Immunotherapy with biodegradable nanoparticles encapsulating the oligosaccharide galactose-alpha-1,3-galactose enhance immune tolerance against alpha-gal sensitization in a murine model of alpha-gal syndrome.

IgE antibodies against the mammalian oligosaccharide allergen galactose-α-1,3-galactose (αGal) can result in a severe allergic disease known as alpha-gal syndrome (AGS). This syndrome, acquired by tick bites that cause αGal sensitization, leads to allergic reactions after ingestion of non-primate mammalian meat and mammalian-derived products that contain αGal. Allergen-specific immunotherapies for this tickborne allergic syndrome are understudied, as are the immune mechanisms of allergic desensitization that induce clinical tolerance to αGal. Here, we reveal that prophylactic administration of αGal glycoprotein-containing nanoparticles to mice prior to tick protein-induced αGal IgE sensitization blunts the production of Th2 cytokines IL-4, IL-5, and IL-13 in an αGal-dependent manner. Furthermore, these effects correlated with suppressed production of αGal-specific IgE and hypersensitivity reactions, as measured by reduced basophil activation and histamine release and the systemic release of mast cell protease-1 (MCPT-1). Therapeutic administration of two doses of αGal-containing nanoparticles to mice sensitized to αGal had partial efficacy by reducing the Th2 cytokine production, αGal-specific IgE production, and MCPT-1 release without reducing basophil activation or histamine release. These data identify nanoparticles carrying encapsulated αGal glycoprotein as a potential strategy for augmenting αGal-specific immune tolerance and reveal diverse mechanisms by which αGal nanoparticles modify immune responses for established αGal-specific IgE-mediated allergic reactions.

Prevalence of problematic pharmaceutical opioid use in patients with chronic non-cancer pain: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Chronic non-cancer pain (CNCP) is one of the most common causes of disability globally. Opioid prescribing to treat CNCP remains widespread, despite limited evidence of long-term clinical benefit and evidence of harm such as problematic pharmaceutical opioid use (POU) and overdose. The study aimed to measure the prevalence of POU in CNCP patients treated with opioid analgesics. METHOD: A comprehensive systematic literature review and meta-analysis was undertaken using MEDLINE, Embase and PsycINFO databases from inception to 27 January 2021. We included studies from all settings with participants aged ≥ 12 with non-cancer pain of ≥ 3 months duration, treated with opioid analgesics. We excluded case-control studies, as they cannot be used to generate prevalence estimates. POU was defined using four categories: dependence and opioid use disorder (D&OUD), signs and symptoms of D&OUD (S&S), aberrant behaviour (AB) and at risk of D&OUD. We used a random-effects multi-level meta-analytical model. We evaluated inconsistency using the I2 statistic and explored heterogeneity using subgroup analyses and meta-regressions. RESULTS: A total of 148 studies were included with > 4.3 million participants; 1% of studies were classified as high risk of bias. The pooled prevalence was 9.3% [95% confidence interval (CI) = 5.7-14.8%; I2 = 99.9%] for D&OUD, 29.6% (95% CI = 22.1-38.3%, I2 = 99.3%) for S&S and 22% (95% CI = 17.4-27.3%, I2 = 99.8%) for AB. The prevalence of those at risk of D&OUD was 12.4% (95% CI = 4.3-30.7%, I2 = 99.6%). Prevalence was affected by study setting, study design and diagnostic tool. Due to the high heterogeneity, the findings should be interpreted with caution. CONCLUSIONS: Problematic pharmaceutical opioid use appears to be common in chronic pain patients treated with opioid analgesics, with nearly one in 10 experiencing dependence and opioid use disorder, one in three showing signs and symptoms of dependence and opioid use disorder and one in five showing aberrant behaviour.

Focusing HIV-1 Gag T-cell Responses to Highly Conserved Regions by DNA Vaccination in HVTN 119.

BACKGROUND: An HIV-1 DNA vaccine composed of seven highly conserved, structurally important elements (Conserved Elements, CE) of HIV p24Gag was tested in a phase I randomized, double-blind clinical trial (HVTN 119, NCT03181789) in people without HIV. A CE prime- CE+full-length p55Gag boost DNA vaccine was compared to p55Gag DNA vaccination only. METHODS: Two groups (n=25 each) received 4 DNA vaccinations [2xCE prime- 2xCE+p55Gag boost or 4x p55Gag] by intramuscular injection/electroporation, including IL-12 DNA adjuvant. The placebo group (n=6) received saline. Participants were followed for safety and tolerability. Immunogenicity was assessed for T cell and antibody responses. RESULTS: Both regimens were safe and generally well-tolerated. The p24CE vaccine was immunogenic (29% CD4+ and 4% CD8+ responders) and was significantly boosted by CE+p55Gag (64% CD4+, p=0.037; 42% CD8+, p=0.004). CE+p55Gag induced CD4+ responses to 5 of 7 CE, compared to only 2 CE by p55Gag DNA alone, with a higher reponse to CE5 in 30% of individuals (p=0.006). CE+p55Gag induced significantly higher mean CD4+ CE Tcell breadth (0.68 vs 0.22 CE; p=0.029) and a strong trend for increased CD4+ and CD8+ T-cell breadth (1.14 vs. 0.52 CE; p=0.051) compared to p55Gag alone. Both groups developed high p55Gag T-cell (91% each) and p24Gag antibody (91% vs. 80%) responses. p24CE vaccine-induced CD4+ CE T-cell responses correlated (p=0.007) with p24Gag antibody responses. CONCLUSION: The combination CE/CE+p55Gag DNA vaccine induced T-cell immune responses to conserved regions in p24Gag resulting in significant increases in breadth and epitope recognition throughout p55Gag. Vaccines able to focus immune responses by priming responses to highly conserved regions could be part of a comprehensive HIV vaccine strategy. CLINICAL TRIALS: gov NCT03181789 Study URL: https://www. CLINICALTRIALS: gov/search?term=NCT03181789 FUNDING. HIV vaccine trial network (HVTN), NIAID/NIH.

Colorectal cancer risk stratification using a polygenic risk score in symptomatic primary care patients-a UK Biobank retrospective cohort study.

Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. Accurate cancer risk assessment approaches could increase rates of early CRC diagnosis, improve health outcomes for patients and reduce pressure on diagnostic services. The faecal immunochemical test (FIT) for blood in stool is widely used in primary care to identify symptomatic patients with likely CRC. However, there is a 6-16% noncompliance rate with FIT in clinic and ~90% of patients over the symptomatic 10 µg/g test threshold do not have CRC. A polygenic risk score (PRS) quantifies an individual's genetic risk of a condition based on many common variants. Existing PRS for CRC have so far been used to stratify asymptomatic populations. We conducted a retrospective cohort study of 50,387 UK Biobank participants with a CRC symptom in their primary care record at age 40+. A PRS based on 201 variants, 5 genetic principal components and 22 other risk factors and markers for CRC were assessed for association with CRC diagnosis within 2 years of first symptom presentation using logistic regression. Associated variables were included in an integrated risk model and trained in 80% of the cohort to predict CRC diagnosis within 2 years. An integrated risk model combining PRS, age, sex, and patient-reported symptoms was predictive of CRC development in a testing cohort (receiver operating characteristic area under the curve, ROCAUC: 0.76, 95% confidence interval: 0.71-0.81). This model has the potential to improve early diagnosis of CRC, particularly in cases of patient noncompliance with FIT.

Genetic risk factors for COVID-19 and influenza are largely distinct.

Coronavirus disease 2019 (COVID-19) and influenza are respiratory illnesses caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses, respectively. Both diseases share symptoms and clinical risk factors1, but the extent to which these conditions have a common genetic etiology is unknown. This is partly because host genetic risk factors are well characterized for COVID-19 but not for influenza, with the largest published genome-wide association studies for these conditions including >2 million individuals2 and about 1,000 individuals3-6, respectively. Shared genetic risk factors could point to targets to prevent or treat both infections. Through a genetic study of 18,334 cases with a positive test for influenza and 276,295 controls, we show that published COVID-19 risk variants are not associated with influenza. Furthermore, we discovered and replicated an association between influenza infection and noncoding variants in B3GALT5 and ST6GAL1, neither of which was associated with COVID-19. In vitro small interfering RNA knockdown of ST6GAL1-an enzyme that adds sialic acid to the cell surface, which is used for viral entry-reduced influenza infectivity by 57%. These results mirror the observation that variants that downregulate ACE2, the SARS-CoV-2 receptor, protect against COVID-19 (ref. 7). Collectively, these findings highlight downregulation of key cell surface receptors used for viral entry as treatment opportunities to prevent COVID-19 and influenza.

Short-Term Groundwater Level Fluctuations Drive Subsurface Redox Variability.

As global change processes modify the extent and functions of terrestrial-aquatic interfaces, the variability of critical and dynamic transitional zones between wetlands and uplands increases. However, it is still unclear how fluctuating water levels at these dynamic boundaries alter groundwater biogeochemical cycling. Here, we used high-temporal resolution data along gradients from wetlands to uplands and during fluctuating water levels at freshwater coastal areas to capture spatiotemporal patterns of groundwater redox potential (Eh). We observed that topography influences groundwater Eh that is higher in uplands than in wetlands; however, the high variability within TAI zones challenged the establishment of distinct redox zonation. Declining water levels generally decreased Eh, but most locations exhibited significant Eh variability, which is associated with rare instances of short-term water level fluctuations, introducing oxygen. The Eh-oxygen relationship showed distinct hysteresis patterns, reflecting redox poising capacity at higher Eh, maintaining more oxidizing states longer than the dissolved oxygen presence. Surprisingly, we observed more frequent oxidizing states in transitional areas and wetlands than in uplands. We infer that occasional oxygen entering specific wetland-upland boundaries acts as critical biogeochemical control points. High-resolution data can capture such rare yet significant biogeochemical instances, supporting redox-informed models and advancing the predictability of climate change feedback.

Automatic rating of incomplete hippocampal inversions evaluated across multiple cohorts.

Incomplete Hippocampal Inversion (IHI), sometimes called hippocampal malrotation, is an atypical anatomical pattern of the hippocampus found in about 20% of the general population. IHI can be visually assessed on coronal slices of T1 weighted MR images, using a composite score that combines four anatomical criteria. IHI has been associated with several brain disorders (epilepsy, schizophrenia). However, these studies were based on small samples. Furthermore, the factors (genetic or environmental) that contribute to the genesis of IHI are largely unknown. Large-scale studies are thus needed to further understand IHI and their potential relationships to neurological and psychiatric disorders. However, visual evaluation is long and tedious, justifying the need for an automatic method. In this paper, we propose, for the first time, to automatically rate IHI. We proceed by predicting four anatomical criteria, which are then summed up to form the IHI score, providing the advantage of an interpretable score. We provided an extensive experimental investigation of different machine learning methods and training strategies. We performed automatic rating using a variety of deep learning models ("conv5-FC3", ResNet and "SECNN") as well as a ridge regression. We studied the generalization of our models using different cohorts and performed multi-cohort learning. We relied on a large population of 2,008 participants from the IMAGEN study, 993 and 403 participants from the QTIM and QTAB studies as well as 985 subjects from the UKBiobank. We showed that deep learning models outperformed a ridge regression. We demonstrated that the performances of the "conv5-FC3" network were at least as good as more complex networks while maintaining a low complexity and computation time. We showed that training on a single cohort may lack in variability while training on several cohorts improves generalization (acceptable performances on all tested cohorts including some that are not included in training). The trained models will be made publicly available should the manuscript be accepted.

When Revascularization May Be Appropriate in Atherosclerotic Renal Artery Stenosis.

Renal artery stenosis (RAS) is a condition that involves the narrowing of one or both renal arteries, most commonly caused by either atherosclerosis or fibroplasia. RAS can present in a multitude of clinical manifestations involving hypertension (HTN), heart failure, and renal failure. Current recommendations for treating patients with RAS involve strict medical therapy often without invasive therapies. However, in more complicated patients with RAS, recent clinical studies and guidelines have offered varying recommendations, which has presented challenges in managing these cases. This review aims to summarize current evidence to best evaluate which patients with RAS may benefit from renal artery revascularization as opposed to medical therapy alone.

mTORC1 phosphorylates and stabilizes LST2 to negatively regulate EGFR.

TORC1 (target of rapamycin complex 1) is a highly conserved protein kinase that plays a central role in regulating cell growth. Given the role of mammalian TORC1 (mTORC1) in metabolism and disease, understanding mTORC1 downstream signaling and feedback loops is important. mTORC1 recognizes some of its substrates via a five amino acid binding sequence called the TOR signaling (TOS) motif. mTORC1 binding to a TOS motif facilitates phosphorylation of a distinct, distal site. Here, we show that LST2, also known as ZFYVE28, contains a TOS motif (amino acids 401 to 405) and is directly phosphorylated by mTORC1 at serine 670 (S670). mTORC1-mediated S670 phosphorylation promotes LST2 monoubiquitination on lysine 87 (K87). Monoubiquitinated LST2 is stable and displays a broad reticular distribution. When mTORC1 is inactive, unphosphorylated LST2 is degraded by the proteasome. The absence of LST2 enhances EGFR (epidermal growth factor receptor) signaling. We propose that mTORC1 negatively feeds back on its upstream receptor EGFR via LST2.

Premalignant Progression in the Lung: Knowledge Gaps and Novel Opportunities for Interception of Non-Small Cell Lung Cancer. An Official American Thoracic Society Research Statement.

Rationale: Despite significant advances in precision treatments and immunotherapy, lung cancer is the most common cause of cancer death worldwide. To reduce incidence and improve survival rates, a deeper understanding of lung premalignancy and the multistep process of tumorigenesis is essential, allowing timely and effective intervention before cancer development. Objectives: To summarize existing information, identify knowledge gaps, formulate research questions, prioritize potential research topics, and propose strategies for future investigations into the premalignant progression in the lung. Methods: An international multidisciplinary team of basic, translational, and clinical scientists reviewed available data to develop and refine research questions pertaining to the transformation of premalignant lung lesions to advanced lung cancer. Results: This research statement identifies significant gaps in knowledge and proposes potential research questions aimed at expanding our understanding of the mechanisms underlying the progression of premalignant lung lesions to lung cancer in an effort to explore potential innovative modalities to intercept lung cancer at its nascent stages. Conclusions: The identified gaps in knowledge about the biological mechanisms of premalignant progression in the lung, together with ongoing challenges in screening, detection, and early intervention, highlight the critical need to prioritize research in this domain. Such focused investigations are essential to devise effective preventive strategies that may ultimately decrease lung cancer incidence and improve patient outcomes.

Assessing Cross-Contamination in Spike-Sorted Electrophysiology Data.

Recent advances in extracellular electrophysiology now facilitate the recording of spikes from hundreds or thousands of neurons simultaneously. This has necessitated both the development of new computational methods for spike sorting and better methods to determine spike-sorting accuracy. One long-standing method of assessing the false discovery rate (FDR) of spike sorting-the rate at which spikes are assigned to the wrong cluster-has been the rate of interspike interval (ISI) violations. Despite their near ubiquitous usage in spike sorting, our understanding of how exactly ISI violations relate to FDR, as well as best practices for using ISI violations as a quality metric, remains limited. Here, we describe an analytical solution that can be used to predict FDR from the ISI violation rate (ISIv). We test this model in silico through Monte Carlo simulation and apply it to publicly available spike-sorted electrophysiology datasets. We find that the relationship between ISIv and FDR is highly nonlinear, with additional dependencies on firing frequency, the correlation in activity between neurons, and contaminant neuron count. Predicted median FDRs in public datasets recorded in mice were found to range from 3.1 to 50.0%. We found that stochasticity in the occurrence of ISI violations as well as uncertainty in cluster-specific parameters make it difficult to predict FDR for single clusters with high confidence but that FDR can be estimated accurately across a population of clusters. Our findings will help the growing community of researchers using extracellular electrophysiology assess spike-sorting accuracy in a principled manner.

Increased Risk of New-Onset Hypertension in Patients With Narcolepsy Initiating Sodium Oxybate: A Real-World Study.

OBJECTIVE: To compare intermediate-term risk of new-onset hypertension between normotensive patients with narcolepsy initiating sodium oxybate (SXB cohort) and those not initiating sodium oxybate (control cohort). PATIENTS AND METHODS: This retrospective cohort study used MarketScan administrative claims data from January 1, 2014, to February 29, 2020. Eligible patients were 18 years of age or older with continuous enrollment (≥180 days before and after cohort entry), had one or more narcolepsy claims or a prescription fill for sodium oxybate, had no history of hypertension or antihypertensive medication use, and had no use of sodium oxybate within 13 months before cohort entry. Patients in the SXB and control cohorts were matched 1:2 for the propensity score to balance baseline characteristics. End points were (1) a composite of new-onset hypertension diagnosis or antihypertensive medication initiation and (2) new-onset hypertension diagnosis. Patients were monitored for 180 days, until outcome occurrence, sodium oxybate discontinuation (SXB cohort), or sodium oxybate initiation (control cohort). Risk per 100 patients was reported; differences were evaluated using logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The SXB and control cohorts included 954 and 1908 patients, respectively. Risk of new-onset hypertension diagnosis or antihypertensive medication initiation was higher in the SXB cohort than in the control cohort (6.60 vs 4.20 per 100 patients; OR, 1.61; 95% CI, 1.15 to 2.27). Risk of a new-onset hypertension diagnosis only in the SXB cohort was 0.94 per 100 patients and 0.52 per 100 patients in the control cohort (OR, 1.81; 95% CI, 0.73 to 4.46). CONCLUSION: In this study, sodium oxybate use was associated with a new-onset hypertension diagnosis or antihypertensive medication initiation in normotensive patients with narcolepsy.

How adolescents learn to build social bonds: A developmental computational account of social explore-exploit decision-making.

Building social bonds is a critical task of adolescence that affords opportunities for learning, identity formation, and social support. Failing to develop close relationships in adolescence hinders adult interpersonal functioning and contributes to problems such as loneliness and depression. During adolescence, increased reward sensitivity and greater social flexibility both contribute to healthy social development, yet we lack a clear theory of how these processes interact to support social functioning. Here, we propose synthesizing these two literatures using a computational reinforcement learning framework that recasts how adolescents pursue and learn from social rewards as a social explore-exploit problem. To become socially skilled, adolescents must balance both their efforts to form individual bonds within specific groups and manage memberships across multiple groups to maximize access to social resources. We draw on insights from sociological studies on social capital in collective networks and neurocognitive research on foraging and cooperation to describe the social explore-exploit dilemma faced by adolescents navigating a modern world with increasing access to diverse resources and group memberships. Our account provides important new directions for examining the dynamics of adolescent behavior in social groups and understanding how social value computations can support positive relationships into adulthood.

Initial Experience with an Absorbable Urologic Scaffold to Mitigate Early Urinary Incontinence following Radical Prostatectomy: A Report of 2 Cases.

INTRODUCTION: Stress urinary incontinence (SUI) is a frequent, known complication following robot-assisted radical prostatectomy (RARP) for prostate cancer. Urethral shortening and reduced urethral support following RARP are contributing factors. CASE PRESENTATIONS: Herein, we describe a surgical approach using a novel absorbable urologic scaffold to mitigate SUI in 2 patients enrolled in an ongoing single-arm prospective study. The scaffold is designed to relieve the burden on the urinary sphincter by lengthening the effective urethra following RARP. The scaffold is placed at the anastomotic site, overlying the bladder neck and urethral stump following prostate removal and prior to the creation of the anastomosis. Both patients successfully underwent the prostatectomy and urologic scaffold placement with no reported perioperative complications. Neither patient suffered from early SUI following RARP as measured by pad weight and usage at 1 and 3 months following the procedure. CONCLUSION: Early experience with the absorbable urologic scaffold suggests it could safely and effectively prevent SUI following RARP. Early and long-term results derived from the ongoing prospective study with this device will better define its potential role in the prevention of SUI.

Correlation of Macular Ganglion Cell Layer + Inner Plexiform Layer (GCL + IPL) and Circumpapillary Retinal Nerve Fiber Layer (cRNFL) Thickness in Glaucoma Suspects and Glaucomatous Eyes.

Purpose: The study aimed to correlate macular ganglion cell layer + inner plexiform layer (GCL + IPL) thickness and circumpapillary retinal nerve fiber layer (cRNFL) thickness and to determine the validity of GCL + IPL in the evaluation of glaucoma across different stages using the area under the curve (AUC) analysis in comparison to cRNFL. Patients and Methods: The charts of 260 adult glaucoma suspect and glaucoma patients having macular ganglion cell analysis, optical coherence tomography (OCT) of the cRNFL and automated visual field (AVF) were reviewed. GCL + IPL thickness (average, minimum and sectoral) and sectoral cRNFL thickness were obtained. Glaucomatous eyes were further classified into stages based on the Hodapp-Anderson-Parrish Visual Field Criteria of Glaucoma Severity. AUC analysis was used to compare GCL + IPL parameters with cRNFL in glaucoma suspects and glaucoma patients. Results: A total of 122 eyes were included in the study and were grouped into glaucoma suspects (n = 43), early or mild glaucoma (n = 40), and moderate-to-severe glaucoma (n = 39). Both GCL + IPL and cRNFL thickness parameters showed a significant decline with greater glaucoma severity. In the determination of visual field defects across all glaucoma stages, the highest AUC was obtained by minimum GCL + IPL (AUC = 0.859) with cut-off value at ≤70 µm. Average GCL + IPL had the highest AUC (0.835) in detecting progression from glaucoma suspect to mild glaucoma, while the inferior sector of the cRNFL had the highest AUC (0.937) in discerning mild from moderate-to-severe glaucoma. Conclusion: The results of this study highlight the significance of macular ganglion cell analysis in the screening, detection and staging of glaucoma. Compared to cRNFL, macular ganglion analysis may be more beneficial in glaucoma screening and detecting progression from glaucoma suspect to mild glaucoma.

Tuning Reinforcement Learning Parameters for Cluster Selection to Enhance Evolutionary Algorithms.

The ability to find optimal molecular structures with desired properties is a popular challenge, with applications in areas such as drug discovery. Genetic algorithms are a common approach to global minima molecular searches due to their ability to search large regions of the energy landscape and decrease computational time via parallelization. In order to decrease the amount of unstable intermediate structures being produced and increase the overall efficiency of an evolutionary algorithm, clustering was introduced in multiple instances. However, there is little literature detailing the effects of differentiating the selection frequencies between clusters. In order to find a balance between exploration and exploitation in our genetic algorithm, we propose a system of clustering the starting population and choosing clusters for an evolutionary algorithm run via a dynamic probability that is dependent on the fitness of molecules generated by each cluster. We define four parameters, MFavOvrAll-A, MFavClus-B, NoNewFavClus-C, and Select-D, that correspond to a reward for producing the best structure overall, a reward for producing the best structure in its own cluster, a penalty for not producing the best structure, and a penalty based on the selection ratio of the cluster, respectively. A reward increases the probability of a cluster's future selection, while a penalty decreases it. In order to optimize these four parameters, we used a Gaussian distribution to approximate the evolutionary algorithm performance of each cluster and performed a grid search for different parameter combinations. Results show parameter MFavOvrAll-A (rewarding clusters for producing the best structure overall) and parameter Select-D (appearance penalty) have a significantly larger effect than parameters MFavClus-B and NoNewFavClus-C. In order to produce the most successful models, a balance between MFavOvrAll-A and Select-D must be made that reflects the exploitation vs exploration trade-off often seen in reinforcement learning algorithms. Results show that our reinforcement-learning-based method for selecting clusters outperforms an unclustered evolutionary algorithm for quinoline-like structure searches.