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Recent studies have highlighted the importance of host-associated microbial communities in inhibiting growth or colonization of pathogenic species and mitigating disease severity. Much research has been conducted on how the microbiome of individuals may impact their disease susceptibility; however, less attention has been given to the role of microbiomes in population-level disease processes. In this study, we examined the effects of the ocular microbiome on pathogen load, disease severity, and transmission success of the conjunctival bacterial pathogen Mycoplasma gallisepticum (MG) in house finches (Haemorhous mexicanus). Fifteen male house finches were exposed to MG and housed pairwise with uninfected females for 32 days. Swabs for ocular microbiome characterization via 16 S rRNA gene amplicon sequencing were collected from male and female finches before and nine days after MG inoculation. MG load and disease severity were quantified throughout the experiment for all individuals. We examined whether ocular microbiome composition prior to MG infection was associated with pathogen load, disease severity, or transmission efficacy. Although the presence of certain taxa in the ocular microbiome is associated with disease protection in this species, we did not find any evidence that ocular microbiome composition was associated with any metric used to quantify disease transmission. MG infection did alter the resident bacterial communities, which aligns with results from previous studies. However, this was only true for the indicator birds that were directly inoculated with MG. Our results suggest the resident ocular microbiome of house finches shifts in responses to direct contact with pathogens, but may be more resilient, at least at the timescales examined, when host exposure is via an infected conspecific. This suggests that outcomes of interactions between pathogens and resident microbial communities may depend on the mode or dose of pathogen exposure.

A case report detailing, for the first time, a case of laboratory-confirmed zoster in an astronaut on board the International Space Station is presented. The findings of reduced T-cell function, cytokine imbalance, and increased stress hormones which preceded the event are detailed. Relevance for deep space countermeasures is discussed.

The tick Ixodes ricinus parasitizes a wide range of vertebrates. These hosts vary in the relative contribution to the feeding of the different tick life stages, and their interplay is pivotal in the transmission dynamics of tick-borne pathogens. We aimed to know if there is a phylogenetic signal in the feeding and propagation hosts of I. ricinus, independently of other traits, as well as in the amplification of Borrelia burgdorferi (s.l.) in feeding larvae. We used a compilation of 1127 published field surveys in Europe, providing data for 96,586 hosts, resulting in 265,124 larvae, 72,080 nymphs and 37,726 adults. The load of immature ticks on hosts showed a significant phylogenetic signal towards the genera Psammodromus, Podarcis, and Lacerta (nymphs only). We hypothesize that such signal is the background hallmark of the primitive hosts associations of I. ricinus, probably in the glaciation refugia. A secondary phylogenetic signal for tick immatures appeared for some genera of Rodentia and Eulipotyphla. Results suggest the notion that the tick gained these hosts after spread from glaciation refugia. Analyses support a phylogenetic signal in the tick adults, firmly linked to Cetartiodactyla, but not to Carnivora or Aves. This study provides the first demonstration of host preferences in the generalist tick I. ricinus. We further demonstrate that combinations of vertebrates contribute in different proportions supporting the tick life-cycle in biogeographical regions of the Western Palaearctic as each region has unique combinations of dominant hosts. Analysis of the amplification of B. burgdorferi (s.l.) demonstrated that each genospecies is better amplified by competent reservoirs with which a strong phylogenetic signal exists. These vertebrates are the same along the spatial range: environmental traits do not change the reservoirs along the large territory studied. The transmission of B. burgdorferi (s.l.) is amplified by a few species of vertebrates, that share biogeographical regions with the tick vector in variable proportions.

Controlling transgene expression through an externally administered inductor is envisioned as a potent strategy to improve safety and efficacy of gene therapy approaches. Generally, inducible ON systems require a chimeric transcription factor (transactivator) that becomes activated by an inductor, which is not optimal for clinical translation due to their toxicity. We generated previously the first all-in-one, transactivator-free, doxycycline (Dox)-responsive (Lent-On-Plus or LOP) lentiviral vectors (LVs) able to control transgene expression in human stem cells. Here, we have generated new versions of the LOP LVs and have analyzed their applicability for the generation of inducible advanced therapy medicinal products (ATMPs) with special focus on primary human T cells. We have shown that, contrary to all other cell types analyzed, an Is2 insulator must be inserted into the 3′ long terminal repeat of the LOP LVs in order to control transgene expression in human primary T cells. Importantly, inducible primary T cells generated by the LOPIs2 LVs are responsive to ultralow doses of Dox and have no changes in phenotype or function compared with untransduced T cells. We validated the LOPIs2 system by generating inducible CAR-T cells that selectively kill CD19+ cells in the presence of Dox. In summary, we describe here the first transactivator-free, all-one-one system capable of generating Dox-inducible ATMPs.

Prior studies examining the effects of cocaine on the dynorphin/kappa opioid receptor (Dyn/KOR) system primarily focus on non-contingent cocaine exposure, but the effects of self-administration, which more closely reflects human drug-taking behaviors, are not well studied. In this study we characterized the effects of escalated intravenous cocaine self-administration on the functional state of the Dyn/KOR system and its interaction with mesolimbic dopamine signaling. Rats self-administered cocaine in an extended access, limited intake cocaine procedure, in which animals obtained 40 infusions per day (1.5 mg/kg/inf) for 5 consecutive days to ensure comparable consumption levels. Following single day tests of cue reactivity and progressive ratio responding, quantitative real-time polymerase chain reaction was used to measure levels of Oprk and Pdyn transcripts in the ventral tegmental area and nucleus accumbens. Additionally, after self-administration, ex vivo fast-scan cyclic voltammetry in the NAc was used to examine the ability of the KOR agonist U50,488 to inhibit dopamine release. We found that KOR-induced inhibition of dopamine release was enhanced in animals that self-administered cocaine compared to controls, suggesting upregulated Dyn/KOR activity after cocaine self-administration. Furthermore, expression levels of Pdyn in the nucleus accumbens and ventral tegmental area, and Oprk in the nucleus accumbens, were elevated in cocaine animals compared to controls. Additionally, Pdyn expression in the nucleus accumbens was negatively correlated with progressive ratio breakpoints, a measure of motivation to self-administer cocaine. Overall, these data suggest that cocaine self-administration elevates KOR/Dyn system activity in the mesolimbic dopamine pathway.

The detoxification of quinones through NAD(P)H:quinone oxidoreductase (NQO1) is a crucial mechanism to maintain cellular homeostasis. The exposure to heavy metals, specifically methylmercury (MeHg), induces several antioxidant enzymes, including NQO1. The nuclear factor erythroid 2-related factor-2 (NRF2) is known to regulate the expression of Nqo1 gene and also the aryl hydrocarbon receptor (AHR) is another Nqo1 gene regulator. This co-regulation prompted us to investigate which transcription factor (NRF2 or AHR) orchestrates the regulation of NQO1 expression upon MeHg exposure. Therefore, we investigated how MeHg can modulate the level of NQO1 expression by exposing Hepa-1c1c7 cells to several concentrations of MeHg with and without the addition of NQO1 inducers, DL-sulforaphane (SUL) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We found that the mRNA expression of Nqo1 is up-regulated by MeHg in time- as well as dose-dependent fashions. Additionally, MeHg increased the NQO1 at all expression levels with and without the presence of its inducers, SUL or TCDD. Furthermore, the MeHg-mediated increase of NQO1 expression was in parallel with a concurrent increase in the nuclear localization of NRF2 protein, but not that of AHR. Mechanistically, the antioxidant response element-driven reporter gene activity was induced by 215% upon MeHg exposure. Also, transfecting Hepa-1c1c7 with Nrf2 siRNA reduced the MeHg-induced NQO1 protein expression by 60%. In conclusion, our findings provide evidence supporting the hypothesis that MeHg upregulates the Nqo1 gene through a transcriptional mechanism at least in part via a NRF2-dependent mechanism.

A growing public health concern, chronic Diesel Exhaust Particle (DEP) exposure is a heavy risk factor for the development of neurodegenerative diseases like Alzheimer’s (AD). Considered the brain’s first line of defense, the Blood–Brain Barrier (BBB) and perivascular microglia work in tandem to protect the brain from circulating neurotoxic molecules like DEP. Importantly, there is a strong association between AD and BBB dysfunction, particularly in the Aβ transporter and multidrug resistant pump, P-glycoprotein (P-gp). However, the response of this efflux transporter is not well understood in the context of environmental exposures, such as to DEP. Moreover, microglia are seldom included in in vitro BBB models, despite their significance in neurovascular health and disease. Therefore, the goal of this study was to evaluate the effect of acute (24 hr.) DEP exposure (2000 μg/ml) on P-gp expression and function, paracellular permeability, and inflammation profiles of the human in vitro BBB model (hCMEC/D3) with and without microglia (hMC3). Our results suggested that DEP exposure can decrease both the expression and function of P-gp in the BBB, and corroborated that DEP exposure impairs BBB integrity (i.e. increased permeability), a response that was significantly worsened by the influence of microglia in co-culture. Interestingly, DEP exposure seemed to produce atypical inflammation profiles and an unexpected general downregulation in inflammatory markers in both the monoculture and co-culture, which differentially expressed IL-1β and GM-CSF. Interestingly, the microglia in co-culture did not appear to influence the response of the BBB, save in the permeability assay, where it worsened the BBB’s response. Overall, our study is important because it is the first (to our knowledge) to investigate the effect of acute DEP exposure on P-gp in the in vitro human BBB, while also investigating the influence of microglia on the BBB’s responses to this environmental chemical.

Rhabdomyosarcomas with bladder involvement in adults is an extremely rare tumor with approximately 35 cases reported. Because of its rarity in adults the exact treatment modalities are not entirely clear. Treatment is based on Children's Oncology Group in RMS. There is no significant difference in stage, lymph node status, gender, and site between adults and children. The 5 year survival for pediatric RMS is 66% and for adults 22%. It is clear that our understanding and treatment of pediatric RMS is much greater than that of adult patients and the possible reason for these differences are discussed.

Background & Aims: Aberrant immune activation is associated with numerous inflammatory and autoimmune diseases and contributes to cancer development and progression. Within the stomach, inflammation drives a well-established sequence from gastritis to metaplasia, eventually resulting in adenocarcinoma. Unfortunately, the processes that regulate gastric inflammation and prevent carcinogenesis remain unknown. Tristetraprolin (TTP) is an RNA-binding protein that promotes the turnover of numerous proinflammatory and oncogenic messenger RNAs. Here, we assess the role of TTP in regulating gastric inflammation and spasmolytic polypeptide-expressing metaplasia (SPEM) development. Methods: We used a TTP-overexpressing model, the TTPΔadenylate-uridylate rich element mouse, to examine whether TTP can protect the stomach from adrenalectomy (ADX)-induced gastric inflammation and SPEM. Results: We found that TTPΔadenylate-uridylate rich element mice were completely protected from ADX-induced gastric inflammation and SPEM. RNA sequencing 5 days after ADX showed that TTP overexpression suppressed the expression of genes associated with the innate immune response. Importantly, TTP overexpression did not protect from high-dose-tamoxifen–induced SPEM development, suggesting that protection in the ADX model is achieved primarily by suppressing inflammation. Finally, we show that protection from gastric inflammation was only partially due to the suppression of Tnf, a well-known TTP target. Conclusions: Our results show that TTP exerts broad anti-inflammatory effects in the stomach and suggest that therapies that increase TTP expression may be effective treatments of proneoplastic gastric inflammation. Transcript profiling: GSE164349.

Summary: Transsynaptic viral tracing requires tissue sectioning, manual cell counting, and anatomical assignment, all of which are time intensive. We describe a protocol for BrainPipe, a scalable software for automated anatomical alignment and object counting in light-sheet microscopy volumes. BrainPipe can be generalized to new counting tasks by using a new atlas and training a neural network for object detection. Combining viral tracing, iDISCO+ tissue clearing, and BrainPipe facilitates mapping of cerebellar connectivity to the rest of the murine brain.For complete details on the use and execution of this protocol, please refer to Pisano et al. (2021).

Toxocara canis and T. cati are zoonotic roundworm parasites of dogs, cats and foxes. These definitive hosts pass eggs in their faeces, which contaminate the environment and can subsequently be ingested via soil or contaminated vegetables. In humans, infection with Toxocara can have serious health implications. This proof-of-concept study aimed to investigate the presence of Toxocara spp. eggs on ‘ready-to-eat’ vegetables (lettuce, spinach, spring onion and celery) sampled from community gardens in southern England. The contamination of vegetables with Toxocara eggs has never been investigated in the UK before, and more widely, this is the first time vegetables grown in community gardens in Europe have been assessed for Toxocara egg contamination. Sixteen community gardens participated in the study, providing 82 vegetable samples fit for analysis. Study participants also completed an anonymous questionnaire on observed visits to the sites by definitive hosts of Toxocara. Comparison of egg recovery methods was performed using lettuce samples spiked with a series of Toxocara spp. egg concentrations, with sedimentation and centrifugal concentration retrieving the highest number of eggs. A sample (100 g) of each vegetable type obtained from participating community gardens was tested for the presence of Toxocara eggs using the optimised method. Two lettuce samples tested positive for Toxocara spp. eggs, giving a prevalence of 2.4% (95% CI =1.3–3.5%) for vegetable samples overall, and 6.5% (95% CI = 4.7–8.3%; n = 31) specifically for lettuce. Questionnaire data revealed that foxes, cats and dogs frequently visited the community gardens in the study, with 88% (68/77) of respondents reporting seeing a definitive host species or the faeces of a definitive host at their site. This proof-of-concept study showed for the first time the presence of Toxocara spp. eggs on vegetables grown in the UK, as well as within the soil where these vegetables originated, and highlights biosecurity and zoonotic risks in community gardens. This study establishes a method for assessment of Toxocara spp. eggs on vegetable produce and paves the way for larger-scale investigations of Toxocara spp. egg contamination on field-grown vegetables.

Cannabis use among individuals before and during pregnancy is increasing alongside the proliferation of new products with various modes of administration. Preconception cannabis use is a strong predictor of prenatal cannabis use. Yet little is known about how individuals administer cannabis during the preconception period, particularly in socioeconomically vulnerable populations. This study examined the prevalence and correlates of modes of cannabis administration (smoke, vape, blunts, edible/oral, dabs/wax, lotion/topical) during the year before conception, among patients who self-reported preconception cannabis use during universal screening in prenatal care. Descriptive statistics included sociodemographic characteristics, preconception cannabis use frequency, and modes of administration. Chi-square tests examined whether mode was associated with sociodemographic characteristics and use frequency. The sample (N = 11,936, screened from February 2020-May 2021) was 59.8% non-White and 26.1% were

Gender bias exists not only in the stereotypes used to portray male and female figures, but more importantly, in the word choice media outlets use to describe political figures. Research in computational linguistics has not yet focused on the problem of identifying gender bias in political news from a variety of leanings, despite decades of research from the political science perspective. In this work, we introduce a new dataset – News-Bias – and demonstrate through extensive experimentation that there exists significant gender bias in political news, even with all gendered terms, and personally identifiable information removed. We show that bias persists through the document embeddings, sentiment and word choice across news outlets and political leanings.

Background: Patients receiving warfarin who spend a lower proportion of time in therapeutic international normalized ratio (INR) range (TTR) have a higher risk of both bleeding complications and thromboembolic events. Using warfarin dosing algorithms is one intervention associated with improved INR stability. Objective: To determine the feasibility of an individualized warfarin dosing algorithm (Fearon Algorithm) under anticoagulation management service (AMS) care and compare measures of INR control using the algorithm with standard care. Methods: A pre/post intervention feasibility study consisting of the 12 months prior to patient enrollment (pre-study phase) and 6 months in which patients used the Fearon Algorithm under the supervision of an AMS pharmacist (AMS phase). The primary study outcome was the change in individual TTR. Results: A total of 30 patients were enrolled in the study, 26 (87%) of whom successfully completed the AMS study phase using the Fearon Algorithm. Median corrected individual TTR increased significantly from 53% (IQR: 39%, 64%) during the year prior to enrollment to 63% (IQR: 57%, 73%) during the AMS phase (p

Purpose: Patients with large, high-grade soft tissue sarcomas are commonly treated with aggressive limb preservation regimens. This study aimed to assess cancer control outcomes of patients treated with neoadjuvant chemoradiation (CRT) compared with radiation therapy (RT) alone. Methods: We reviewed records of patients with high-grade extremity or trunk soft tissue sarcomas ≥5 cm who were treated with neoadjuvant radiation with or without chemotherapy. Patient and disease characteristics were compared using t test and χ2 tests. Standardized mortality ratio weighted method was used to compare overall survival (OS), local control, and disease-free (DFS) survival. Acute radiation and surgical toxicity were reported. Results: In the study, 64 patients (34 CRT and 30 RT) treated between 1997 and 2015 were analyzed. In the RT group compared with the CRT group, the patient population was older, with a median age of 65 versus 50 years (P < .001), and more likely to have cardiovascular disease (CVD; 30% vs 0%, P < .001). At a median follow-up of 41 months, after adjusting for propensity score of receiving RT, the 3-year LC was 87.3% versus 86.1%, DFS was 58.5% versus 56.6%, and OS was 75.6% versus 69.0% for the CRT and RT groups, respectively (P > .05). Acute dermatitis occurred in 18% versus 3% and surgical complications occurred in 32% versus 17% of CRT and RT patients, respectively. Conclusions: In this study, patients receiving RT alone were more likely to be older and have comorbid cardiovascular disease. When controlling for baseline differences, neoadjuvant CRT and RT provided similar rates of LC, DFS, and OS.

Introduction: Warfarin maintenance dosing algorithms improve the time in therapeutic International Normalized Ratio (INR) range (TTR), a surrogate marker for clinical outcomes. Despite demonstrated benefit, many anticoagulation providers utilize experience-based dosing instead. This study assessed rates of concordance between experience-based and algorithm-based warfarin dosing at a single anticoagulation clinic. Methods: Within University of Utah Health Thrombosis Service, patients on a maintenance dose of warfarin with an INR goal of 2.0–3.0 or 2.5–3.5 and who had INR results during November 2019 were included. Experienced-based approaches for out-of-range INRs were compared to a validated dosing algorithm to determine algorithm concordance rates as well as likelihood that algorithm concordance would return the INR into therapeutic range. Results: During the one-month study period, there were 1120 out-of-range INRs in 770 patients included in this analysis. Providers’ decisions were 50.5% algorithm-concordant for dosing adjustments and 59.2% concordant for follow-up intervals. Algorithm-concordant dosing practices resulted in a significantly higher likelihood of returning the subsequent INR to the target range (odds ratio [OR] 1.33, 95% confidence interval [CI] 1.05–1.68), whereas algorithm-concordant follow-up intervals did not significantly impact return of INR to therapeutic range (OR 0.79, 95% CI 0.62–1.00). Baseline deviation from INR goal was determined to be significantly different between concordant and discordant study groups. Controlling for the deviation magnitude attenuated the significance of dosing concordance rates on return to INR target range (adjusted OR 1.16, 95% CI 0.91–1.48), while impact of follow-up concordance remained not statistically significant (adjusted OR 0.84, 95% CI 0.66–1.07). No provider characteristics were associated with the likelihood of return to INR goal. Conclusion: Experience-based dosing was concordant with a validated dosing algorithm only half the time. Algorithm-concordant dosing increased the likelihood of returning the next INR to therapeutic range, though controlling for deviation magnitude attenuated the statistical significance of dosing concordance with return to INR goal rates. These findings support further research regarding implementing strategies that promote the use of a validated dosing algorithm among experienced anticoagulation providers.

Alzheimer's disease (AD) is the most common form of dementia, which is neuropathologically characterized by extracellular senile plaques containing amyloid-β and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. Previous studies have suggested a role for septin (SEPTIN) protein family members in AD-associated cellular processes. Here, we elucidated the potential role of presynaptic SEPTIN5 protein and its post-translational modifications in the molecular pathogenesis of AD. RNA and protein levels of SEPTIN5 showed a significant decrease in human temporal cortex in relation to the increasing degree of AD-related neurofibrillary pathology. Conversely, an increase in the phosphorylation of the functionally relevant SEPTIN5 phosphorylation site S327 was observed already in the early phases of AD-related neurofibrillary pathology, but not in the cerebrospinal fluid of individuals fulfilling the criteria for mild cognitive impairment due to AD. According to the mechanistic assessments, a link between SEPTIN5 S327 phosphorylation status and the effects of SEPTIN5 on amyloid precursor protein processing and markers of autophagy was discovered in mouse primary cortical neurons transduced with lentiviral constructs encoding wild type SEPTIN5 or SEPTIN5 phosphomutants (S327A and S327D). C57BL/6 J mice intrahippocampally injected with lentiviral wild type SEPTIN5 or phosphomutant constructs did not show changes in cognitive performance after five to six weeks from the start of injections. However, SEPTIN5 S327 phosphorylation status was linked to changes in short-term synaptic plasticity ex vivo at the CA3-CA1 synapse. Collectively, these data suggest that SEPTIN5 and its S327 phosphorylation status play a pivotal role in several cellular processes relevant for AD.

Summary: Comprehensive characterization of tumor antigens is essential for the design of cancer immunotherapies, and mass spectrometry (MS)-based immunopeptidomics enables high-throughput identification of major histocompatibility complex (MHC)-bound peptide antigens in vivo. Here we construct an immunopeptidome atlas of human cancer through an extensive collection of 43 published immunopeptidomic datasets and standardized analysis of 81.6 million MS/MS spectra using an open search engine. Our analysis greatly expands the current knowledge of MHC-bound antigens, including an unprecedented characterization of post-translationally modified antigens and their cancer-association. We also perform systematic analysis of cancer-testis antigens, cancer-associated antigens, and neoantigens. We make all these data together with annotated MS/MS spectra supporting identification of each antigen in an easily browsable web portal named cancer antigen atlas (caAtlas). caAtlas provides a central resource for the selection and prioritization of MHC-bound peptides for in vitro HLA binding assay and immunogenicity testing, which will pave the way to eventual development of cancer immunotherapies.

Background: Almost one-fourth of medically ill patients may remain at risk for venous thromboembolism (VTE) following hospital discharge, yet few receive extended-duration VTE prophylaxis. Methods: This qualitative study at a single academic medical center assessed hospitalists’ perceptions of and barriers to implementation of extended-duration VTE prophylaxis following hospital discharge for the medically ill with the purpose of generating topics and hypotheses for future study. A focus group was conducted using semi-structured facilitator template to guide the discussion. Anonymous verbatim data transcribed from focus group participants were summarized using thematic analysis. Results: Fifteen hospitalist providers at University of Utah Hospital participated in this focus group. Themes uncovered during the session included perceived low burden of post-hospitalization VTE; lack of compelling evidence supporting the net clinical benefit of extended-duration prophylaxis; concern for high medication cost; practical uncertainty about prescribing extended-duration prophylaxis; and added risk of complications (bleeding events, transitions of care confusion, polypharmacy). Conclusions: This group of providers believed post-hospitalization VTE risk in the medically ill is not sufficiently high to justify potential risks of extended-duration VTE prophylaxis and that a strong case for net clinical benefit and cost-effectiveness has not been made. These qualitative data are hypothesis-generating and future research should clearly define and quantify the timing and risk of VTE following hospitalization for medical illness in a real-world population, validate practical VTE and bleeding risk stratification schema, and explore cost-effectiveness of extended-duration prophylaxis. Ultimately, providers seek a clear message of which patients derive net clinical benefit from extended-duration VTE prophylaxis.

Summary: Spaceflight missions can cause immune system dysfunction in astronauts with little understanding of immune outcomes in deep space. This study assessed immune responses in mice following ground-based, simulated deep spaceflight conditions, compared with data from astronauts on International Space Station missions. For ground studies, we simulated microgravity using the hindlimb unloaded mouse model alone or in combination with acute simulated galactic cosmic rays or solar particle events irradiation. Immune profiling results revealed unique immune diversity following each experimental condition, suggesting each stressor results in distinct circulating immune responses, with clear consequences for deep spaceflight. Circulating plasma microRNA sequence analysis revealed involvement in immune system dysregulation. Furthermore, a large astronaut cohort showed elevated inflammation during low-Earth orbit missions, thereby supporting our simulated ground experiments in mice. Herein, circulating immune biomarkers are defined by distinct deep space irradiation types coupled to simulated microgravity and could be targets for future space health initiatives.

HIV-1 selectively disrupts neuronal integrity within specific brain regions, reflecting differences in viral tropism and/or the regional differences in the vulnerability of distinct neuronal subpopulations within the CNS. Deficits in prefrontal cortex (PFC)-mediated executive function and the resultant loss of behavioral control are a particularly debilitating consequence of neuroHIV. To explore how HIV-1 disrupts executive function, we investigated the effects of 48 ​h, 2 and/or 8 weeks of HIV-1 Tat exposure on behavioral control, synaptic connectivity, and neuroimmune function in the anterior cingulate cortex (ACC) and associated cortico-basal ganglia (BG)-thalamocortical circuitry in adult, Tat transgenic male mice. HIV-1 Tat exposure increased novelty-exploration in response to novel food, flavor, and environmental stimuli, suggesting that Tat triggers increased novelty-exploration in situations of competing motivation (e.g., drive to feed or explore vs. fear of novel, brightly lit open areas). Furthermore, Tat induced adaptability in response to an environmental stressor and pre-attentive filtering deficits. The behavioral insufficiencies coincided with decreases in the inhibitory pre- and post-synaptic proteins, synaptotagmin 2 and gephyrin, respectively, in the ACC, and alterations in specific pro- and anti-inflammatory cytokines out of 23 assayed. The interaction of Tat exposure and the resultant time-dependent, selective alterations in CCL4, CXCL1, IL-12p40, and IL-17A levels in the PFC predicted significant decreases in adaptability. Tat decreased dendritic spine density and cortical VGLUT1 inputs, while increasing IL-1β, IL-6, CCL5, and CCL11 in the striatum. Alternatively, IL-1α, CCL5, and IL-13 were decreased in the mediodorsal thalamus despite the absence of synaptic changes. Thus, HIV-1 Tat appears to uniquely and systematically disrupt immune regulation and the inhibitory and excitatory synaptic balance throughout the ACC-BG-thalamocortical circuitry resulting in a loss of behavioral control.

Pregnane steroids, particularly allopregnanolone (AlloP), are neuroprotective in response to central insult. While unexplored in vivo, AlloP may confer protection against the neurological dysfunction associated with human immunodeficiency virus type 1 (HIV-1). The HIV-1 regulatory protein, trans-activator of transcription (Tat), is neurotoxic and its expression in mice increases anxiety-like behavior; an effect that can be ameliorated by progesterone, but not when 5α-reduction is blocked. Given that Tat's neurotoxic effects involve mitochondrial dysfunction and can be worsened with opioid exposure, we hypothesized that Tat and/or combined morphine would perturb steroidogenesis in mice, promoting neuronal death, and that exogenous AlloP would rescue these effects. Like other models of neural injury, conditionally inducing HIV-1 Tat in transgenic mice significantly increased the central synthesis of pregnenolone and progesterone's 5α-reduced metabolites, including AlloP, while decreasing central deoxycorticosterone (independent of changes in plasma). Morphine significantly increased brain and plasma concentrations of several steroids (including progesterone, deoxycorticosterone, corticosterone, and their metabolites) likely via activation of the hypothalamic-pituitary-adrenal stress axis. Tat, but not morphine, caused glucocorticoid resistance in primary splenocytes. In neurons, Tat depolarized mitochondrial membrane potential and increased cell death. Physiological concentrations of AlloP (0.1, 1, or 10 nM) reversed these effects. High-concentration AlloP (100 nM) was neurotoxic in combination with morphine. Tat induction in transgenic mice potentiated the psychomotor effects of acute morphine, while exogenous AlloP (1.0 mg/kg, but not 0.5 mg/kg) was ameliorative. Data demonstrate that steroidogenesis is altered by HIV-1 Tat or morphine and that physiological AlloP attenuates resulting neurotoxic and psychomotor effects.

Summary: The incidence of human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is increasing and implicated in more than 60% of all oropharyngeal carcinomas (OPSCCs). Although whole-genome, transcriptome, and proteome analyses have identified altered signaling pathways in HPV-induced HNSCCs, additional tools are needed to investigate the unique pathobiology of OPSCC. Herein, bioinformatics analyses of human HPV(+) HNSCCs revealed that all tumors express full-length E6 and identified molecular subtypes based on relative E6 and E7 expression levels. To recapitulate the levels, stoichiometric ratios, and anatomic location of E6/E7 expression, we generated a genetically engineered mouse model whereby balanced expression of E6/E7 is directed to the oropharyngeal epithelium. The addition of a mutant PIK3CAE545K allele leads to the rapid development of pre-malignant lesions marked by immune cell accumulation, and a subset of these lesions progress to OPSCC. This mouse provides a faithful immunocompetent model for testing treatments and investigating mechanisms of immunosuppression. : Carper et al. present the “iKHP” mouse, in which HPV16 oncogenes are inducibly activated in vivo in a tissue-specific and temporal manner. Oropharyngeal-specific expression of E6/E7 with PIK3CAE545K in these mice promotes the development of premalignant lesions marked by immune cell infiltration, but only a subset spontaneously convert to OPSCC. Keywords: genetically engineered mouse model, GEMM, human papilloma virus, HPV, HPV16, head and neck squamous cell carcinoma, HNSCC, oropharyngeal squamous cell carcinoma, OPSCC, immunocompetent, tumorigenesis, oncogene, tumor suppressor, LumiFluor

The Affordable Care Act (ACA) promised to narrow smoking disparities by expanding access to healthcare and mandating comprehensive coverage for tobacco treatment starting in 2014. We examined whether two years after ACA implementation disparities in receiving clinician advice to quit and smokers' knowledge and use of treatment resources remained.We conducted telephone interviews in 2016 with a stratified random sample of self-reported smokers newly enrolled in the Kaiser Permanente Northern California's (KPNC) integrated healthcare delivery system in 2014 (N = 491; 50% female; 53% non-white; 6% Spanish language). We used Poisson regression with robust standard errors to test whether sociodemographics, insurance type, comorbidities, smoking status in 2016 (former, light/nondaily [

Background: An investigational drug service (IDS) has a foundational role in ensuring the safe and efficient management of investigational drugs. The objective of this assessment is to determine economic value of an IDS within a Veterans Affairs health care system. Methods: This assessment was a single-center retrospective record review. Study protocols managed by the IDS over a 2-year period were evaluated for cost avoidance, revenue, and waived revenue. Cost avoidance was defined as the cost savings generated when a research subject received sponsor-provided treatment in place of a therapy that would have been otherwise funded by the institution. Revenue from fees charged to investigators and waived revenue based on the standardized IDS fee schedule were also totaled. The total economic value to the institution accounted for the personnel costs of the IDS. Results: Twenty-three investigational study protocols managed by the IDS resulted in economic outcomes. The total cost avoidance during the two-year period was $482,627.33. The total revenue and waived revenue associated with the IDS was $16,822 and $54,200, respectively. Oncology protocols had the highest contribution to the outcomes of cost avoidance and revenue and mental health protocols had the highest contribution for waived revenue. The overall economic value of the IDS to the institution was $393,649.33. Conclusions: Over a two-year period, the IDS demonstrated a substantial economic value that was largely driven by cost avoidance. Revenue generation from fees charged to investigators and cost savings to the investigator through waived revenue also contributed economic benefits to the institution. Keywords: Pharmacy, Research pharmacist, Pharmacoeconomics, Cost avoidance, Cost savings, Clinical research

Background and objectives: Supraglottic airway devices are increasingly used as an option to tracheal intubation for elective procedures of varying complexity. The aim of this study was to prospectively evaluate the clinical use of the laryngeal mask airway Supreme® (LMAS) in patients undergoing elective breast surgery and compare it with endotracheal tube (ETT). Methods: Sixty patients undergoing breast procedures under general anesthesia were randomly divided into two groups according to the device used (LMAS or ETT). Time of insertion, number of insertion attempts, hemodynamic response to insertion, presence of blood on the device used; and incidence of sore throat, dysphagia, nausea and vomiting were assessed postoperatively. Results: There was no difference between groups regarding time of insertion, number of attempts for successful insertion, and presence of blood on the device. Heart rate and blood pressure after insertion were higher in ETT group. Incidence of sore throat and dysphagia was also higher in ETT group after two hours in the postoperative period. There was no difference regarding incidence and severity of complications evaluated after six hours postoperatively. Conclusions: The use of the LMAS technique to access airway during general anesthesia for elective breast surgery is as safe and effective as tracheal intubation, with the advantage of promoting smaller hemodynamic response during its management and lower incidence of sore throat and dysphagia in the first hours after surgery. Keywords: Equipment, Laryngeal mask airway, Complications, General anesthesia

The sterol regulatory element binding-proteins (SREBPs) are transcription factors that regulate the genes of lipid metabolism. Cholesterol and unsaturated fatty acids regulate SREBPs. Giardia lamblia (GL) is an intestinal parasite and one of the earliest derived members within the eukaryotic lineage. GLs exist as trophozoites and cysts. Growth in cholesterol depletion induces transcription of cyst-wall protein (CWP) genes that are upregulated during encystation. The hypothesis was investigated that SREBP-like pathways have a role in cwp gene transcription. Chinese hamster ovary cells were transfected with a cwp-2 promoter reporter construct. Incubation with cholesterol or oleate reduced cwp-2 mediated gene transcription to about half of the control. Incubation in sterol-depleted media, or in the presence of either an inhibitor of intracellular cholesterol movement or inhibitor of cholesterol synthesis, increased gene expression up to 3-fold. Overexpression of SREBPs increased reporter gene activity 2.5-fold. In the absence of functional SREBPs, cwp-2 was not regulated by cholesterol. Footprint analysis of cwp-2 reveals three novel binding sites for mammalian SREBPs with no homologies in other species or humans.The data show that SREBP binds to and can modulate transcription of a regulatory element from an ancient eukaryote and suggest the existence of an SREBP homolog in GL.

Objective: To analyze the Swiss public perception of COVID-19 communication by the government and its impact on behavior and trust. Methods: A cross-sectional representative online survey was conducted in January 2022 in a sample of 2587 Swiss residents. Results: Overall the survey showed moderate satisfaction with communication, with relevance rated highly. Perceptions of communication varied across demographics. Also, differences were noted in trust in institutions, risk perception, and attitudes towards public health measures based on perceived communication quality. Conclusion: This study highlights the dynamic nature of public health communication and underscores the significance of continuous adaptation and evaluation of strategies to effectively reach and influence diverse audiences. As misinformation persists, the study underscores the need for informative, empathetic, and honest communication, as well as tailored approaches to build public trust—an essential asset for managing health crises successfully. Innovation: This study provides innovative concrete insights into how governmental communication could be designed more strategically to effectively communicate with the public in contexts characterized by disinformation, emphasizing the role of quality, honest, and empathetic communication in public health messaging.

Introduction: Glaucoma, the leading cause of irreversible blindness globally, presents a growing public health concern with its prevalence expected to reach 111.8 million by 2040. This condition imposes both direct and indirect economic costs. In addition to medical expenses, indirect costs encompass lost productivity and adverse effects on mental health and independence. Early glaucoma stages primarily manifest as peripheral vision loss, but as it progresses, it significantly impairs one's quality of life. There is a growing body of research exploring the relationship between glaucoma and workplace functioning, including absenteeism and productivity loss. This systematic review aims to comprehensively investigate how glaucoma affects work productivity and the associated economic burden. Methods: This study adheres to the PRISMA guidelines. A literature search was conducted across multiple databases, including MEDLINE, Embase, CINAHL, and PsycINFO. Two independent reviewers screened titles, abstracts, and full-text articles based on predefined inclusion and exclusion criteria. Covidence software was employed for study selection and quality assessment. The Modified Downs and Black Checklist was used to evaluate study quality and thematic analysis was used to analyze data. Results: 17 studies met the inclusion criteria. The results revealed a significant impact of glaucoma on workplace functioning including, individuals with glaucoma experienced higher sickness absenteeism rates than those without glaucoma, glaucoma was associated with reduced labor force participation, leading to substantial productivity losses. Individuals with visual impairments and blindness earned less than those with normal vision, contributing to a significant financial burden. Glaucoma had a substantial impact on daily physical, emotional, and occupational functioning. Individuals with glaucoma faced limitations in performing daily activities and experienced difficulties in social interactions and household chores. Visual impairment due to glaucoma resulted in work disability, with some individuals reporting glaucoma-related visual disability as the main cause of their unemployment. A significant association between unemployment and glaucoma was observed in various studies, particularly in developing countries. Conclusion: Glaucoma significantly impairs work productivity and performance, resulting in substantial economic burdens on individuals, businesses, and society. Addressing these challenges requires multifaceted approaches, including workplace accommodations and holistic care.