Predicting Choroidal Nevus Transformation to Melanoma Using Machine Learning.

Purpose: To develop and validate machine learning (ML) models to predict choroidal nevus transformation to melanoma based on multimodal imaging at initial presentation. Design: Retrospective multicenter study. Participants: Patients diagnosed with choroidal nevus on the Ocular Oncology Service at Wills Eye Hospital (2007-2017) or Mayo Clinic Rochester (2015-2023). Methods: Multimodal imaging was obtained, including fundus photography, fundus autofluorescence, spectral domain OCT, and B-scan ultrasonography. Machine learning models were created (XGBoost, LGBM, Random Forest, Extra Tree) and optimized for area under receiver operating characteristic curve (AUROC). The Wills Eye Hospital cohort was used for training and testing (80% training-20% testing) with fivefold cross validation. The Mayo Clinic cohort provided external validation. Model performance was characterized by AUROC and area under precision-recall curve (AUPRC). Models were interrogated using SHapley Additive exPlanations (SHAP) to identify the features most predictive of conversion from nevus to melanoma. Differences in AUROC and AUPRC between models were tested using 10 000 bootstrap samples with replacement and results. Main Outcome Measures: Area under receiver operating curve and AUPRC for each ML model. Results: There were 2870 nevi included in the study, with conversion to melanoma confirmed in 128 cases. Simple AI Nevus Transformation System (SAINTS; XGBoost) was the top-performing model in the test cohort [pooled AUROC 0.864 (95% confidence interval (CI): 0.864-0.865), pooled AUPRC 0.244 (95% CI: 0.243-0.246)] and in the external validation cohort [pooled AUROC 0.931 (95% CI: 0.930-0.931), pooled AUPRC 0.533 (95% CI: 0.531-0.535)]. Other models also had good discriminative performance: LGBM (test set pooled AUROC 0.831, validation set pooled AUROC 0.815), Random Forest (test set pooled AUROC 0.812, validation set pooled AUROC 0.866), and Extra Tree (test set pooled AUROC 0.826, validation set pooled AUROC 0.915). A model including only nevi with at least 5 years of follow-up demonstrated the best performance in AUPRC (test: pooled 0.592 (95% CI: 0.590-0.594); validation: pooled 0.656 [95% CI: 0.655-0.657]). The top 5 features in SAINTS by SHAP values were: tumor thickness, largest tumor basal diameter, tumor shape, distance to optic nerve, and subretinal fluid extent. Conclusions: We demonstrate accuracy and generalizability of a ML model for predicting choroidal nevus transformation to melanoma based on multimodal imaging. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

A Second-Generation (44-Channel) Suprachoroidal Retinal Prosthesis: A Single-Arm Clinical Trial of Feasibility.

Purpose: To assess the feasibility of a second-generation (44-channel) suprachoroidal retinal prosthesis for provision of functional vision in recipients with end-stage retinitis pigmentosa (RP) over 2.7 years. Design: Prospective, single-arm, unmasked interventional clinical trial. Participants: Four participants, with advanced RP and bare-light perception vision. Methods: The 44-channel suprachoroidal retinal prosthesis was implanted in the worse-seeing eye. Device stability, functionality, and adverse events were investigated at approximately 12-week intervals up to 140 weeks (2.7 years) postdevice activation. Main Outcome Measures: Serious adverse event (SAE) reporting, visual response outcomes, functional vision outcomes, and quality-of-life outcomes. Results: All 4 participants (aged 39-66 years, 3 males) were successfully implanted in 2018, and there were no device-related SAEs over the duration of the study. A mild postoperative subretinal hemorrhage was detected in 2 recipients, which cleared spontaneously within 2 weeks. OCT confirmed device stability and position under the macula. Improvements in localization abilities were demonstrated for all 4 participants in screen-based, tabletop, and orientation and mobility tasks. In addition, 3 of 4 participants recorded improvements in motion discrimination and 2 of 4 participants recorded substantial improvements in spatial discrimination and identification of tabletop objects. Participants reported their unsupervised use of the device included exploring new environments, detecting people, and safely navigating around obstacles. A positive effect of the implant on participants' daily lives in their local environments was confirmed by an orientation and mobility assessor and participant self-report. Emotional well-being was not impacted by device implantation or usage. Conclusions: The completed clinical study demonstrates that the suprachoroidal prosthesis raises no safety concerns and provides improvements in functional vision, activities of daily living, and observer-rated quality of life. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Pediatric Long COVID Subphenotypes: An EHR-based study from the RECOVER program.

Pediatric Long COVID has been associated with a wide variety of symptoms, conditions, and organ systems, but distinct clinical presentations, or subphenotypes, are still being elucidated. In this exploratory analysis, we identified a cohort of pediatric (age <21) patients with evidence of Long COVID and no pre-existing complex chronic conditions using electronic health record data from 38 institutions and used an unsupervised machine learning-based approach to identify subphenotypes. Our method, an extension of the Phe2Vec algorithm, uses tens of thousands of clinical concepts from multiple domains to represent patients' clinical histories to then identify groups of patients with similar presentations. The results indicate that cardiorespiratory presentations are most common (present in 54% of patients) followed by subphenotypes marked (in decreasing order of frequency) by musculoskeletal pain, neuropsychiatric conditions, gastrointestinal symptoms, headache, and fatigue.

Cholesterol promotes IFNG mRNA expression in CD4+ effector/memory cells by SGK1 activation.

IFNγ-secreting T cells are central for the maintenance of immune surveillance within the central nervous system (CNS). It was previously reported in healthy donors that the T-cell environment in the CNS induces distinct signatures related to cytotoxic capacity, CNS trafficking, tissue adaptation, and lipid homeostasis. These findings suggested that the CNS milieu consisting predominantly of lipids mediated the metabolic conditions leading to IFNγ-secreting brain CD4 T cells. Here, we demonstrate that the supplementation of CD4+CD45RO+CXCR3+ cells with cholesterol modulates their function and increases IFNG expression. The heightened IFNG expression was mediated by the activation of the serum/glucocorticoid-regulated kinase (SGK1). Inhibition of SGK1 by a specific enzymatic inhibitor significantly reduces the expression of IFNG Our results confirm the crucial role of lipids in maintaining T-cell homeostasis and demonstrate a putative role of environmental factors to induce effector responses in CD4+ effector/memory cells. These findings offer potential avenues for further research targeting lipid pathways to modulate inflammatory conditions.

The generation of stable microvessels in ischemia is mediated by endothelial cell derived TRAIL.

Reversal of ischemia is mediated by neo-angiogenesis requiring endothelial cell (EC) and pericyte interactions to form stable microvascular networks. We describe an unrecognized role for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in potentiating neo-angiogenesis and vessel stabilization. We show that the endothelium is a major source of TRAIL in the healthy circulation compromised in peripheral artery disease (PAD). EC deletion of TRAIL in vivo or in vitro inhibited neo-angiogenesis, pericyte recruitment, and vessel stabilization, resulting in reduced lower-limb blood perfusion with ischemia. Activation of the TRAIL receptor (TRAIL-R) restored blood perfusion and stable blood vessel networks in mice. Proof-of-concept studies showed that Conatumumab, an agonistic TRAIL-R2 antibody, promoted vascular sprouts from explanted patient arteries. Single-cell RNA sequencing revealed heparin-binding EGF-like growth factor in mediating EC-pericyte communications dependent on TRAIL. These studies highlight unique TRAIL-dependent mechanisms mediating neo-angiogenesis and vessel stabilization and the potential of repurposing TRAIL-R2 agonists to stimulate stable and functional microvessel networks to treat ischemia in PAD.

Reward neurocircuitry predicts longitudinal changes in alcohol use following trauma exposure.

BACKGROUND: Trauma is a risk factor for developing maladaptive alcohol use. Preclinical research has shown that stress alters the processing of midbrain and striatal reward and incentive signals. However, little research has been conducted on alterations in reward-related neurocircuitry post-trauma in humans. Neuroimaging markers may be particularly useful as they can provide insight into the mechanisms that may make an individual vulnerable to developing trauma-related psychopathologies. This study aimed to identify reward-related neural correlates associated with changes in alcohol use after trauma exposure. METHODS: Participants were recruited from U.S. emergency departments for the AURORA study (N=286, 178 female). Trauma-related change in alcohol use at 8 weeks post-trauma relative to pre-trauma was quantified as a change in 30-day total drinking per the PhenX Toolkit Alcohol 30-Day Quantity and Frequency Measure. Reward-related neurocircuitry activation and functional connectivity (FC) were assessed 2 weeks post-trauma using fMRI during a monetary reward task using region of interest and whole-brain voxelwise analyses. RESULTS: Greater increase in alcohol use from pre-trauma to 8 weeks post-trauma was predicted by (1) greater ventral tegmental area (VTA) and (2) greater cerebellum activation during Gain>Loss trials measured 2 weeks post-trauma and (3) greater seed-based FC between the VTA and lateral occipital cortex and precuneus. CONCLUSIONS: Altered VTA activation and FC early post-trauma may be associated with reward-seeking and processing, contributing to greater alcohol use post-trauma. These data provide novel evidence of neural correlates that underlie increased alcohol use early post-trauma that may be targeted via early interventions to prevent the development of maladaptive alcohol use.

Genome-wide association study meta-analysis of 9,619 cases with tic disorders.

BACKGROUND: Despite the significant personal and societal burden of tic disorders (TD), treatment outcomes remain modest, necessitating a deeper understanding of their etiology. Family history is the biggest known risk factor and identifying risk genes could accelerate progress in the field. METHODS: Expanding upon previous sample size limitations, we added 4,800 new TD cases and 971,560 controls, conducting a GWAS meta-analysis with 9,619 cases and 981,048 controls of European ancestry. We attempted to replicate the results in an independent deCODE Genetics GWAS (885 TD cases and 310,367 controls). To characterize GWAS findings, we conducted several post-GWAS gene-based and enrichment analyses. RESULTS: A genome-wide significant hit (rs79244681, p=2.27x10-08) within MCHR2-AS1 was identified, though it was not replicated. Post-GWAS analyses revealed a 13.8% SNP-heritability and three significant genes: BCL11B, NDFIP2, and RBM26. Common variant risk for TD was enriched within genes preferentially expressed in the cortico-striato-thalamo-cortical circuit (including the putamen, caudate, nucleus accumbens, and Brodman area 9) and five brain cell types (excitatory and inhibitory telencephalon-, inhibitory- di- and mesencephalon, hindbrain-, and medium spiny neurons). TD polygenic risk was enriched within loss-of-function intolerant genes (p=0.0017) and high-confidence neurodevelopmental disorder genes (p=0.0108). Of 112 genetic correlations, 43 were statistically significant, showing high positive correlations with most psychiatric disorders. Of the two SNPs previously associated with TD, one (rs2453763) replicated in an independent sub-sample of our GWAS (p=0.00018). CONCLUSIONS: This GWAS was still underpowered to identify high-confidence, replicable loci, but the results suggest imminent discovery of common genetic variants for TD.

Evaluation of an Outpatient Cervical Ripening Program Using Osmotic Dilators and Foley Balloon Catheters.

OBJECTIVE: This study aimed to describe patient characteristics, satisfaction, and outcome measures for patients undergoing outpatient cervical ripening. STUDY DESIGN: A retrospective cohort study using electronic health record data from March 2020 to March 2022 from a large health system. The sample included patients with a low-risk singleton pregnancy undergoing outpatient cervical ripening with either an osmotic dilator or Foley balloon catheter. A subset of patients completed satisfaction surveys. Frequencies and means were used to describe the population and conduct comparisons by device type. Inverse probability of treatment weighted estimates were generated to address baseline differences between patients in the two device groups. RESULTS: Outpatient cervical ripening was completed by 120 patients (80 osmotic dilators and 40 Foley balloon catheters). The mean time from insertion to inpatient admission was 16.2 ± 4.8 hours. The mean change in simplified Bishop score (SBS) was 1.8 ± 1.4 and the mean change in dilation was 1.8 ± 1.1 cm. There were no differences in the amount of cervical change by device type. Patients returned earlier than planned 16.7% of the time, primarily for contractions or rupture of membranes. Following outpatient cervical ripening, the time from admission to delivery was 19.9 ± 10.3 hours, with no difference by device type. Vaginal delivery occurred for 74.8% of patients. Patients reported overall satisfaction with the outpatient cervical ripening experience, with the highest satisfaction among those with osmotic dilators. Patients with both device types stated they would recommend outpatient cervical ripening to others, and experienced low levels of stress and discomfort at home prior to hospital admission. CONCLUSION: Patients participating in outpatient cervical ripening with osmotic dilators or Foley balloon catheters experienced clinically meaningful changes in dilation and SBSs while at home and reported general satisfaction with the outpatient program experience. KEY POINTS: · Outpatient use of osmotic dilators or Foley balloon catheters improved Bishop scores.. · Patient and device complications were comparable to other research findings.. · Patients reported overall satisfaction with outpatient cervical ripening..

High fidelity predictions of diffusion in the brain microenvironment.

Multiple particle tracking (MPT) is a microscopy technique capable of simultaneously tracking hundreds to thousands of nanoparticles in a biological sample and has been used extensively to characterize biological microenvironments, including the brain extracellular space (ECS). Machine learning techniques have been applied to MPT datasets to predict the diffusion mode of nanoparticle trajectories as well as more complex biological variables, such age biological age. In this study, we develop a machine learning pipeline to predict and investigate changes to the brain ECS due to injury using supervised classification and feature importance calculations. We first validate the pipeline on three related but distinct MPT datasets from the living brain ECS - age differences, region differences, and enzymatic degradation of ECS structure. We predict three ages with 86% accuracy, three regions with 90% accuracy, and healthy versus enzyme-treated tissue with 69% accuracy. Since injury across groups is normally compared with traditional statistical approaches, we first used linear mixed effects models to compare features between healthy control conditions and injury induced by two different oxygen glucose deprivation [1] exposure times. We then used machine learning to predict injury state using MPT features. We show that the pipeline predicts between the healthy control, 0.5-hour OGD treatment, and 1.5-hour OGD treatment with 59% accuracy in the cortex and 66% in the striatum and identifies nonlinear relationships between trajectory features that were not evident from traditional linear models. Our work demonstrates that machine learning applied to MPT data is effective across multiple experimental conditions and can find unique biologically relevant features of nanoparticle diffusion.

Engineering Boron Vacancy Defects in Boron Nitride Nanotubes.

Spin defects in hexagonal boron nitride (hBN) are emerging as promising platforms for quantum sensing applications. In particular, the negatively charged boron vacancy (VB-) centers have been engineered in bulk hBN and few-layer hBN flakes, and employed for sensing. Here, we investigate the engineering of VB- spin defects in boron nitride nanotubes (BNNTs). The generated spin defects are distributed along and around the BNNTs. Moreover, in contrast to hBN flakes, the spins in BNNTs exhibit a directional response relative to the direction of a surrounding magnetic field, which is consistent with the tubular geometry. The unique geometry of BNNTs allows for a more controlled and predictable placement of spin defects compared to bulk hBN, paving the way for innovative sensing applications with high spatial resolution and optomechanical studies of spin defects in hBN.

A method to evaluate enhanced rock weathering using intact soil monoliths under field conditions.

Enhanced rock weathering (ERW) has attracted considerable attention as a carbon dioxide removal (CDR) strategy. However, a reliable method for accurately measuring, monitoring, and verifying carbon dioxide (CO2) removal, particularly under field conditions, remains elusive. Here we describe a method for installing soil monoliths in an in situ buried apparatus that allows collection of water draining through a soil, undisturbed by external environmental factors that may affect similar apparatus located above ground. The method provides a robust, cost-effective means of collecting, developing, and establishing soil monoliths, allowing through drainage soil water sample collection and analysis, and so facilitating estimation of ERW CO2 removal. A 200 mm diameter polyvinyl chloride (PVC) pipe is inserted into the soil to extract intact monoliths from a site of interest, withdrawn and then fitted with a basal double socket coupling and end cap for leachate collection. It is buried to reproduce soil environmental conditions, and water is collected via a sampling tube to surface. Validity was confirmed through an experimental trial with 36 monoliths over 6 months. This method enables accurate chemical analysis of solute draining through the soil monolith, which can be used to validate models of ERW efficacy.•PVC pipes are inserted into the target soil and subsequently extracted to retrieve intact soil monoliths•PVC sockets, equipped with a mesh and a geotextile membrane in the middle to retain the collected intact soil monolith and prevent soil particle transport, are then attached to the PVC pipe•PVC caps, featuring a small drainage tube attached to its outer side, are used to collect the leachate at the bottom part of the system.

Technology-based instrumental activities of daily living in persons with Alzheimer's disease and related disorders.

INTRODUCTION: Instrumental activities of daily living (iADLs) increasingly involve technology (e.g., making payments online, texting). The current study examined the applicability and diagnostic accuracy of technology-based iADLs in those evaluated for Alzheimer's disease and related dementias (ADRD). METHODS: A total of 264 care partners of persons undergoing comprehensive interdisciplinary evaluations completed the Functional Activities Questionnaire and 11 technology-based iADL items. RESULTS: Technology-based iADLs applied to more than 80% of patients. Average dependence on technology-based items was overall less than for traditional iADLs. The addition of technology-based items to traditional iADL items slightly improved the ability to identify individuals with dementia. When considered separately, technology-based iADL items demonstrated comparable ability to distinguish between diagnostic stages. DISCUSSION: Technology use is common in older adults with ADRD for a range of daily activities. Accounting for technology use increases the content validity of existing iADL measures for the modern context and yields comparable diagnostic accuracy. Highlights: Technology use is often integral to daily activity performance for individuals with Alzheimer's disease and related dementias (ADRD).Daily technologies, such as smartphones, were used frequently by those with ADRD.Many individuals were less dependent on technology activities than traditional activities.Adding technology questions slightly increased diagnostic accuracy for detecting dementia.

Undiagnosed scrotal swelling in a 36-year-old man: A congenital arteriovenous malformation.

We have reported the case of a 36-year-old man with severe scrotal swelling that had remained undiagnosed after multiple diagnostic tests. The patient had presented with scrotal swelling, multiple weeping ulcers on the dorsal aspect of the scrotum, and worsening pain affecting his day-to-day functioning. Duplex ultrasound showed low- to no-flow hypervascularity and dependent edema suspicious for a vascular malformation. Treatment included sequential Gelfoam (Pfizer, New York, NY) embolization using ultrasound-guided direct cannulation and traditional angiography. The scrotal circumference decreased by 65%, with moderate relief of his pain. The details from the present case have highlighted the significance of vascular malformations, various diagnostic and therapeutic techniques used, and value of endovascular embolization.

Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy.

BACKGROUND: Gene therapy with elivaldogene autotemcel (eli-cel) consisting of autologous CD34+ cells transduced with lentiviral vector containing ABCD1 complementary DNA (Lenti-D) has shown efficacy in clinical studies for the treatment of cerebral adrenoleukodystrophy. However, the risk of oncogenesis with eli-cel is unclear. METHODS: We performed integration-site analysis, genetic studies, flow cytometry, and morphologic studies in peripheral-blood and bone marrow samples from patients who received eli-cel therapy in two completed phase 2-3 studies (ALD-102 and ALD-104) and an ongoing follow-up study (LTF-304) involving the patients in both ALD-102 and ALD-104. RESULTS: Hematologic cancer developed in 7 of 67 patients after the receipt of eli-cel (1 of 32 patients in the ALD-102 study and 6 of 35 patients in the ALD-104 study): myelodysplastic syndrome (MDS) with unilineage dysplasia in 2 patients at 14 and 26 months; MDS with excess blasts in 3 patients at 28, 42, and 92 months; MDS in 1 patient at 36 months; and acute myeloid leukemia (AML) in 1 patient at 57 months. In the 6 patients with available data, predominant clones contained lentiviral vector insertions at multiple loci, including at either MECOM-EVI1 (MDS and EVI1 complex protein EVI1 [ecotropic virus integration site 1], in 5 patients) or PRDM16 (positive regulatory domain zinc finger protein 16, in 1 patient). Several patients had cytopenias, and most had vector insertions in multiple genes within the same clone; 6 of the 7 patients also had somatic mutations (KRAS, NRAS, WT1, CDKN2A or CDKN2B, or RUNX1), and 1 of the 7 patients had monosomy 7. Of the 5 patients with MDS with excess blasts or MDS with unilineage dysplasia who underwent allogeneic hematopoietic stem-cell transplantation (HSCT), 4 patients remain free of MDS without recurrence of symptoms of cerebral adrenoleukodystrophy, and 1 patient died from presumed graft-versus-host disease 20 months after HSCT (49 months after receiving eli-cel). The patient with AML is alive and had full donor chimerism after HSCT; the patient with the most recent case of MDS is alive and awaiting HSCT. CONCLUSIONS: Hematologic cancer developed in a subgroup of patients who were treated with eli-cel; the cases are associated with clonal vector insertions within oncogenes and clonal evolution with acquisition of somatic genetic defects. (Funded by Bluebird Bio; ALD-102, ALD-104, and LTF-304 ClinicalTrials.gov numbers, NCT01896102, NCT03852498, and NCT02698579, respectively.).

Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy.

BACKGROUND: Cerebral adrenoleukodystrophy is a severe form of X-linked adrenoleukodystrophy characterized by white-matter disease, loss of neurologic function, and early death. Elivaldogene autotemcel (eli-cel) gene therapy, which consists of autologous CD34+ cells transduced with Lenti-D lentiviral vector containing ABCD1 complementary DNA, is being tested in persons with cerebral adrenoleukodystrophy. METHODS: In a phase 2-3 study, we evaluated the efficacy and safety of eli-cel therapy in boys with early-stage cerebral adrenoleukodystrophy and evidence of active inflammation on magnetic resonance imaging (MRI). The primary efficacy end point was survival without any of six major functional disabilities at month 24. The secondary end points included overall survival at month 24 and the change from baseline to month 24 in the total neurologic function score. RESULTS: A total of 32 patients received eli-cel; 29 patients (91%) completed the 24-month study and are being monitored in the long-term follow-up study. At month 24, none of these 29 patients had major functional disabilities; overall survival was 94%. At the most recent assessment (median follow-up, 6 years), the neurologic function score was stable as compared with the baseline score in 30 of 32 patients (94%); 26 patients (81%) had no major functional disabilities. Four patients had adverse events that were directly related to eli-cel. Myelodysplastic syndrome (MDS) with excess blasts developed in 1 patient at month 92; the patient underwent allogeneic hematopoietic stem-cell transplantation and did not have MDS at the most recent follow-up. CONCLUSIONS: At a median follow-up of 6 years after lentiviral gene therapy, most patients with early cerebral adrenoleukodystrophy and MRI abnormalities had no major functional disabilities. However, insertional oncogenesis is an ongoing risk associated with the integration of viral vectors. (Funded by Bluebird Bio; ALD-102 and LTF-304 ClinicalTrials.gov numbers NCT01896102 and NCT02698579, respectively.).

Symposium: What Does the Microbiome Tell Us about Prevention and Treatment of AD/ADRD?

Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRDs) are broad-impact multifactorial neurodegenerative diseases. Their complexity presents unique challenges for developing effective therapies. This review highlights research presented at the 2024 Society for Neuroscience meeting which emphasized the gut microbiome's role in AD pathogenesis by influencing brain function and neurodegeneration through the microbiota-gut-brain axis. This emerging evidence underscores the potential for targeting the gut microbiota to treat AD/ADRD.

Maternal oral probiotic use is associated with decreased breastmilk inflammatory markers, infant fecal microbiome variation, and altered recognition memory responses in infants-a pilot observational study.

Introduction: Early life gut microbiomes are important for brain and immune system development in animal models. Probiotic use has been proposed as a strategy to promote health via modulation of microbiomes. In this observational study, we explore if early life exposure to probiotics via the mother during pregnancy and lactation, is associated with decreased inflammation in breastmilk, maternal and infant microbiome variation, and altered infant neurodevelopmental features. Methods: Exclusively breastfeeding mother-infant dyads were recruited as part of the "Mothers and Infants Linked for Healthy Growth (MILk) Study." Probiotic comparison groups were defined by exposure to maternal probiotics (NO/YES) and by timing of probiotic exposure (prenatal, postnatal, total). C-reactive protein (CRP) and IL-6 levels were determined in breastmilk by immunoassays, and microbiomes were characterized from 1-month milk and from 1- and 6-month infant feces by 16S rDNA sequencing. Infant brain function was profiled via electroencephalogram (EEG); we assessed recognition memory using event-related potential (ERP) responses to familiar and novel auditory (1 month) and visual (6 months) stimuli. Statistical comparisons of study outcomes between probiotic groups were performed using permutational analysis of variance (PERMANOVA) (microbiome) and linear models (all other study outcomes), including relevant covariables as indicated. Results: We observed associations between probiotic exposure and lower breastmilk CRP and IL-6 levels, and infant gut microbiome variation at 1- and 6-months of age (including higher abundances of Bifidobacteria and Lactobacillus). In addition, maternal probiotic exposure was associated with differences in infant ERP features at 6-months of age. Specifically, infants who were exposed to postnatal maternal probiotics (between the 1- and 6-month study visits) via breastfeeding/breastmilk, had larger differential responses between familiar and novel visual stimuli with respect to the late slow wave component of the EEG, which may indicate greater memory updating potential. The milk of mothers of this subgroup of infants had lower IL-6 levels and infants had different 6-month fecal microbiomes as compared to those in the "NO" maternal probiotics group. Discussion: These results support continued research into "Microbiota-Gut-Brain" connections during early life and the role of pre- and postnatal probiotics in mothers to promote healthy microbiome-associated outcomes in infants.

SARS-CoV-2 variant replacement constrains vaccine-specific viral diversification.

Coronavirus disease 2019 (COVID-19) vaccine breakthrough infections have been important for all circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant periods, but the contribution of vaccine-specific SARS-CoV-2 viral diversification to vaccine failure remains unclear. This study analyzed 595 SARS-CoV-2 sequences collected from the Military Health System beneficiaries between December 2020 and April 2022 to investigate the impact of vaccination on viral diversity. By comparing sequences based on the vaccination status of the participant, we found limited evidence indicating that vaccination was associated with increased viral diversity in the SARS-CoV-2 spike, and we show little to no evidence of a substantial sieve effect within major variants; rather, we show that rapid variant replacement constrained intragenotype COVID-19 vaccine strain immune escape. These data suggest that, during past and perhaps future periods of rapid SARS-CoV-2 variant replacement, vaccine-mediated effects were subsumed with other drivers of viral diversity due to the massive scale of infections and vaccinations that occurred in a short time frame. However, our results also highlight some limitations of using sieve analysis methods outside of placebo-controlled clinical trials.

Dramatic droplet deformation through interfacial particles jamming.

Droplets of one fluid in a second, immiscible fluid are typically spherical in shape due to the interfacial tension between the two fluids. Shear forces can lead to droplet deformation when they are subjected to flow, and these effects can be further modified when the droplet is stabilized by a surfactant due to a flow-induced gradients in the surfactant concentration. An alternative method of stabilizing droplets is through the use of colloidal particles, whose stabilization behavior is intrinsically different from molecular surfactants. Under the same flow condition, a gradient of particle concentration can result in the jamming of particles in regions with a high packing density, making the interface solid-like, albeit only under compression and not tension. However, how this asymmetry in the surfactant properties alters the droplet shape under shear is unknown. Here, we show that shear of particle-stabilized droplets can lead to a remarkable array of shape deformations as the droplets flow through a constrained microchannel. The shear-induced migration of particles on the surface results in the formation of an elastic shell at the back of the droplet, which can wrinkle and invaginate, ultimately leading to a unique core-shell structure. The shapes depend on the Peclet number of the flow, reflecting the balance of shear forces that drive the particles and diffusion that randomizes them. These findings highlight the consequences of the asymmetry in the forces between the particles and provide a unique method to controllably create droplets with a vast array of different shapes.