors of hangover in non-dependent drinkers. Ninety-five drinkers without AUD completed an IV-ASA session. Pharmacodynamic measures of alcohol consumption included peak and average breath alcohol concentrations. Subjective measures of alcohol response included the Drug Effects Questionnaire and Biphasic Effects of Alcohol Scale. The Alcohol Hangover Scale assessed hangover symptoms from the end of the session until the following morning. 78% of participants endorsed at least one hangover symptom following IV-ASA. There was no association between hangover scores and IV-ASA measures of alcohol consumption. Additional mediation and moderation analysis revealed that self-reported intoxication was a significant mediator of the relationship between recent drinking and hangover symptoms. Hangover symptoms may be an early marker of the relationship between subjective response to alcohol and heavy drinking for those with no prior history of AUD. In particular, the effects of hangover go beyond exposure to alcohol and the individual's subjective response to this exposure is associated with their experience of hangover. Future studies should further characterize the determinants of hangover across different populations of drinkers to better understand the risk for AUD and inform prevention methods.

A new and uniquely structured matrix of mammalian phenotypes,MaTrics(MammalianTraits for Comparative Genomics) is presented in a digital form. By focussing on mammalian species for which genome assemblies are available,MaTricsprovides an interface between mammalogy and comparative genomics.MaTricswas developed as part of a project to link phenotypic differences between mammals to differences in their genomes usingForward Genomics.Apart from genomes this approach requires information on homologous phenotypes that are numerically encoded (presence-absence; multistate character coding*) in a matrix.MaTricsprovides these data, links them to at least one reference (e.g., literature, photographs, histological sections, CT-scans, or museum specimens) and makes them available in a machine actionable NEXUS-format. By making the data computer readable,MatTricsopens a new way for digitizing collections. Currently,MaTricscovers 147 mammalian species and includes 207 characters referring to structure, morphology, physiology, ecology and ethology. Researching these traits revealed substantial knowledge gaps, highlighting the need for substantial phenotyping efforts in the genomic era. Using the trait information documented inMaTrics, previous Forward Genomics screens identified changes in genes that are associated with various phenotypes, ranging from fully-aquatic lifestyle to dietary specializations. These results motivate the continuous expansion of phenotype information, both by filling research gaps or by adding additional taxa and traits.MaTricsis digitally available online within the data repository Morph·D·Base (www.morphdbase.de).

The type VI secretion system (T6SS) is a contractile nanomachine widely distributed among pathogenic and commensal Gram-negative bacteria. The T6SS is used for inter-bacterial competition to directly kill competing species; however, its importance during bacterial infection in vivo remains poorly understood. We report that the murine pathogen Citrobacter rodentium, used as a model for human pathogenic Escherichia coli, harbors two functional T6SSs. C. rodentium employs its T6SS-1 to colonize the murine gastrointestinal tract by targeting commensal Enterobacteriaceae. We identify VgrG1 as a C. rodentium T6SS antibacterial effector, which exhibits toxicity in E. coli. Conversely, commensal prey species E. coli Mt1B1 employs two T6SSs of its own to counter C. rodentium colonization. Collectively, these data demonstrate that the T6SS is a potent weapon during bacterial competition and is used by both invading pathogens and resident microbiota to fight for a niche in the hostile gut environment.

Background Gut microbiome composition is shaped by a combination of host genetic make-up and dietary habits. In addition, large ethnic differences exist in microbiome composition. Several studies in humans and animals have shown that differences in gut microbiota and its metabolites, including short chain fatty acids (SCFA), are associated with blood pressure (BP). We hypothesized that gut microbiome composition and its metabolites may be differently associated with BP across ethnic groups. Purpose To investigate associations of gut microbiome composition and fecal SCFA levels with BP across different ethnic groups. Methods We assessed the association between gut microbiome composition and office BP among 4672 subjects (mean age 49.8±11.7 years, 52%F) of 6 different ethnic groups participating in the HELIUS study. Gut microbiome composition was determined using 16S rRNA sequencing. Associations between microbiome composition and blood pressure were assessed using machine learning prediction models. The resulting best predictors were correlated with BP using Spearman's rank correlations. Fecal SCFA levels were measured with high-performance liquid chromatography in an age- and body mass index (BMI)-matched subgroup of 200 participants with either extreme low or high systolic BP. Differences in abundances of best predictors and fecal SCFA levels between high and low BP groups were assessed with Mann-Whitney U tests. Results Gut microbiome composition explained 4.4% of systolic BP variance. Best predictors for systolic BP included Roseburia spp. (ρ −0.15, p Conclusions In this cross-sectional study, gut microbiome composition was moderately associated with BP. Associations were strongly divergent between ethnic groups, with strongest associations in Dutch participants. Intriguingly, while Dutch participants with high BP had lower abundances of several SCFA-producing microbes, they had higher fecal SCFA levels. Intervention studies with SCFAs could provide more insight in the effects of these metabolites on BP. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): The Academic Medical Center (AMC) of Amsterdam and the Public Health Service of Amsterdam (GGD Amsterdam) provided core financial support for HELIUS. The HELIUS study is also funded by research grants of the Dutch Heart Foundation (Hartstichting; grant no. 2010T084), the Netherlands Organization for Health Research and Development (ZonMw; grant no. 200500003), the European Integration Fund (EIF; grant no. 2013EIF013) and the European Union (Seventh Framework Programme, FP-7; grant no. 278901).

Although writing is a valued public health competency, authors face a multitude of barriers (eg, lack of time, lack of mentorship, lack of appropriate instruction) to publication. Few writing courses for applied public health professionals have been documented. In 2017 and 2018, the Council of State and Territorial Epidemiologists and the Centers for Disease Control and Prevention partnered to implement a Morbidity and Mortality Weekly Report Intensive Writing Training course to improve the quality of submissions from applied epidemiologists working at health departments. The course included 3 webinars, expert mentorship from experienced authors, and a 2-day in-person session. As of April 2020, 39 epidemiologists had participated in the course. Twenty-four (62%) of the 39 epidemiologists had submitted manuscripts, 17 (71%) of which were published. The program’s evaluation demonstrates the value of mentorship and peer feedback during the publishing process, the importance of case study exercises, and the need to address structural challenges (eg, competing work responsibilities or supervisor support) in the work environment.

Aims We quantified the concurring dynamics affecting total and hippocampal brain volume and cognitive function in patients with chronic heart failure (HF) over a period of three years. Methods and results A total of 148 patients with mild stable HF entered this monocentric prospective cohort study: mean age 64.5 (10.8) years; 16.2% female; 77% in New York Heart Association functional classes I–II; 128 and 105 patients attended follow-up visits after 1 and 3 years, respectively. The assessment included cardiological, neurological, psychological work-up, and brain magnetic resonance imaging. Total and regional brain volumes were quantified using an operator-independent fully automated approach and reported normalized to the mean estimated intracranial volume. At baseline, the mean hippocampal volume was ∼13% lower than expected. However, the 3-year progressive hippocampal volume loss was small: −62 mm3 [95% confidence interval (CI) −81 to −42, P Conclusion In patients with predominantly mild HF, the markedly reduced hippocampal volume observed at baseline was associated with impaired cognitive function, but no accelerated deterioration in cognition and brain atrophy became evident over a mid-term period of three years.

Although telepsychiatry has emerged as an innovative tool for increasing access to behavioral health services, few studies have examined the complexities associated with designing and implementing telepsychiatry programs. This column examines a multisite, multimodal telepsychiatry program that has been providing direct care, synchronous consultation, and asynchronous consultation services in rural Illinois since 2016. The program used quality improvement metrics and implementation science strategies to improve its long-term impact and sustainability. Program impact was assessed through satisfaction surveys of patients and primary care physicians, chart reviews, wait times, and volume of patients served. Results indicate that the design and implementation of this telepsychiatry program improved access to behavioral health services and effectively supported primary care providers, with high degrees of patient and provider satisfaction.

Objective: To examine the effectiveness of an interdisciplinary, discovery-oriented teaching unit designed to provide science and health information about HIV from the perspective of viral biology, population statistics and epidemiology. Design: Single group pre- and post-curriculum pilot study. Setting: Fifteen middle and high school classrooms recruited from districts in and around a large, diverse, urban area in the mid-southern USA. Method: Science educators, clinicians, virologists and biologists collaborated to develop a set of five activities intended to increase content knowledge related to HIV, while developing students’ science-related skills in the context of an authentic, relevant example. The activities were piloted with six hundred and twenty-four 12- to 18-year-old students. Multiple-choice pre- and post-tests were used to assess changes in students’ knowledge, and teacher evaluations were used to gauge appropriateness of content, ease of activity implementation and teacher perceptions of student skill development, learning and engagement. Results: Student pre- and post-tests and teacher post-evaluations indicated that the curriculum was effective in increasing content knowledge for students across all age ranges, with 13- to 14-year-old, grade 8 students achieving the greatest knowledge gains. Teacher-reported information also suggested that students were able to apply relevant skills to their interpretation of authentic data related to the incidence and transmission of HIV infection around the world. Conclusion: The developed activities have the potential to provide timely, relevant information to students while strengthening science-related content knowledge and skills as well as health literacy.

Physician burnout and stress have reached alarming levels. Psychiatrists are at risk of experiencing burnout due to emotional stressors related to the nature of the clinical work, occupational hazards, changing nature of service delivery, and increasing administrative pressures. Currently, little is known about the impact of telepsychiatry on psychiatrist well-being and burnout. This Open Forum examines potential benefits and challenges of telepsychiatry with regard to psychiatrist stress and burnout. It also discusses the broader implications of telepsychiatry for psychiatrist well-being.

The dynamical structure of glucose fluctuation has largely been disregarded in the contemporary management of diabetes. In a retrospective study of patients with diabetes, we evaluated the relationship between glucose dynamics, antihyperglycemic therapy, glucose variability, and glucose exposure, while taking into account potential determinants of the complexity index. We used multiscale entropy (MSE) analysis of continuous glucose monitoring data from 131 subjects with type 1 (n = 18), type 2 diabetes (n = 102), and 11 nondiabetic control subjects. We compared the MSE complexity index derived from the glucose time series among the treatment groups, after adjusting for sex, age, diabetes duration, body mass index, and carbohydrate intake. In type 2 diabetic patients who were on a diet or insulin regimen with/without oral agents, the MSE index was significantly lower than in nondiabetic subjects but was lowest in the type 1 diabetes group (p

This deliverable report examines the outcomes of the REACH research project with regard to data privacy and data security, associated with Task T7.5. This document gives an overview of our analyses involving ethics and privacy concerns in terms of the individual touchpoints and shows how these findings guided the project towards the determination of the medical purpose and intended use – cornerstones to on the path to market entry. In addition, we provide a brief overview of how the guidelines regarding data protection and encryption influenced the technical design and implementation of project components. Furthermore, we provide an update on the management of legal implications (and the implications resulting from this for system requirements and business strategy) of the use of machine learning and artificial intelligence in the context of REACH solutions, incorporating an external expert opinion. Finally, this deliverable report contains a summary of our approach towards risk governance and standardization in this regard: our work in REACH on privacy and security schemata, culminated in a CEN Workshop Agreement (guideline) that generalizes REACH outcomes and makes them accessible and usable beyond the REACH consortium.

The middle school years are a crucial time for cultivating students’ interest in and preparedness for future STEM careers. However, not all middle school children are provided opportunities to engage, learn and achieve in STEM subject areas. Engineering, in particular, is neglected in these grades because it usually is not part of science or mathematics curricula. This study investigates the effectiveness of an engineering-integrated STEM curriculum designed for use in an after-school environment. The inquiry-based activities comprising the unit, Think Like an Astronaut, were intended to introduce students to STEM careers—specifically engineering and aerospace engineering—and enhance their skills and knowledge applicable related to typical middle school science objectives. Results of a field test with a diverse population of 5th grade students in nine schools revealed that Think Like an Astronaut lessons are appropriate for an after-school environment, and may potentially help increase students’ STEM-related content knowledge and skills.

Chemically functionalized carbon nanowalls (CNWs) are promising materials for a wide range of applications, i.e. gas sensors, membranes for fuel cells, or as supports for catalysts. However, the difficulty of manipulation of these materials hinders their integration into devices. In this manuscript a procedure for rapid prototyping of CNWs and functionalized CNWs (i.e. decorated with SnO 2 nanoparticles) is described. This procedure enables the use of laser-induced forward transfer (LIFT) as a powerful technique for printing CNWs and CNW:SnO 2 pixels onto rigid and flexible substrates. A morphological study shows that for a large range of laser fluences i.e. 500–700 mJ/cm 2 it is possible to transfer thick (4 μm) CNW and CNW:SnO 2 pixels. Micro-Raman investigation of the transferred pixels reveals that the chemical composition of the CNWs and functionalized CNWs does not change as a result of the laser transfer. Following these results one can envision that CNWs and CNW:SnO 2 pixels obtained by LIFT can be ultimately applied in technological applications.

Non-ability-based confidence is one of the most pervasive human psychological biases. It is a part of a family of confidence judgments, including overconfidence and metacognitive calibration accuracy, defined by a discrepancy between self-perception of ability and actual ability. Across many domains, most people exhibit some degree of miscalibration in their confidence. Some people may be overconfident and others are underconfident. Despite the prevalence of non-ability-based confidence, relatively little research has investigated how non-ability-based confidence develops and why some people are more or less confident than others despite sharing the same level of ability. We use a longitudinal dataset to explore the childhood predictors of adolescent non-ability-based confidence. Achievement growth in math and reading in childhood was modeled and used to predict adolescent non-ability-based confidence in math and reading. Results show that the initial level of achievement predicts lower non-ability-based confidence in math. On the other hand, a faster rate of achievement growth across childhood predicts greater non-ability-based confidence in reading. These results highlight how previous experiences inform people’s self-perceptions over and above their true abilities. Discussion focuses on the factors that shape non-ability-based confidence over the lifespan and the limitations of the current findings.

Envelope-localized proteins, such as adhesins and secretion systems, play critical roles in host infection by Gram-negative pathogens. As such, their folding is monitored by envelope stress response systems. Previous studies demonstrated that the Cpx envelope stress response is required for virulence of Citrobacter rodentium, a murine pathogen used to model infections by the human pathogens enteropathogenic and enterohemorrhagic Escherichia coli; however, the mechanisms by which the Cpx response promotes host infection were previously unknown. Here, we characterized the C. rodentium Cpx regulon in order to identify genes required for host infection. Using transcriptomic and proteomic approaches, we found that the Cpx response upregulates envelope-localized protein folding and degrading factors but downregulates pilus genes and type III secretion effectors. Mouse infections with C. rodentium strains lacking individual Cpx-regulated genes showed that the chaperone/protease DegP and the disulfide bond oxidoreductase DsbA were essential for infection, but Cpx regulation of these genes did not fully account for attenuation of C. rodentium ΔcpxRA. Both deletion of dsbA and treatment with the reducing agent dithiothreitol activated the C. rodentium Cpx response, suggesting that it may sense disruption of disulfide bonding. Our results highlight the importance of envelope protein folding in host infection by Gram-negative pathogens.

The opioid epidemic faced by the USA is a complex public health crisis, with staggering loss of life and overwhelming social, health, and economic costs. Despite the rising need for medication-assisted treatment, individuals struggling with opioid use continue to face multiple barriers hindering their access to care, particularly in rural areas. Innovative approaches to enhance access to treatment are needed. Telepsychiatry has proven to be effective and economical across multiple settings and psychiatric diagnoses, including opioid use disorder. As the implementation of telepsychiatry continues to expand, this method of healthcare delivery offers significant opportunities to overcome several barriers to access patients with opioid use disorder face. While addressing the opioid crisis will require multifaceted efforts involving multiple stakeholders and different approaches, a comprehensive strategy must incorporate the adoption of telepsychiatry as an innovative approach to overcoming barriers to treatment and enhancing access to care.

The activation status of neutrophils can cycle from basal through primed to fully activated (“green‐amber‐red”), and at least in vitro, primed cells can spontaneously revert to a near basal phenotype. This broad range of neutrophil responsiveness confers extensive functional flexibility, allowing neutrophils to respond rapidly and appropriately to varied and evolving threats throughout the body. Primed and activated cells display dramatically enhanced bactericidal capacity (including augmented respiratory burst activity, degranulation and longevity), but this enhancement also confers the capacity for significant unintended tissue injury. Neutrophil priming and its consequences have been associated with adverse outcomes in a range of disease states, hence understanding the signalling processes that regulate the transition between basal and primed states (and back again) may offer new opportunities for therapeutic intervention in pathological settings. A wide array of host‐ and pathogen‐derived molecules is able to modulate the functional status of these versatile cells. Reflecting this extensive repertoire of potential mediators, priming can be established by a range of signalling pathways (including mitogen‐activated protein kinases, phosphoinositide 3‐kinases, phospholipase D and calcium transients) and intracellular processes (including endocytosis, vesicle trafficking and the engagement of adhesion molecules). The signalling pathways engaged, and the exact cellular phenotype that results, vary according to the priming agent(s) to which the neutrophil is exposed and the precise environmental context. Herein we describe the signals that establish priming (in particular for enhanced respiratory burst, degranulation and prolonged lifespan) and describe the recently recognised process of de‐priming, correlating in vitro observations with in vivo significance.

Gastrointestinal pathogens must overcome many obstacles in order to successfully colonize a host, not the least of which is the presence of the gut microbiota, the trillions of commensal microorganisms inhabiting mammals' digestive tracts, and their products. It is well established that a healthy gut microbiota provides its host with protection from numerous pathogens, including Salmonella species, Clostridium difficile, diarrheagenic Escherichia coli, and Vibrio cholerae. Conversely, pathogenic bacteria have evolved mechanisms to establish an infection and thrive in the face of fierce competition from the microbiota for space and nutrients. Here, we review the evidence that gut microbiota-generated metabolites play a key role in determining the outcome of infection by bacterial pathogens. By consuming and transforming dietary and host-produced metabolites, as well as secreting primary and secondary metabolites of their own, the microbiota define the chemical environment of the gut and often determine specific host responses. Although most gut microbiota-produced metabolites are currently uncharacterized, several well-studied molecules made or modified by the microbiota are known to affect the growth and virulence of pathogens, including short-chain fatty acids, succinate, mucin O-glycans, molecular hydrogen, secondary bile acids, and the AI-2 quorum sensing autoinducer. We also discuss challenges and possible approaches to further study of the chemical interplay between microbiota and gastrointestinal pathogens.

High-quality after-school programs devoted to science have the potential to enhance students' science knowledge and attitudes, which may impact their decisions about pursuing science-related careers. Due to the unique nature of these informal learning environments, an understanding of the relationships among aspects of students' content knowledge acquisition and attitudes toward science may aid in the development of effective science-related interventions. We investigated the impact of a semester-long after-school intervention utilizing an inquiry-based infectious diseases curriculum (designed for use after-school) on 63 urban students' content knowledge and aspects of their attitudes towards science. Content knowledge increased 24.6% from pre- to posttest. Multiple regression analyses indicated suggested that the "self-directed effort" subscale of the Simpson-Troost Attitude Questionnaire - Revised best predicted increases in students' science content knowledge. The construct "science is fun for me" served as a suppressor effect. These findings suggest that future after-school programs focusing on aspects of attitudes toward science most closely associated with gains in content knowledge might improve students' enthusiasm and academic preparedness for additional science coursework by improving student attitudes towards their perceptions of their self-directed effort.

Summary Gram-negative bacteria possess several envelope stress responses that detect and respond to damage to this critical cellular compartment. The σE envelope stress response senses the misfolding of outer membrane proteins (OMPs), while the Cpx two-component system is believed to detect the misfolding of periplasmic and inner membrane proteins. Recent studies in several Gram-negative organisms found that deletion of hfq, encoding a small RNA chaperone protein, activates the σE envelope stress response. In this study, we assessed the effects of deleting hfq upon activity of the σE and Cpx responses in non-pathogenic and enteropathogenic (EPEC) strains of Escherichia coli. We found that the σE response was activated in Δhfq mutants of all E. coli strains tested, resulting from the misregulation of OMPs. The Cpx response was activated by loss of hfq in EPEC, but not in E. coli K-12. Cpx pathway activation resulted in part from overexpression of the bundle-forming pilus (BFP) in EPEC Δhfq. We found that Hfq repressed expression of the BFP via PerA, a master regulator of virulence in EPEC. This study shows that Hfq has a more extensive role in regulating the expression of envelope proteins and horizontally acquired virulence genes in E. coli than previously recognized.