Nirmatrelvir/Ritonavir (Paxlovid) Use Among Individuals at Risk of Severe COVID-19: An Analysis of the National COVID Cohort Collaborative (N3C).

PURPOSE: Paxlovid is effective in reducing COVID-19 hospitalization and mortality. This study characterized Paxlovid use and evaluated racial/ethnic disparities over time among community-dwelling adults at high risk of progression to severe COVID-19 disease. METHODS: This retrospective cohort study used the National COVID Cohort Collaborative (N3C) data and included individuals aged 18 years or older diagnosed with COVID-19 between January 2022 and December 2023. The study cohort included nonhospitalized individuals who were at high risk of COVID-19 progression, and selected the first COVID-19 episode in each quarter, including reinfection episodes. Paxlovid use was defined as receiving Paxlovid within ±5 days of a COVID-19 diagnosis. We used descriptive statistics to characterize Paxlovid use overall and by calendar quarter and race/ethnicity. We used a generalized estimating equations (GEE) models to quantify the association of race/ethnicity with Paxlovid use controlling for age, gender, and clinical characteristics. RESULTS: Among 1 264 215 individuals at high risk of disease progression (1 404 607 episodes), Paxlovid use increased from 1.2% in January-March 2022 to 35.1% in October-December 2023. Paxlovid use was more common among non-Hispanic White individuals (23.9%) than non-Hispanic Black (16.5%) and Latinx/e (16.7%) patients. After adjusting age, gender, and clinical characteristics, Paxlovid use was less likely among non-Hispanic Black (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.68-0.70) and Latinx/e (OR 0.72, CI 0.71-0.73) patients than non-Hispanic White patients. CONCLUSIONS: Among a large, diverse cohort of community-dwelling individuals with COVID-19, nearly two out of three eligible individuals did not receive Paxlovid, and minoritized racial/ethnic groups were less likely to use Paxlovid than their non-Hispanic White individuals.

GRADE Guidance 39: Using GRADE-ADOLOPMENT to adopt, adapt or create contextualized recommendations from source guidelines and evidence syntheses.

INTRODUCTION: The GRADE-ADOLOPMENT methodology has been widely used to adopt, adapt or de novo develop recommendations from existing or new guideline and evidence synthesis efforts. This guidance refines the operationalization for applying GRADE-ADOLOPMENT. METHODS: Through iterative discussions, online meetings and email communications, the GRADE-ADOLOPMENT Project Group drafted the updated guidance. We then conducted a review of handbooks of guideline-producing organizations, and a scoping review of published and planned Adolopment guideline projects. The lead authors refined the existing approach based on the scoping review findings and feedback from members of the GRADE Working Group. We presented the revised approach to the group in November 2022 (approximately 115 people), in May 2023 (approximately 100 people) and twice in September 2023 (approximately 60 and 90 people) for approval. RESULTS: This GRADE guidance shows how to effectively and efficiently contextualize recommendations using the GRADE-ADOLOPMENT approach by: (1) showcasing alternative pathways for starting an adolopment effort; (2) elaborating on the different essential steps of this approach, such as building on existing EtDs when available or developing new EtDs if necessary; and (3) providing examples from adolopment case studies to facilitate the application of the approach. We demonstrate how to use contextual evidence to make judgments about EtD criteria, and highlight the importance of making the resulting EtDs available to facilitate adolopment efforts by others. CONCLUSION: This updated GRADE guidance further operationalizes the application of GRADE-ADOLOPMENT based on over six years of experience. It serves to support uptake and application by end users interested in contextualizing recommendations to a local setting or specific reality in a short period of time or with limited resources.

PheMIME: an interactive web app and knowledge base for phenome-wide, multi-institutional multimorbidity analysis.

OBJECTIVES: To address the need for interactive visualization tools and databases in characterizing multimorbidity patterns across different populations, we developed the Phenome-wide Multi-Institutional Multimorbidity Explorer (PheMIME). This tool leverages three large-scale EHR systems to facilitate efficient analysis and visualization of disease multimorbidity, aiming to reveal both robust and novel disease associations that are consistent across different systems and to provide insight for enhancing personalized healthcare strategies. MATERIALS AND METHODS: PheMIME integrates summary statistics from phenome-wide analyses of disease multimorbidities, utilizing data from Vanderbilt University Medical Center, Mass General Brigham, and the UK Biobank. It offers interactive and multifaceted visualizations for exploring multimorbidity. Incorporating an enhanced version of associationSubgraphs, PheMIME also enables dynamic analysis and inference of disease clusters, promoting the discovery of complex multimorbidity patterns. A case study on schizophrenia demonstrates its capability for generating interactive visualizations of multimorbidity networks within and across multiple systems. Additionally, PheMIME supports diverse multimorbidity-based discoveries, detailed further in online case studies. RESULTS: The PheMIME is accessible at https://prod.tbilab.org/PheMIME/. A comprehensive tutorial and multiple case studies for demonstration are available at https://prod.tbilab.org/PheMIME_supplementary_materials/. The source code can be downloaded from https://github.com/tbilab/PheMIME. DISCUSSION: PheMIME represents a significant advancement in medical informatics, offering an efficient solution for accessing, analyzing, and interpreting the complex and noisy real-world patient data in electronic health records. CONCLUSION: PheMIME provides an extensive multimorbidity knowledge base that consolidates data from three EHR systems, and it is a novel interactive tool designed to analyze and visualize multimorbidities across multiple EHR datasets. It stands out as the first of its kind to offer extensive multimorbidity knowledge integration with substantial support for efficient online analysis and interactive visualization.

A Novel Species of the Genus Thermanaerothrix Isolated from a Kamchatka Hot Spring Possesses Hydrolytic Capabilities.

Hot springs are inhabited by specific microbial communities which are reservoirs of novel taxa. In this work strain 4228-RoLT was isolated from the Solnechny hot spring, Uzon Caldera, Kamchatka. Cells of the strain 4228-RoLT were Gram-negative rods forming multicellular filaments. The strain grew optimally at 60 °C and pH 7.0 and fermented various organic compounds including polysaccharides (microcrystalline cellulose, xylan, chitin, starch, dextrin, dextran, beta-glucan, galactomannan, glucomannan, mannan). Major fatty acids were iso-C17:0, C16:0, C18:0, C20:0, iso-C19:0, anteiso-C17:0 and C22:0. Genome of the strain was of 3.25 Mbp with GC content of 54.2%. Based on the whole genome comparisons and phylogenomic analysis the new isolate was affiliated to a novel species of Thermanaerothrix genus within Anaerolineae class of phylum Chloroflexota, for which the name T. solaris sp. nov. was proposed with 4228-RoLT (= VKM B-3776 T = UQM 41594 T = BIM B-2058 T) as the type strain. 114 CAZymes including 43 glycoside hydrolases were found to be encoded in the genome of strain 4228-RoLT. Cell-bound and extracellular enzymes of strain 4228-RoLT were active against starch, dextran, mannan, xylan and various kinds of celluloses, with the highest activity against beta-glucan. Altogether, growth experiments, enzymatic activities determination and genomic analysis suggested that T. solaris strain 4228-RoLT could serve as a source of glycosidases suitable for plant biomass hydrolysis.

A potent, broadly neutralizing human monoclonal antibody that efficiently protects hACE2-transgenic mice from infection with the Wuhan, BA.5, and XBB.1.5 SARS-CoV-2 variants.

The COVID-19 pandemic has uncovered the high genetic variability of the SARS-CoV-2 virus and its ability to evade the immune responses that were induced by earlier viral variants. Only a few monoclonal antibodies that have been reported to date are capable of neutralizing a broad spectrum of SARS-CoV-2 variants. Here, we report the isolation of a new broadly neutralizing human monoclonal antibody, iC1. The antibody was identified through sorting the SARS-CoV-1 RBD-stained individual B cells that were isolated from the blood of a vaccinated donor following a breakthrough infection. In vitro, iC1 potently neutralizes pseudoviruses expressing a wide range of SARS-CoV-2 Spike variants, including those of the XBB sublineage. In an hACE2-transgenic mouse model, iC1 provided effective protection against the Wuhan strain of the virus as well as the BA.5 and XBB.1.5 variants. Therefore, iC1 can be considered as a potential component of the broadly neutralizing antibody cocktails resisting the SARS-CoV-2 mutation escape.

JAK2-mutant Clonal Hematopoiesis is Associated with Venous Thromboembolism.

Venous thromboembolism (VTE) is common among older individuals, but provoking factors are not identified in many cases. Patients with myeloid malignancies, especially myeloproliferative neoplasms, are at increased risk for venous thrombosis. Clonal hematopoiesis of indeterminate potential (CHIP), a precursor state to myeloid malignancies, is common among the elderly and may similarly predispose to venous thrombosis. We evaluated overall and genotype-specific associations between CHIP and prevalent and incident VTE in >400,000 samples from the UK Biobank. CHIP was modestly associated with incident VTE with a hazard ratio of 1.17 (95% confidence interval (CI) 1.09-1.3; p= 0.002) but was not significantly associated with prevalent VTE with an odds ratio of 1.02 (95% CI 0.81-1.23; p= 0.81). TET2-mutant CHIP was associated with incident VTE with a hazard ratio of 1.33 (95% CI 1.05-1.69; p= 0.02). JAK2 mutations were highly associated with both prevalent and incident VTE risk with odds ratio of 6.58 (95% CI 2.65-16.29; p= 4.7 x 10-5) and hazard ratio of 4.2 (95% CI 2.18-8.08; p= 1.7 x 10-5), respectively, consistent with the thrombophilia associated with JAK2-mutant myeloproliferative neoplasms. The association between JAK2-mutant CHIP and VTE remained significant after excluding potential undiagnosed myeloproliferative neoplasms based on laboratory parameters. Compared to heterozygous factor V Leiden and heterozygous prothrombin gene mutation, JAK2-mutant CHIP was more strongly associated with VTE but was less common. These results indicate that most individuals with CHIP do not have an altered risk of thrombosis, but that individuals with JAK2-mutant CHIP have a significantly elevated risk of VTE.

Clonal hematopoiesis, cardiovascular events and treatment benefit in 63,700 individuals from five TIMI randomized trials.

Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with an increased risk of cardiovascular (CV) disease in the general population. Currently, it is unclear whether this association is observed in large clinical trial cohorts with a high burden of existing CV disease or whether CV therapies can mitigate CHIP-associated CV risk. To address these questions, we studied 63,700 patients from five randomized trials that tested established therapies for CV disease, including treatments targeting the proteins PCSK9, SGLT2, P2Y12 and FXa. During a median follow-up of 2.5 years, 7,453 patients had at least one CV event (CV death, myocardial infarction (MI), ischemic stroke or coronary revascularization). The adjusted hazard ratio (aHR) for CV events for CHIP+ patients was 1.07 (95% CI: 0.99-1.16, P = 0.08), with consistent risk estimates across each component of CV risk. Significant heterogeneity in the risk of MI was observed, such that CHIP+ patients had a 30% increased risk of first MI (aHR = 1.31 (1.05-1.64), P = 0.02) but no increased risk of recurrent MI (aHR = 0.94 (0.79-1.13), Pint = 0.008), as compared to CHIP- patients. Moreover, no significant heterogeneity in treatment effect between individuals with and without CHIP was observed for any of the therapies studied in the five trials. These results indicate that in clinical trial populations, CHIP is associated with incident but not recurrent coronary events and that the presence of CHIP does not appear to identify patients who will derive greater benefit from commonly used CV therapies.

Genetic determinants and phenotypic consequences of blood T-cell proportions in 207,000 diverse individuals.

T-cells play a critical role in multiple aspects of human health and disease. However, to date the genetic determinants of human T-cell abundance have not been studied at scale because assays quantifying T-cell abundance are not widely used in clinical or research settings. The complete blood count clinical assay quantifies lymphocyte abundance which includes T-cells, B-cells, and NK-cells. To address this gap, we directly estimate T-cell fractions from whole genome sequencing data in over 200,000 individuals from the multi-ethnic TOPMed and All of Us studies. We identified 27 loci associated with T-cell fraction. Interrogating electronic health records identified clinical phenotypes associated with T-cell fraction, including notable changes in T-cell proportions that were highly dynamic over the course of pregnancy. In summary, by estimating T-cell fraction, we obtained new insights into the genetic regulation of T-cells and identified disease consequences of T-cell fractions across the human phenome.

Ex vivo model of breast cancer cell invasion in live lymph node tissue.

Lymph nodes (LNs) are common sites of metastatic invasion in breast cancer, often preceding spread to distant organs and serving as key indicators of clinical disease progression. However, the mechanisms of cancer cell invasion into LNs are not well understood. Existing in vivo models struggle to isolate the specific impacts of the tumor-draining lymph node (TDLN) milieu on cancer cell invasion due to the co-evolving relationship between TDLNs and the upstream tumor. To address these limitations, we used live ex vivo LN tissue slices with intact chemotactic function to model cancer cell spread within a spatially organized microenvironment. After showing that BRPKp110 breast cancer cells were chemoattracted to factors secreted by naïve LN tissue in a 3D migration assay, we demonstrated that ex vivo LN slices could support cancer cell seeding, invasion, and spread. This novel approach revealed dynamic, preferential cancer cell invasion within specific anatomical regions of LNs, particularly the subcapsular sinus (SCS) and cortex, as well as chemokine-rich domains of immobilized CXCL13 and CCL1. While CXCR5 was necessary for a portion of BRPKp110 invasion into naïve LNs, disruption of CXCR5/CXCL13 signaling alone was insufficient to prevent invasion towards CXCL13-rich domains. Finally, we extended this system to pre-metastatic TDLNs, where the ex vivo model predicted a lower invasion of cancer cells. The reduced invasion was not due to diminished chemokine secretion, but it correlated with elevated intranodal IL-21. In summary, this innovative ex vivo model of cancer cell spread in live LN slices provides a platform to investigate cancer invasion within the intricate tissue microenvironment, supporting time-course analysis and parallel read-outs. We anticipate that this system will enable further research into cancer-immune interactions and allow isolation of specific factors that make TDLNs resistant to cancer cell invasion, which are challenging to dissect in vivo.

A novel minimally invasive and versatile kyphoplasty balloon-based model of porcine spinal cord injury.

Introduction: Spinal cord injury (SCI) animal models often utilize an open surgical laminectomy, which results in animal morbidity and also leads to changes in spinal canal diameter, spinal cord perfusion, cerebrospinal fluid flow dynamics, and spinal stability which may confound SCI research. Moreover, the use of open surgical laminectomy for injury creation lacks realism when considering human SCI scenarios. Methods: We developed a novel, image-guided, minimally invasive, large animal model of SCI which utilizes a kyphoplasty balloon inserted into the epidural space via an interlaminar approach without the need for open surgery. Results: The model was validated in 5 Yucatán pigs with imaging, neurofunctional, histologic, and electrophysiologic findings consistent with a mild compression injury. Discussion: Few large animal models exist that have the potential to reproduce the mechanisms of spinal cord injury (SCI) commonly seen in humans, which in turn limits the relevance and applicability of SCI translational research. SCI research relies heavily on animal models, which typically involve an open surgical, dorsal laminectomy which is inherently invasive and may have untoward consequences on animal morbidity and spinal physiology that limit translational impact. We developed a minimally invasive, large animal model of spinal cord injury which utilizes a kyphoplasty balloon inserted percutaneously into the spinal epidural space. Balloon inflation results in a targeted, compressive spinal cord injury with histological and electrophysiological features directly relevant to human spinal cord injury cases without the need for invasive surgery. Balloon inflation pressure, length of time that balloon remains inflated, and speed of inflation may be modified to achieve variations in injury severity and subtype.

Ignisphaera cupida sp. nov., a hyperthermophilic hydrolytic archaeon from a hot spring of Uzon (Kamchatka), and emended description of the genus Ignisphaera.

A novel strictly anaerobic hyperthermophilic archaeon, strain 4213-coT, was isolated from a terrestrial hot spring in the Uzon Caldera, Kamchatka (Russian Federation). Coccoid cells were present singly, in pairs, or aggregates, and occasionally were motile. The strain grew at 75-100 °C and within a pH range of 5.4-8.2 with the optimum at 92 °C and pH 6.4-6.7. Strain 4213-coT was a chemoorganoheterotroph, growing on proteinaceous substrates and mono-, di- and polysaccharides (starch, guar gum, xanthan gum). It did not require sodium chloride for growth. The complete genome of strain 4213-coT was 1.74 Mbp in size; its G+C content was 36.18 %. Genome analysis allowed to identify 25 genes encoding glycosidases involved in polysaccharide hydrolysis as well as genes of ADP-forming acetate-CoA ligase, lactate dehydrogenase and two [NiFe] hydrogenases responsible for acetate, lactate and hydrogen formation during fermentation. Moreover gene cluster encoding archaellum subunits was found. According to the phylogenomic analysis strain 4213-coT formed a species-level phylogenetic lineage within Ignisphaera genus. Our phylogenomic analysis also supports the delineation of the Ignisphaera genus into a separate family Ignisphaeraceae, as recently published. Here we propose a novel species Ignisphaera cupida, sp. nov. with type strain 4213-coT (=JCM 39446T=VKM B-3715T=UQM 41593T). Ecogenomic analysis showed that representatives of the Ignisphaera are thermophilic archaea, the majority of them were found in terrestrial hot springs and deep-sea hydrothermal vents. This study allowed a better understanding of physiology and ecology of Ignisphaeraceae - a rather understudied archaeal group.

Cretaceous crown male ant reveals the rise of modern lineages.

Most described Mesozoic ants belong to stem groups that existed only during the Cretaceous period. Previously, the earliest known crown ants were dated to the Turonian (Late Cretaceous, ca. 94-90 million years ago (Ma)) deposits found in the USA, Kazakhstan, and Botswana. However, the recent discovery of an alate male ant in Kachin amber from the earliest Cenomanian (ca. 99 Ma), representing a new genus and species, Antiquiformica alata, revises the narrative on ant diversification. Antiquiformica can be distinctly differentiated from all known male stem ants by its geniculate antennae with elongated scape, extending far beyond the occipital margin of the head and half the length of the funiculus, as well as its partly reduced forewing venation. Furthermore, the combination of a one-segmented waist with a well-developed node, elongated scape extending beyond the occipital margin, and reduced forewing venation, particularly the completely reduced m-cu and rs-m crossveins and absence of rm and mcu closed cells, firmly places the fossil within the extant subfamily Formicinae. Fourier transform infrared spectroscopy (FTIR) confirmed that the amber containing Antiquiformica alata originated from the Kachin mines in Myanmar. This discovery significantly revises our understanding of the early evolution of Formicinae. The presence of Antiquiformica in Cenomanian amber indicates that the subfamily Formicinae emerged at least by the start of the Late Cretaceous, with crown ants likely originating earlier during the earliest Cretaceous or possibly the Late Jurassic, although paleontological evidence is lacking to support the latter hypothesis.

Spinal Cord Stimulator Inequities Within the US Military Health System.

OBJECTIVES: Although studies have described inequities in spinal cord stimulation (SCS) receipt, there is a lack of information to inform system-level changes to support health care equity. This study evaluated whether Black patients exhaust more treatment options than do White patients, before receiving SCS. MATERIALS AND METHODS: This retrospective cohort study included claims data of Black and non-Latinx White patients who were active-duty service members or military retirees who received a persistent spinal pain syndrome (PSPS) diagnosis associated with back surgery within the US Military Health System, January 2017 to January 2020 (N = 8753). A generalized linear model examined predictors of SCS receipt within two years of diagnosis, including the interaction between race and number of pain-treatment types received. RESULTS: In the generalized linear model, Black patients (10.3% [8.7%, 12.0%]) were less likely to receive SCS than were White patients (13.6% [12.7%, 14.6%]) The interaction term was significant; White patients who received zero to three different types of treatments were more likely to receive SCS than were Black patients who received zero to three treatments, whereas Black and White patients who received >three treatments had similar likelihoods of receiving a SCS. CONCLUSIONS: In a health care system with intended universal access, White patients diagnosed with PSPS tried fewer treatment types before receiving SCS, whereas the number of treatment types tried was not significantly related to SCS receipt in Black patients. Overall, Black patients received SCS less often than did White patients. Findings indicate the need for structured referral pathways, provider evaluation on equity metrics, and top-down support.

Prospective, longitudinal study of cancer predictors and rates in a New York City cohort of 598 patients with acromegaly.

PURPOSE: Long-term GH/IGF-1 excess could increase risk of cancer in acromegaly, but individual levels of these hormones do not relate to this risk. Therefore, we newly investigated longitudinally-measured IGF-1 levels as a potential predictor of cancer in a large NYC acromegaly cohort. METHODS: We conducted a prospective, longitudinal study of 598 acromegaly (309 men, 289 women) and 292 clinically nonfunctioning pituitary adenoma (CNFPA)(140 women, 152 men) patients from the same underlying population. GH and IGF-1 levels were measured longitudinally and outcomes were observed during long-term follow-up. Cumulative exposure to IGF-1 excess was tested as a predictor of cancer. We compared cancer prevalence in acromegaly and CNFPA cohorts and incidence in each to that expected from SEER data. RESULTS: Cancer prevalence by last follow up was 22.6% in acromegaly and 12.7% in CNFPAs (OR = 1.99 (95% CI, 1.34, 2.97)(P=0.0005). Overall SIR for cancer was 1.78 (1.51, 1.81) in the acromegaly and 1.26 (0.89, 1.70) in the CNFPA cohorts. Cumulative exposure to IGF-1 excess, OR=1.278 (1.060, 1.541)(P = 0.01), years from acromegaly diagnosis to cancer or last follow up, OR= 1.03 (1.004, 1.057)(P=0.024), and age at follow up, OR =1.064 (1.047, 1.082)(P<0.001), were predictors of cancer. CONCLUSIONS: Cancer risk is increased in acromegaly, but not in CNFPA patients. Cumulative exposure to IGF-1 excess is a predictor of cancer in acromegaly. Our data suggest that cancer risk in acromegaly relates to the degree and duration of IGF-1 excess and that full appreciation of this risk requires long-term follow up.

The evolution of mammalian Rem2: unraveling the impact of purifying selection and coevolution on protein function, and implications for human disorders.

Rad And Gem-Like GTP-Binding Protein 2 (Rem2), a member of the RGK family of Ras-like GTPases, is implicated in Huntington's disease and Long QT Syndrome and is highly expressed in the brain and endocrine cells. We examine the evolutionary history of Rem2 identified in various mammalian species, focusing on the role of purifying selection and coevolution in shaping its sequence and protein structural constraints. Our analysis of Rem2 sequences across 175 mammalian species found evidence for strong purifying selection in 70% of non-invariant codon sites which is characteristic of essential proteins that play critical roles in biological processes and is consistent with Rem2's role in the regulation of neuronal development and function. We inferred epistatic effects in 50 pairs of codon sites in Rem2, some of which are predicted to have deleterious effects on human health. Additionally, we reconstructed the ancestral evolutionary history of mammalian Rem2 using protein structure prediction of extinct and extant sequences which revealed the dynamics of how substitutions that change the gene sequence of Rem2 can impact protein structure in variable regions while maintaining core functional mechanisms. By understanding the selective pressures, protein- and gene - interactions that have shaped the sequence and structure of the Rem2 protein, we gain a stronger understanding of its biological and functional constraints.

Synergism of primary and secondary interactions in a crystalline hydrogen peroxide complex with tin.

Despite the significance of H2O2-metal adducts in catalysis, materials science and biotechnology, the nature of the interactions between H2O2 and metal cations remains elusive and debatable. This is primarily due to the extremely weak coordinating ability of H2O2, which poses challenges in characterizing and understanding the specific nature of these interactions. Herein, we present an approach to obtain H2O2-metal complexes that employs neat H2O2 as both solvent and ligand. SnCl4 effectively binds H2O2, forming a SnCl4(H2O2)2 complex, as confirmed by 119Sn and 17O NMR spectroscopy. Crystalline adducts, SnCl4(H2O2)2·H2O2·18-crown-6 and 2[SnCl4(H2O2)(H2O)]·18-crown-6, are isolated and characterized by X-ray diffraction, providing the complete characterization of the hydrogen bonding of H2O2 ligands including geometric parameters and energy values. DFT analysis reveals the synergy between a coordinative bond of H2O2 with metal cation and its hydrogen bonding with a second coordination sphere. This synergism of primary and secondary interactions might be a key to understanding H2O2 reactivity in biological systems.

Occipital-temporal cortical tuning to semantic and affective features of natural images predicts associated behavioral responses.

In everyday life, people need to respond appropriately to many types of emotional stimuli. Here, we investigate whether human occipital-temporal cortex (OTC) shows co-representation of the semantic category and affective content of visual stimuli. We also explore whether OTC transformation of semantic and affective features extracts information of value for guiding behavior. Participants viewed 1620 emotional natural images while functional magnetic resonance imaging data were acquired. Using voxel-wise modeling we show widespread tuning to semantic and affective image features across OTC. The top three principal components underlying OTC voxel-wise responses to image features encoded stimulus animacy, stimulus arousal and interactions of animacy with stimulus valence and arousal. At low to moderate dimensionality, OTC tuning patterns predicted behavioral responses linked to each image better than regressors directly based on image features. This is consistent with OTC representing stimulus semantic category and affective content in a manner suited to guiding behavior.

Two-dimensional high-throughput on-cell screening of immunoglobulins against broad antigen repertoires.

Identifying high-affinity antibodies in human serum is challenging due to extremely low number of circulating B cells specific to the desired antigens. Delays caused by a lack of information on the immunogenic proteins of viral origin hamper the development of therapeutic antibodies. We propose an efficient approach allowing for enrichment of high-affinity antibodies against pathogen proteins with simultaneous epitope mapping, even in the absence of structural information about the pathogenic immunogens. To screen therapeutic antibodies from blood of recovered donors, only pathogen transcriptome is required to design an antigen polypeptide library, representing pathogen proteins, exposed on the bacteriophage surface. We developed a two-dimensional screening approach enriching lentiviral immunoglobulin libraries from the convalescent or vaccinated donors against bacteriophage library expressing the overlapping set of polypeptides covering the spike protein of SARS-CoV-2. This platform is suitable for pathogen-specific immunoglobulin enrichment and allows high-throughput selection of therapeutic human antibodies.

Polymer-Assisted Polymorph Transition in Melt-Processed Molecular Semiconductor Crystals.

A previously unreported polymorph of 5,11-bis(triisopropylsilylethynyl)anthradithiophene (TIPS ADT), Form II, crystallizes from melt-processed TIPS ADT films blended with 16 ± 1 wt % medium density polyethylene (PE). TIPS ADT/PE blends that initially are crystallized from the melt produce twisted TIPS ADT crystals of a metastable polymorph (Form IV, space group P1̅) with a brickwork packing motif distinct from the slipstack packing by solution-processed TIPS ADT crystals (Form I, space group P21/c) at room temperature. When these films were cooled to room temperature and subsequently annealed at 100 °C, near a PE melting temperature of 110 °C, Form II crystals nucleated and grew while consuming Form IV. The growth rate and orientations of Form II crystals were predetermined by the twisting pitch and growth direction of the original banded spherulites in the melt-processed films of the blends. Notably, the Form IV → II transition was not observed during thermal annealing of neat TIPS ADT films without PE. The presence of the mobile PE phase during thermal annealing of TIPS ADT/PE blend films increases the diffusion rate of TIPS ADT molecules, and the rate of nucleation of Form II. Form IV crystals are more conductive but less emissive compared to Form II crystals.

Laser interstitial thermal therapy of a single nodule in a complex epileptic network with multiple periventricular nodular heterotopias.

Surgical management of drug-resistant epilepsy (DRE) in patients with multiple periventricular nodular heterotopias (PVNHs) is challenging. Identifying the location of seizure onset within these complex epileptic networks is difficult, and open resection carries risks of injury to surrounding functional white matter tracts such as optic radiations (ORs). The authors demonstrate tractography-assisted laser ablation of a single nodule in a patient with DRE and multiple PVNHs. Following surgery, visual fields were intact, highlighting the benefits of OR tractographic reconstruction. At 12 months postoperatively, the patient remained seizure free, suggesting the potential efficacy of targeting a single heterotopia within complex networks in well-selected cases. The video can be found here: https://stream.cadmore.media/r10.3171/2024.4.FOCVID2417.