Sustained, drug-free control of HIV-1 replication is naturally achieved in less than 0.5% of infected individuals (here termed 'elite controllers'), despite the presence of a replication-competent ...viral reservoir
. Inducing such an ability to spontaneously maintain undetectable plasma viraemia is a major objective of HIV-1 cure research, but the characteristics of proviral reservoirs in elite controllers remain to be determined. Here, using next-generation sequencing of near-full-length single HIV-1 genomes and corresponding chromosomal integration sites, we show that the proviral reservoirs of elite controllers frequently consist of oligoclonal to near-monoclonal clusters of intact proviral sequences. In contrast to individuals treated with long-term antiretroviral therapy, intact proviral sequences from elite controllers were integrated at highly distinct sites in the human genome and were preferentially located in centromeric satellite DNA or in Krüppel-associated box domain-containing zinc finger genes on chromosome 19, both of which are associated with heterochromatin features. Moreover, the integration sites of intact proviral sequences from elite controllers showed an increased distance to transcriptional start sites and accessible chromatin of the host genome and were enriched in repressive chromatin marks. These data suggest that a distinct configuration of the proviral reservoir represents a structural correlate of natural viral control, and that the quality, rather than the quantity, of viral reservoirs can be an important distinguishing feature for a functional cure of HIV-1 infection. Moreover, in one elite controller, we were unable to detect intact proviral sequences despite analysing more than 1.5 billion peripheral blood mononuclear cells, which raises the possibility that a sterilizing cure of HIV-1 infection, which has previously been observed only following allogeneic haematopoietic stem cell transplantation
, may be feasible in rare instances.
Patients exhibiting signs of hyperactive delirium with severe agitation (HDSA) may require sedating medications for stabilization and safe transport to the hospital. Determining the patient's weight ...and calculating the correct weight-based dose may be challenging in an emergency. A fixed dose ketamine protocol is an alternative to the traditional weight-based administration, which may also reduce dosing errors. The objective of this study was to evaluate the frequency and characteristics of adverse events following pre-hospital ketamine administration for HDSA.
Emergency Medical Services (EMS) records from four agencies were searched for prehospital ketamine administration. Cases were included if a 250 mg dose of ketamine was administered on standing order to an adult patient for clinical signs consistent with HDSA. Protocols allowed for a second 250 mg dose of ketamine if the first dose was not effective. Both the 250 mg initial dose and the total prehospital dose were analyzed for weight based dosing and adverse events.
Review of 132 cases revealed 60 cases that met inclusion criteria. Patients' median weight was 80 kg (range: 50-176 kg). No patients were intubated by EMS, one only requiring suction, three required respiratory support via bag valve mask (BVM). Six (10%) patients were intubated in the emergency department (ED) including the three (5%) supported by EMS via BVM, three (5%) others who were sedated further in the ED prior to requiring intubation. All six patients who were intubated were discharged from the hospital with a Cerebral Performance Category (CPC) 1 score. The weight-based dosing equivalent for the 250 mg initial dose (OR: 2.62, CI: 0.67–10.22) and the total prehospital dose, inclusive of the 12 patients that were administered a second dose, (OR: 0.74, CI: 0.27, 2.03), were not associated with the need for intubation.
The 250 mg fixed dose of ketamine was not >5 mg/kg weight-based dose equivalent for all patients in this study. Although a second 250 mg dose of ketamine was permitted under standing orders, only 12 (20%) of the patients were administered a second dose, none experienced an adverse event. This indicates that the 250 mg initial dose was effective for 80% of the patients. Four patients with prehospital adverse events likely related to the administration of ketamine were found. One required suction, three (5%) requiring BVM respiratory support by EMS were subsequently intubated upon arrival in the ED. All 60 patients were discharged from the hospital alive. Further research is needed to determine an optimal single administration dose for ketamine in patients exhibiting signs of HDSA, if employing a standardized fixed dose medication protocol streamlines administration, and if the fixed dose medication reduces the occurrence of dosage errors.
Vision loss due to vascular disease of the retina is a leading cause of blindness in the world. Retinal angiomatous proliferation (RAP) is a subgroup of neovascular age-related macular degeneration ...(AMD), whereby abnormal blood vessels develop in the retina leading to debilitating vision loss and eventual blindness. The novel mouse strain, neoretinal vascularization 2 (NRV2), shows spontaneous fundus changes associated with abnormal neovascularization. The purpose of this study is to characterize the induction of pathologic angiogenesis in this mouse model.
The NRV2 mice were examined from postnatal day 12 (p12) to 3 months. The phenotypic changes within the retina were evaluated by fundus photography, fluorescein angiography, optical coherence tomography, and immunohistochemical and electron microscopic analysis. The pathological neovascularization was imaged by confocal microscopy and reconstructed using three-dimensional image analysis software.
We found that NRV2 mice develop multifocal retinal depigmentation in the posterior fundus. Depigmented lesions developed vascular leakage observed by fluorescein angiography. The spontaneous angiogenesis arose from the retinal vascular plexus at postnatal day (p)15 and extended toward retinal pigment epithelium (RPE). By three months of age, histological analysis revealed encapsulation of the neovascular lesion by the RPE in the photoreceptor cell layer and subretinal space.
The NRV2 mouse strain develops early neovascular lesions within the retina, which grow downward towards the RPE beginning at p15. This retinal neovascularization model mimics early stages of human retinal angiomatous proliferation (RAP) and will likely be a useful in elucidating targeted therapeutics for patients with ocular neovascular disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
People tend to overestimate their expectations for weight loss relative to what is achievable in a typical evidence-based behavioral weight management program, which can impact treatment satisfaction ...and outcomes. We are engaged in formative research to design a digital intervention that addresses binge eating and weight management; thus, understanding expectations among this group can inform more engaging intervention designs to produce a digital intervention that can achieve greater clinical success. Studies examining weight loss expectations have primarily focused on people who have overweight or obesity. Only one study has investigated weight loss expectations among people with binge eating disorder, a population that frequently experiences elevated weight and shape concerns and often presents to treatment with the goal of losing weight.
The aim of the study is to investigate differences in weight loss expectations among people with varying levels of binge eating to inform the design of a digital intervention for binge eating and weight management. Such an evaluation may be crucial for people presenting for a digital intervention, given that engagement and dropout are notable problems for digital behavior change interventions. We tested the hypotheses that (1) people who endorsed some or recurrent binge eating would expect to lose more weight than those who did not endorse binge eating and (2) people who endorsed a more severe versus a low or moderate overvaluation of weight and shape would have higher weight loss expectations.
A total of 760 adults (n=504, 66% female; n=441, 58% non-Hispanic White) completed a web-based screening questionnaire. One-way ANOVAs were conducted to explore weight loss expectations for binge eating status as well as overvaluation of shape and weight.
Weight loss expectations significantly differed by binge eating status. Those who endorsed some and recurrent binge eating expected to lose more weight than those who endorsed no binge eating. Participants with severe overvaluation of weight or shape expected to lose the most weight compared to those with low or moderate levels of overvaluation of weight and shape.
In the sample, people interested in a study to inform a digital intervention for binge eating and weight management overestimated their expectations for weight loss. Given that weight loss expectations can impact treatment completion and success, it may be important to assess and modify weight loss expectations among people with binge eating prior to enrolling in a digital intervention. Future work should design and test features that can modify these expectations relative to individuals' intended treatment goals to facilitate engagement and successful outcomes in a digital intervention.
Abstract
We estimated the trends and correlates of vaccine hesitancy and its association with subsequent vaccine uptake among 5,458 adults in the United States. Participants belonged to the ...Communities, Households, and SARS-CoV-2 Epidemiology COVID (CHASING COVID) Cohort, a national longitudinal study. Trends and correlates of vaccine hesitancy were examined longitudinally in 8 interview rounds from October 2020 to July 2021. We also estimated the association between willingness to vaccinate and subsequent vaccine uptake through July 2021. Vaccine delay and refusal decreased from 51% and 8% in October 2020 to 8% and 6% in July 2021, respectively. Compared with non-Hispanic (NH) White participants, NH Black and Hispanic participants had higher adjusted odds ratios (aOR) for both vaccine delay (for NH Black, aOR = 2.0 (95% confidence interval (CI): 1.5, 2.7), and for Hispanic, 1.3 (95% CI: 1.0, 1.7)) and vaccine refusal (for NH Black, aOR = 2.5 (95% CI: 1.8, 3.6), and for Hispanic, 1.4 (95% CI: 1.0, 2.0)) in June 2021. COVID-19 vaccine hesitancy, compared with vaccine-willingness, was associated with lower odds of subsequent vaccine uptake (for vaccine delayers, aOR = 0.15, 95% CI: 0.13, 0.18; for vaccine refusers, aOR = 0.02; 95% CI: 0.01, 0.03 ), adjusted for sociodemographic factors and COVID-19 history. Vaccination awareness and distribution efforts should focus on vaccine delayers.
Female reproductive health is recognized as a predictor of morbidity, mortality, and quality of life, although data in the setting of chronic kidney disease (CKD) are limited.
A mixed-methods study ...was employed. Phase 1 was an anonymous, internet-based survey. Phase 2 was semistructured interviews offered to all respondents upon survey completion.
The survey was disseminated internationally from October 4, 2021, to January 7, 2022, to individuals aged 18-50 years with both a uterus and CKD diagnosis.
Menstrual health and contraceptive use by CKD stage (dialysis, nondialysis CKD, and transplant).
Survey data were analyzed using descriptive statistics. Interview data were analyzed using the framework method of analysis.
Of 152 respondents, 98 (mean age 33±0.7 years; n=20dialysis, n=59nondialysis CKD, n=19transplant) satisfied the inclusion criteria, representing 3 continents. The most common causes of CKD among survey respondents were hereditary causes in dialysis (n=6, 30%) and glomerulonephritis in nondialysis CKD (n=22, 37%) and transplant (n=6, 32%). The majority reported heavy menstrual bleeding (n=12, 86% dialysis; n=46, 94% nondialysis CKD; n=14, 100% transplant). Less than half of participants were consistently able to afford period products. Condoms were the most common contraceptive reported. Most participants reported no contraceptive use (n=10, 50% dialysis; n=37, 63% nondialysis CKD; n=7, 37% transplant), primarily because of “fear”. Interviews (n=6) revealed a perception of a relationship between kidney function and menstrual health, concerns about contraceptive use, and a desire for greater multidisciplinary care to improve kidney and reproductive health.
Self-reported outcomes, need for internet access and a device.
Abnormal menstruation and period poverty (ie, inability to afford period products and the socioeconomic consequences of menstruation) were common, and contraceptive use was low among female individuals with CKD, highlighting an important gap in the sex-specific care of this population.
Chronic kidney disease (CKD) in female individuals is accompanied by menstrual disorders and low contraceptive use. However, most data are limited to the dialysis and transplant populations. Therefore, this mixed-methods study aimed to describe self-assessed menstruation and contraceptive use across all stages of CKD. People aged 18-50 years with a uterus and CKD diagnosis were invited to participate in an online survey shared internationally as well as an optional telephone interview. Abnormal menstruation and period poverty (ie, inability to afford period products and the socioeconomic consequences of menstruation) were common, and contraceptive use was low among female individuals with CKD, highlighting an important gap in the sex-specific care of this population.
Glioblastoma multiforme (GBM) pathobiology is characterized by its significant induction of immunosuppression within the tumor microenvironment, predominantly mediated by immunosuppressive ...tumor-associated myeloid cells (TAMCs). Myeloid cells play a pivotal role in shaping the GBM microenvironment and influencing immune responses, with direct interactions with effector immune cells critically impacting these processes.
Our study investigates the role of the CXCR6/CXCL16 axis in T-cell myeloid interactions within GBM tissues. We examined the surface expression of CXCL16, revealing its limitation to TAMCs, while microglia release CXCL16 as a cytokine. The study explores how these distinct expression patterns affect T-cell engagement, focusing on the consequences for T-cell function within the tumor environment. Additionally, we assessed the significance of CXCR6 expression in T-cell activation and the initial migration to tumor tissues.
Our data demonstrates that CXCL16 surface expression on TAMCs results in predominant T-cell engagement with these cells, leading to impaired T-cell function within the tumor environment. Conversely, our findings highlight the essential role of CXCR6 expression in facilitating T-cell activation and initial migration to tumor tissues. The CXCL16-CXCR6 axis exhibits dualistic characteristics, facilitating the early stages of the T-cell immune response and promoting T-cell infiltration into tumors. However, once inside the tumor, this axis contributes to immunosuppression.
The dual nature of the CXCL16-CXCR6 axis underscores its potential as a therapeutic target in GBM. However, our results emphasize the importance of carefully considering the timing and context of intervention. While targeting this axis holds promise in combating GBM, the complex interplay between TAMCs, microglia, and T cells suggests that intervention strategies need to be tailored to optimize the balance between promoting antitumor immunity and preventing immunosuppression within the dynamic tumor microenvironment.
Abstract
Glioblastoma (GBM) is the most common brain malignancy in adults and has a dismal prognosis. Advances in standard-of-care treatments for GBM have not kept pace with those for other ...malignancies, in part due to the inefficacy of immunotherapies in treating GBM. The tumor microenvironment (TME) of GBM is heavily populated with pro-tumorigenic tumor-associated macrophages (TAMs) and lacks robust infiltration of T cells. Given that the number of TAMs in the TME correlates with poor prognosis, understanding the mechanisms by which they thrive is essential for discovering new therapies. Bulk RNASeq data from mouse tumors indicates that the fructose transporter, SLC2A5, is highly expressed on TAMs relative to peripheral myeloid cells. Furthermore, human glioblastoma single cell RNASeq (scRNASeq) data indicates that SLC2A5 is expressed specifically on microglia, the tissue resident macrophage of the brain. To assess the necessity of SLC2A5 in microglia, we orthotopically implanted CT2A or QPP4 glioblastoma cells into wild-type mice and mice lacking SLC2A5 (SLC2A5 KO mice). We observed a significant increase in median survival in SLC2A5 KO mice compared to wild-type mice. This indicates a necessity of fructose metabolism in microglia to promote tumorigenesis. Upon ex vivo analysis of the immune compartment of the TME, we observed that microglial cells from tumors in SLC2A5 KO mice have higher expression of MHC-II and PDL1 molecules on the cell surface compared to those from wild-type mice. Additionally, the CD4:CD8 T cell ratio in tumors from SLC2A5 KO mice was lower than that in tumors from wild-type mice. These data suggest that fructose metabolism in microglia facilitates an immunosuppressive phenotype that promotes GBM progression.
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