Frequent first-trimester pregnancy loss in rhesus macaques infected with African-lineage Zika virus.

In the 2016 Zika virus (ZIKV) pandemic, a previously unrecognized risk of birth defects surfaced in babies whose mothers were infected with Asian-lineage ZIKV during pregnancy. Less is known about the impacts of gestational African-lineage ZIKV infections. Given high human immunodeficiency virus (HIV) burdens in regions where African-lineage ZIKV circulates, we evaluated whether pregnant rhesus macaques infected with simian immunodeficiency virus (SIV) have a higher risk of African-lineage ZIKV-associated birth defects. Remarkably, in both SIV+ and SIV- animals, ZIKV infection early in the first trimester caused a high incidence (78%) of spontaneous pregnancy loss within 20 days. These findings suggest a significant risk for early pregnancy loss associated with African-lineage ZIKV infection and provide the first consistent ZIKV-associated phenotype in macaques for testing medical countermeasures.

Impact of Cannabis Use on Immune Cell Populations and the Viral Reservoir in People With HIV on Suppressive Antiretroviral Therapy.

BACKGROUND: Human immunodeficiency virus (HIV) infection remains incurable due to the persistence of a viral reservoir despite antiretroviral therapy (ART). Cannabis (CB) use is prevalent amongst people with HIV (PWH), but the impact of CB on the latent HIV reservoir has not been investigated. METHODS: Peripheral blood cells from a cohort of PWH who use CB and a matched cohort of PWH who do not use CB on ART were evaluated for expression of maturation/activation markers, HIV-specific T-cell responses, and intact proviral DNA. RESULTS: CB use was associated with increased abundance of naive T cells, reduced effector T cells, and reduced expression of activation markers. CB use was also associated with reduced levels of exhausted and senescent T cells compared to nonusing controls. HIV-specific T-cell responses were unaffected by CB use. CB use was not associated with intact or total HIV DNA frequency in CD4 T cells. CONCLUSIONS: This analysis is consistent with the hypothesis that CB use reduces activation, exhaustion, and senescence in the T cells of PWH, and does not impair HIV-specific CD8 T-cell responses. Longitudinal and interventional studies with evaluation of CB exposure are needed to fully evaluate the impact of CB use on the HIV reservoir.

Artificial intelligence in dementia.

PURPOSE OF REVIEW: Artificial intelligence tools are being rapidly integrated into clinical environments and may soon be incorporated into dementia diagnostic paradigms. A comprehensive review of emerging trends will allow physicians and other healthcare providers to better anticipate and understand these powerful tools. RECENT FINDINGS: Machine learning models that utilize cerebral biomarkers are demonstrably effective for dementia identification and prediction; however, cerebral biomarkers are relatively expensive and not widely available. As eye images harbor several ophthalmic biomarkers that mirror the state of the brain and can be clinically observed with routine imaging, eye-based machine learning models are an emerging area, with efficacy comparable with cerebral-based machine learning models. Emerging machine learning architectures like recurrent, convolutional, and partially pretrained neural networks have proven to be promising frontiers for feature extraction and classification with ocular biomarkers. SUMMARY: Machine learning models that can accurately distinguish those with symptomatic Alzheimer's dementia from those with mild cognitive impairment and normal cognition as well as predict progressive disease using relatively inexpensive and accessible ocular imaging inputs are impactful tools for the diagnosis and risk stratification of Alzheimer's dementia continuum. If these machine learning models can be incorporated into clinical care, they may simplify diagnostic efforts. Recent advancements in ocular-based machine learning efforts are promising steps forward.

Peripheral (not central) corneal epithelia contribute to the closure of an annular debridement injury.

Corneal epithelia have limited self-renewal and therefore reparative capacity. They are continuously replaced by transient amplifying cells which spawn from stem cells and migrate from the periphery. Because this view has recently been challenged, our goal was to resolve the conflict by giving mice annular injuries in different locations within the corneolimbal epithelium, then spatiotemporally fate-mapping cell behavior during healing. Under these conditions, elevated proliferation was observed in the periphery but not the center, and wounds predominantly resolved by centripetally migrating limbal epithelia. After wound closure, the central corneal epithelium was completely replaced by K14+ limbal-derived clones, an observation supported by high-resolution fluorescence imaging of genetically marked cells in organ-cultured corneas and via computational modeling. These results solidify the essential role of K14+ limbal epithelial stem cells for wound healing and refute the notion that stem cells exist within the central cornea and that their progeny have the capacity to migrate centrifugally.

The Multiple Object Avoidance (MOA) task measures attention for action: Evidence from driving and sport.

Performance in everyday tasks, such as driving and sport, requires allocation of attention to task-relevant information and the ability to inhibit task-irrelevant information. Yet there are individual differences in this attentional function ability. This research investigates a novel task for measuring attention for action, called the Multiple Object Avoidance task (MOA), in its relation to the everyday tasks of driving and sport. The aim in Study 1 was to explore the efficacy of the MOA task to predict simulated driving behaviour and hazard perception. Whilst also investigating its test-retest reliability and how it correlates to self-report driving measures. We found that superior performance in the MOA task predicted simulated driving performance in complex environments and was superior at predicting performance compared to the Useful Field of View task. We found a moderate test-retest reliability and a correlation between the attentional lapses subscale of the Driving Behaviour Questionnaire. Study 2 investigated the discriminative power of the MOA in sport by exploring performance differences in those that do and do not play sports. We also investigated if the MOA shared attentional elements with other measures of visual attention commonly attributed to sporting expertise: Multiple Object Tracking (MOT) and cognitive processing speed. We found that those that played sports exhibited superior MOA performance and found a positive relationship between MOA performance and Multiple Object Tracking performance and cognitive processing speed. Collectively, this research highlights the utility of the MOA when investigating visual attention in everyday contexts.

Nuclear Leukocyte Immunoglobulin-like Receptor A3 Is Monomeric and Is Involved in Multiple Layers of Regulated Gene Expression and Translation.

The leukocyte immunoglobulin-like receptor A3 (LILRA3) is a soluble protein primarily expressed by peripheral blood monocytes and is abundant in sera of healthy donors. Extracellular LILRA3 is anti-inflammatory and displays neuro-regenerative functions in vitro. However, its intracellular expression, distribution, and function(s) remain unknown. Using a combination of high-resolution confocal and super-resolution microscopy, we identified intracellular expression of native LILRA3 in the nucleus of peripheral blood monocytes and in vitro-derived macrophages. This unexpected nuclear localization of LILRA3 was confirmed in LILRA3-GFP-transfected HEK293T cells. Western blot of proteins fractionated from primary macrophages and the transfected HEK293T cells confirmed nuclear localization of the native and expressed LILRA3 proteins. Interestingly, most of the LILRA3 in the nucleus was in a monomeric form like the biologically active secreted protein, while that in the other cellular compartments was in mixed monomeric, dimeric, and oligomeric forms. The predominant presence of monomeric LILRA3 in the nucleus was independently corroborated in transfected live HEK293T cells using the number and molecular brightness (N&B) analysis method. Immunoprecipitation and mass spectrometric peptide sequencing studies revealed that nuclear LILRA3 co-immunoprecipitated with several nuclear proteins involved in host protein synthesis machinery via direct interactions to a key multifunctional RNA-binding protein, the Ewing sarcoma breakpoint region 1 protein (EWS) (data are available via ProteomeXchange with identifier PXD024602). The biological significance of the nuclear expression of LILRA3 and its interaction with these key proteins remain to be elucidated.

Correction to: CT angiograms of the neck in strangulation victims: incidence of positive findings at a level one trauma center over a 7-year period.

The original source of the flowchart in Fig. 3 has not been referenced and acknowledged correctly in the original article. This is now corrected.

The metastasis suppressor, NDRG1, attenuates oncogenic TGF-ß and NF-κB signaling to enhance membrane E-cadherin expression in pancreatic cancer cells.

The metastasis suppressor, N-myc downstream-regulated gene-1 (NDRG1), plays multifaceted roles in inhibiting oncogenic signaling and can suppress the epithelial mesenchymal transition (EMT), a key step in metastasis. In this investigation, NDRG1 inhibited the oncogenic effects of transforming growth factor-ß (TGF-ß) in PANC-1 pancreatic cancer cells, promoting expression and co-localization of E-cadherin and ß-catenin at the cell membrane. A similar effect of NDRG1 at supporting E-cadherin and ß-catenin co-localization at the cell membrane was also demonstrated for HT-29 colon and CFPAC-1 pancreatic cancer cells. The increase in E-cadherin in PANC-1 cells in response to NDRG1 was mediated by the reduction of three transcriptional repressors of E-cadherin, namely SNAIL, SLUG and ZEB1. To dissect the mechanisms how NDRG1 inhibits nuclear SNAIL, SLUG and ZEB1, we assessed involvement of the nuclear factor-κB (NF-κB) pathway, as its aberrant activation contributes to the EMT. Interestingly, NDRG1 comprehensively inhibited oncogenic NF-κB signaling at multiple sites in this pathway, suppressing NEMO, Iĸĸα and IĸBα expression, as well as reducing the activating phosphorylation of Iĸĸα/ß and IĸBα. NDRG1 also reduced the levels, nuclear co-localization and DNA-binding activity of NF-κB p65. Further, Iĸĸα, which integrates NF-κB and TGF-ß signaling to upregulate ZEB1, SNAIL and SLUG, was identified as an NDRG1 target. Considering this, therapies targeting NDRG1 could be a new strategy to inhibit metastasis, and as such, we examined novel anticancer agents, namely di-2-pyridylketone thiosemicarbazones, which upregulate NDRG1. These agents downregulated SNAIL, SLUG and ZEB1 in vitro and in vivo using a PANC-1 tumor xenograft model, demonstrating their marked potential.

CT angiograms of the neck in strangulation victims: incidence of positive findings at a level one trauma center over a 7-year period.

PURPOSE: To determine the incidence of acute findings diagnosed with computed tomography angiography (CTA) of the neck among emergency department patients presenting with strangulation injury. METHOD AND MATERIALS: This institutional review board-approved, HIPAA-compliant retrospective review was performed at our academic urban level 1 trauma center. The PACS database was queried for all consecutive patients who had CTAs of the neck performed for the exam indication of strangulation between January 1, 2009, and April 30, 2016, resulting in 142 included patients. Analysis of the individual cases was then performed, recording any positive results, with clinical findings classified using, when possible, standardized terminology found in the literature. Frequency of acute injury in the CTA neck examinations was determined with the calculation of 95% confidence interval (CI) and positive clinical findings were evaluated by calculation of prevalence. Additionally, two board certified radiologists with training in neuroradiology assessed the cases for vascular injury. RESULTS: There were 142 patients who met inclusion criteria (average age, 32.6 years) and 116 (81.7%) patients were female. CTA of the neck revealed 21 patients to have acute injuries (15.5%, 95% CI 9.5, 21.4) including 6 initially reported vascular injuries (4.2%, 95% CI 0.9, 7.5). Although neck pain (73, 51.4%), loss of consciousness (67, 47.2%), and headache (31, 21.8%) were frequently reported in the ROS, their predictive value of vascular injury was weak (4.1%, 4.5%, and 3.2%, respectively). On physical exam, redness/bruising of the neck (73, 51.4%) and neck tenderness (47, 33.1%) were both the most common and had the highest prevalence (19.2% and 12.8%, respectively), however, when selecting for vascular injuries alone were found to have low predictive yield (vascular injury 4.1% and 2.1%, respectively). The above statistics were based on the initial radiologist report and Emergency Department findings. After retrospective review, 3 Grade 1 BIFFL vascular injuries were identified (2.1%), with one false negative case (0.7%). CONCLUSION: Performing CTA of the neck after acute strangulation injury rarely identifies clinically significant findings, with vascular injuries proving exceedingly rare. As positive vascular injury could not be clinically predicted by history and physical examination, prospective validation of a clinical prediction rule in this population is warranted.

A Comparison between Two Dilute Citrate Solutions (15 vs. 18 mmol/l) in Continuous Renal Replacement Therapy: The Base Excess and Renal Substitution Solution Study.

BACKGROUND/AIMS: The study aimed to compare the changes in biochemistry occurring in patients undergoing continuous renal replacement therapy (CRRT) using 2 trisodium citrate solutions, Baxter hemofiltration fluid containing 18 mmol/l (C18) and Baxter NamSol, a custom manufactured solution containing 15 mmol/l (C15), both delivered as regional citrate anticoagulation (RCA) predilution fluids for hemofiltration. METHODS: This is a prospective randomized control trial conducted in a major regional adult intensive care unit. Patients were randomized to 1 of 2 RCA fluids. Progress was monitored using a standard daily panel of acid-base and biochemical tests. RESULTS: Forty-eight patients, 23 C18 and 25 C15, were recruited. In both groups, acidosis resolved within 36 h of institution of CRRT. By day 3, there were significant differences in serum [Na+], standard base excess and serum bicarbonate concentration, all being higher in the C18 group (p < 0.01). By day 5, the PaCO2 had also risen in the C18 group (p = 0.03). CONCLUSIONS: The C15 solution provided equivalent filter life to the C18 solution but without significant hypernatremia and metabolic alkalosis.