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BACKGROUND AND OBJECTIVES: Traumatic brain injury (TBI) is frequently characterized by chronic motor deficits. Therefore, this clinical trial assessed whether intracranial implantation of allogeneic modified mesenchymal stromal (SB623) cells can improve chronic motor deficits after TBI. METHODS: Post hoc analysis of the double-blind, randomized, prospective, surgical sham-controlled, phase 2, STEMTRA clinical trial (June 2016 and March 2019) with 48 weeks of follow-up was conducted. In this international, multicenter clinical trial, eligible participants had moderate-to-severe TBI, were ≥12 months postinjury, and had chronic motor deficits. Participants were randomized in a 1:1:1:1 ratio to stereotactic surgical intracranial implantation of SB623 cells (2.5 × 106, 5.0 × 106, 10 × 106) or surgical sham-controlled procedure. The prespecified primary efficacy end point was significantly greater change from baseline of the Fugl-Meyer Motor Scale (FMMS) score, a measure of motor status, for the SB623 pooled vs control arm at 24 weeks. RESULTS: A total of 211 participants were screened, 148 were excluded, and 63 underwent randomization, of which 61 (97%; mean age, 34 [SD, 12] years; 43 men [70.5%]) completed the trial. Single participants in the SB623 2.5 × 106 and 5.0 × 106 cell dose groups discontinued before surgery. Safety and efficacy (modified intent-to-treat) were assessed in participants who underwent surgery (N = 61; SB623 = 46, controls = 15). The primary efficacy end point (FMMS) was achieved (least squares mean [SE] SB623: +8.3 [1.4]; 95% CI 5.5-11.2 vs control: +2.3 [2.5]; 95% CI -2.7 to 7.3; p = 0.04), with faster improvement of the FMMS score in SB623-treated groups than in controls at 24 weeks and sustained improvement at 48 weeks. At 48 weeks, improvement of function and activities of daily living (ADL) was greater, but not significantly different in SB623-treated groups vs controls. The incidence of adverse events was equivalent in SB623-treated groups and controls. There were no deaths or withdrawals due to adverse events. DISCUSSION: Intraparenchymal implantation of SB623 cells was safe and significantly improved motor status at 24 weeks in participants with chronic motor deficits after TBI, with continued improvement of function and ADL at 48 weeks. Cell therapy can modify chronic neurologic deficits after TBI. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02416492. Submitted to registry: April 15, 2015. First participant enrolled: July 6, 2016. Available at: classic.clinicaltrials.gov/ct2/show/NCT02416492. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that intracranial implantation of allogeneic stem (SB623) cells in adults with motor deficits from chronic TBI improves motor function at 24 weeks.

Measures of life outlook in older adults have been investigated in connection to pain, as both pain management and outlook are important factors of successful aging. We hypothesized that higher pain is associated with lower optimism among community-dwelling older adults. We utilized data from the UC San Diego Successful Aging Evaluation (SAGE), a prospective longitudinal cohort study initiated in 2010, to evaluate the relationship between pain and optimism in 378 community-dwelling adults aged ≥50 years. We used the revised Life Orientation Test (LOT-R) to measure optimism and three pain subscales-PROMIS Pain Interference, PROMIS Pain Intensity, and MOS 36-Item Short-Form Health Survey (SF-36)-as pain measures. Regression analyses reveal negative relationships between pain and optimism for all three pain scales, with regression coefficients of -0.277 (p

Cellular nanoparticles (CNPs), which refer to nanoparticles coated with natural cell membranes, are promising for neutralizing pathological agents. Here, we use CNPs as a medical countermeasure against the infection of SARS-CoV-2 variants in an animal model. CNPs comprise polymeric cores coated with the plasma membranes of human macrophages. The resulting nanoparticles (MΦ-NPs) act as host cell decoys to intercept SARS-CoV-2 and block its cellular entry, thus inhibiting subsequent viral infection. Our findings indicate that MΦ-NPs bind to the spike proteins of SARS-CoV-2 variants in a dose-dependent manner and inhibit the infectivity of live viruses. In hamsters infected with SARS-CoV-2 variants, MΦ-NPs significantly reduce the viral burden in the lungs, demonstrating their effectiveness in inhibiting viral infectivity in vivo. Furthermore, MΦ-NPs are primarily taken up by alveolar macrophages without inducing noticeable adverse effects. Given the crucial role of macrophages in viral infections, MΦ-NPs present a promising approach to combating emerging viral threats.

BackgroundOral pre-exposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (F/TDF) has high efficacy against HIV-1 acquisition. Seventy-two prospective studies of daily oral F/TDF PrEP were conducted to evaluate HIV-1 incidence, drug resistance, adherence, and bone and renal safety in diverse settings.MethodsHIV-1 incidence was calculated from incident HIV-1 diagnoses after PrEP initiation and within 60 days of discontinuation. Tenofovir concentrations in dried blood spots (DBS), drug resistance, and bone/renal safety indicators were evaluated in a subset of studies.ResultsAmong 17 274 participants, there were 101 cases with new HIV-1 diagnosis (.77 per 100 person-years; 95% confidence interval [CI]: .63-.94). In 78 cases with resistance data, 18 (23%) had M184I or V, 1 (1.3%) had K65R, and 3 (3.8%) had both mutations. In 54 cases with tenofovir concentration data from DBS, 45 (83.3%), 2 (3.7%), 6 (11.1%), and 1 (1.9%) had average adherence of

Lung megakaryocytes (Mks) are a unique subset of Mks that are distinct from their bone marrow counterparts. Recent evidence suggests that lung Mks favor an immune phenotype, but have unclear contributions to the total platelet mass. In this issue of the JCI, Livada et al. used an array of complementary in vivo labeling and tracing models in mice to investigate a longstanding question of where lung Mks are derived. By combining these models with stressed conditions, the authors assessed the contribution of lung Mks to total platelet counts in a homeostatic and thrombocytopenic state. Mks were minor contributors to the circulating pool of platelets during homeostasis but increased output during thrombocytopenia. These findings add critical understanding to the development of lung Mks and demonstrate the dynamic potential of these specialized cells to respond to thrombocytopenia.

The human hippocampus and prefrontal cortex play critical roles in learning and cognition1,2, yet the dynamic molecular characteristics of their development remain enigmatic. Here we investigated the epigenomic and three-dimensional chromatin conformational reorganization during the development of the hippocampus and prefrontal cortex, using more than 53,000 joint single-nucleus profiles of chromatin conformation and DNA methylation generated by single-nucleus methyl-3C sequencing (snm3C-seq3)3. The remodelling of DNA methylation is temporally separated from chromatin conformation dynamics. Using single-cell profiling and multimodal single-molecule imaging approaches, we have found that short-range chromatin interactions are enriched in neurons, whereas long-range interactions are enriched in glial cells and non-brain tissues. We reconstructed the regulatory programs of cell-type development and differentiation, finding putatively causal common variants for schizophrenia strongly overlapping with chromatin loop-connected, cell-type-specific regulatory regions. Our data provide multimodal resources for studying gene regulatory dynamics in brain development and demonstrate that single-cell three-dimensional multi-omics is a powerful approach for dissecting neuropsychiatric risk loci.

Macrophages contribute to the induction and resolution of inflammation and play a central role in chronic low-grade inflammation in cardiovascular diseases caused by atherosclerosis. Human milk oligosaccharides (HMOs) are complex unconjugated glycans unique to human milk that benefit infant health and act as innate immune modulators. Here, we identify the HMO 3'sialyllactose (3'SL) as a natural inhibitor of TLR4-induced low-grade inflammation in macrophages and endothelium. Transcriptome analysis in macrophages revealed that 3'SL attenuates mRNA levels of a selected set of inflammatory genes and promotes the activity of liver X receptor (LXR) and sterol regulatory element binding protein-1 (SREBP1). These acute antiinflammatory effects of 3'SL were associated with reduced histone H3K27 acetylation at a subset of LPS-inducible enhancers distinguished by preferential enrichment for CCCTC-binding factor (CTCF), IFN regulatory factor 2 (IRF2), B cell lymphoma 6 (BCL6), and other transcription factor recognition motifs. In a murine atherosclerosis model, both s.c. and oral administration of 3'SL significantly reduced atherosclerosis development and the associated inflammation. This study provides evidence that 3'SL attenuates inflammation by a transcriptional mechanism to reduce atherosclerosis development in the context of cardiovascular disease.

Cowpea mosaic virus (CPMV) is a plant virus that is currently being developed for intratumoral immunotherapy. CPMV relieves the immune system from tumor-induced immunosuppression; reprograms the tumor microenvironment to an activated state whereby the treated and distant tumors are recognized and eradicated. Toward translational studies, we investigated the safety of CPMV, specifically addressing whether pathogenicity would be induced in mammalian cells. We show that murine macrophage immune cells recognize CPMV; however, there is no indication of de novo viral protein synthesis or RNA replication. Furthermore, we show that CPMV does not induce hemolysis, platelet aggregation and plasma coagulation amongst other assays in human blood and immune cells. Taken together, we anticipate that these results will reinforce the development of CPMV as an immunotherapeutic platform.

Mozambique is making progress towards elimination of trachoma as a public health problem, but in some districts trachomatous inflammation-follicular (TF) prevalence remains above the 5% elimination threshold despite years of various interventions, including antibiotic mass drug administration. To characterize transmission in four districts, we incorporated testing of ocular infection and serology into routine trachoma impact surveys (TIS) in August 2022. We examined residents aged ≥ 1 year for trachoma and collected information on household water, sanitation, and hygiene. Among children aged 1-9 years, we tested conjunctival swabs for Chlamydia trachomatis nucleic acid and dried blood spots for C. trachomatis antibodies. We modeled age-dependent seroprevalence to estimate seroconversion rate (SCR). We examined 4841 children aged 1-9 years. TF prevalence ranged between 1.1 and 6.0% with three districts below the 5% threshold. PCR-confirmed infection prevalence ranged between 1.1 and 4.8%, and Pgp3 seroprevalence ranged between 8.8 and 24.3%. Pgp3 SCR was 1.9 per 100 children per year in the district with the lowest TF prevalence. Two other districts with TF

Enhancing the efficacy of immunotherapy in brain metastases (BrM) requires an improved understanding of the immune composition of BrM and how this is affected by radiation and dexamethasone. Our two-arm pilot study (NCT04895592) allocated 26 patients with BrM to either low (Arm A) or high (Arm B) dose peri-operative dexamethasone followed by pre-operative stereotactic radiosurgery (pSRS) and resection (n= 13 per arm). The primary endpoint, a safety analysis at 4 months, was met. The secondary clinical endpoints of overall survival, distant brain failure, leptomeningeal disease and local recurrence at 12-months were 66%, 37.3%, 6%, and 0% respectively and were not significantly different between arms (p= 0.7739, p= 0.3884, p= 0.3469). Immunological data from two large retrospective BrM datasets and confirmed by correlates from both arms of this pSRS prospective trial revealed that BrM CD8 T cells were composed of predominantly PD1+ TCF1+ stem-like and PD1+ TCF1-TIM3+ effector-like cells. Clustering of TCF1+ CD8 T cells with antigen presenting cells in immune niches was prognostic for local control, even without pSRS. Following pSRS, CD8 T cell and immune niche density were transiently reduced compared to untreated BrM, followed by a rebound 6+ days post pSRS with an increased frequency of TCF1- effector-like cells. In sum, pSRS is safe and therapeutically beneficial, and these data provide a framework for how pSRS may be leveraged to maximize intracranial CD8 T cell responses.

PURPOSE: The new CAP guideline published in August 2022 recommends using immunohistochemistry (IHC) to test for mismatch repair defects in gastroesophageal (GE), small bowel (SB), or endometrial carcinoma (EC) cancers over next-generation sequencing assessment of microsatellite instability (NGS-MSI) for immune checkpoint inhibitor (ICI) therapy eligibility and states there is a preference to use IHC over NGS-MSI in colorectal carcinoma (CRC). METHODS: We assessed the concordance of NGS-MSI and IHC-MMR from a very large cohort across the spectrum of solid tumors. RESULTS: Of the over 190,000 samples with both NGS-MSI and IHC-MMR about 1,160 were initially flagged as discordant. Of those samples initially flagged as discordant, 50.9% remained discordant after being reviewed by an additional pathologist. This resulted in a final discordance rate of 0.31% (590/191,767). Among CRC, GE, SB and EC, 55.4% of mismatch repair proficient/MSI high (MMRp/MSI-H) tumors had at least one somatic pathogenic mutation in an MMR gene or POLE. Mismatch repair deficient/microsatellite stable (MMRd/MSS) tumors had a significantly lower rate of high tumor mutational burden than MMRp/MSI-H tumors. Across all solid tumors, MMRd/MSI-H tumors had significantly longer overall survival (OS; hazard ratio [HR], 1.47, P < .001) and post-ICI survival (HR, 1.82, P < .001) as compared with MMRp/MSS tumors. The OS for the MMRd/MSS group was slightly worse compared to the MMRp/MSI-H tumors, but this difference was not statistically significant (HR, 0.73, P = .058), with a similar pattern when looking at post-ICI survival (HR, 0.43, P = .155). CONCLUSION: This study demonstrates that NGS-MSI is noninferior to IHC-MMR and can identify MSI-H tumors that IHC-MMR is unable to detect and conversely IHC-MMR can identify MMRd tumors that NGS-MSI misses.

BACKGROUND AND OBJECTIVE: Upadacitinib is indicated for diseases affecting persons of childbearing potential including rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, atopic dermatitis, Crohns disease, and ulcerative colitis; however, teratogenicity was observed in animal studies. Given the potential for human fetal risk, pregnancy avoidance measures were required during clinical trials. This analysis describes pregnancy outcomes in patients exposed to upadacitinib during pregnancy. METHODS: Clinical trial and postmarketing cases of in utero exposure to upadacitinib were identified in AbbVies safety database through 25 April, 2023. Analysis of clinical trial cases and postmarketing reports are presented separately; prospective and retrospectively reported pregnancy outcomes are integrated for each. Descriptive rates are presented to summarize outcomes. RESULTS: There were 128 maternal upadacitinib-exposed pregnancies with known outcomes identified; 80 and 48 pregnancies were reported in clinical trials and the postmarketing setting, respectively. In clinical trials (mean in utero exposure of 5 weeks, 3 days), live births (54%), spontaneous abortions (24%), elective terminations (21%), and ectopic pregnancy (1%) were reported. There was one report of a congenital malformation: a 35-week infant with an atrial septal defect. In postmarketing cases, live births (46%), spontaneous abortions (38%), elective terminations (15%), and ectopic pregnancy (2%) were reported. CONCLUSIONS: As the data are limited for in utero exposure to upadacitinib, definitive conclusions cannot be drawn regarding the effect of upadacitinib on pregnancy outcomes. Rates of adverse pregnancy outcomes with upadacitinib exposure were comparable to rates observed in the general population or patients with autoimmune inflammatory diseases. To date, no apparent evidence of teratogenicity exists in the analyses of human pregnancies exposed to upadacitinib during the first trimester.

The proteasome is a proteolytic enzyme complex essential for protein homeostasis in mammalian cells and protozoan parasites like Trichomonas vaginalis (Tv), the cause of the most common, non-viral sexually transmitted disease. Tv and other protozoan 20S proteasomes have been validated as druggable targets for antimicrobials. However, low yields and purity of the native proteasome have hindered studies of the Tv 20S proteasome (Tv20S). We address this challenge by creating a recombinant protozoan proteasome by expressing all seven α and seven β subunits of Tv20S alongside the Ump-1 chaperone in insect cells. The recombinant Tv20S displays biochemical equivalence to its native counterpart, confirmed by various assays. Notably, the marizomib (MZB) inhibits all catalytic subunits of Tv20S, while the peptide inhibitor carmaphycin-17 (CP-17) specifically targets β2 and β5. Cryo-electron microscopy (cryo-EM) unveils the structures of Tv20S bound to MZB and CP-17 at 2.8 Å. These findings explain MZB's low specificity for Tv20S compared to the human proteasome and demonstrate CP-17's higher specificity. Overall, these data provide a structure-based strategy for the development of specific Tv20S inhibitors to treat trichomoniasis.

Liver X receptor-α (LXRα) regulates cellular cholesterol abundance and potently activates hepatic lipogenesis. Here we show that at least 1 in 450 people in the UK Biobank carry functionally impaired mutations in LXRα, which is associated with biochemical evidence of hepatic dysfunction. On a western diet, male and female mice homozygous for a dominant negative mutation in LXRα have elevated liver cholesterol, diffuse cholesterol crystal accumulation and develop severe hepatitis and fibrosis, despite reduced liver triglyceride and no steatosis. This phenotype does not occur on low-cholesterol diets and can be prevented by hepatocyte-specific overexpression of LXRα. LXRα knockout mice exhibit a milder phenotype with regional variation in cholesterol crystal deposition and inflammation inversely correlating with steatosis. In summary, LXRα is necessary for the maintenance of hepatocyte health, likely due to regulation of cellular cholesterol content. The inverse association between steatosis and both inflammation and cholesterol crystallization may represent a protective action of hepatic lipogenesis in the context of excess hepatic cholesterol.

Climate change, wildfires, and environmental justice concerns have drawn increased attention to the impact of air pollution on children's health and development. Children are especially vulnerable to air pollution exposure, as their brains and bodies are still developing. The objective of this systematic review was to synthesize available empirical evidence on the associations between air pollution exposure and brain outcomes in developmental samples (ages 0-18 years old). Studies were identified by searching the PubMed and Web of Science Core Collection databases and underwent a two-phase screening process before inclusion. 40 studies were included in the review, which included measures of air pollution and brain outcomes at various points in development. Results linked air pollution to varied brain outcomes, including structural volumetric and cortical thickness differences, alterations in white matter microstructure, functional network changes, metabolic and molecular effects, as well as tumor incidence. Few studies included longitudinal changes in brain outcomes. This review also suggests methodologies for incorporating air pollution measures in developmental cognitive neuroscience studies and provides specific policy recommendations to reduce air pollution exposure and promote healthy brain development by improving access to clean air.

TGF-β, essential for development and immunity, is expressed as a latent complex (L-TGF-β) non-covalently associated with its prodomain and presented on immune cell surfaces by covalent association with GARP. Binding to integrin αvβ8 activates L-TGF-β1/GARP. The dogma is that mature TGF-β must physically dissociate from L-TGF-β1 for signaling to occur. Our previous studies discovered that αvβ8-mediated TGF-β autocrine signaling can occur without TGF-β1 release from its latent form. Here, we show that mice engineered to express TGF-β1 that cannot release from L-TGF-β1 survive without early lethal tissue inflammation, unlike those with TGF-β1 deficiency. Combining cryogenic electron microscopy with cell-based assays, we reveal a dynamic allosteric mechanism of autocrine TGF-β1 signaling without release where αvβ8 binding redistributes the intrinsic flexibility of L-TGF-β1 to expose TGF-β1 to its receptors. Dynamic allostery explains the TGF-β3 latency/activation mechanism and why TGF-β3 functions distinctly from TGF-β1, suggesting that it broadly applies to other flexible cell surface receptor/ligand systems.

BACKGROUND: Incorporating genomic data into risk prediction has become an increasingly popular approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. METHODS: Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. RESULTS: The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p=0.006), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p

The remarkable material properties of spider silk, such as its high toughness and tensile strength combined with its low density, make it a highly sought-after material with myriad applications. In addition, the biological nature of spider silk makes it a promising, potentially sustainable alternative to many toxic or petrochemical-derived materials. Therefore, interest in the heterologous production of spider silk proteins has greatly increased over the past few decades, making recombinant spider silk an important frontier in biomanufacturing. This has resulted in a diversity of potential host organisms, a large space for sequence design, and a variety of downstream processing techniques and product applications for spider silk production. Here, we highlight advances in each of these technical aspects as well as white spaces therein, still ripe for further investigation and discovery. Additionally, industry landscaping, patent analyses, and interviews with Key Opinion Leaders help define both the research and industry landscapes. In particular, we found that though textiles dominated the early products proposed by companies, the versatile nature of spider silk has opened up possibilities in other industries, such as high-performance materials in automotive applications or biomedical therapies. While continuing enthusiasm has imbued scientists and investors alike, many technical and business considerations still remain unsolved before spider silk can be democratized as a high-performance product. We provide insights and strategies for overcoming these initial hurdles, and we highlight the importance of collaboration between academia, industry, and policy makers. Linking technical considerations to business and market entry strategies highlights the importance of a holistic approach for the effective scale-up and commercial viability of spider silk bioproduction.

In our cells, a limited number of RNA binding proteins (RBPs) are responsible for all aspects of RNA metabolism across the entire transcriptome. To accomplish this, RBPs form regulatory units that act on specific target regulons. However, the landscape of RBP combinatorial interactions remains poorly explored. Here, we perform a systematic annotation of RBP combinatorial interactions via multimodal data integration. We build a large-scale map of RBP protein neighborhoods by generating in vivo proximity-dependent biotinylation datasets of 50 human RBPs. In parallel, we use CRISPR interference with single-cell readout to capture transcriptomic changes upon RBP knockdowns. By combining these physical and functional interaction readouts, along with the atlas of RBP mRNA targets from eCLIP assays, we generate an integrated map of functional RBP interactions. We then use this map to match RBPs to their context-specific functions and validate the predicted functions biochemically for four RBPs. This study provides a detailed map of RBP interactions and deconvolves them into distinct regulatory modules with annotated functions and target regulons. This multimodal and integrative framework provides a principled approach for studying post-transcriptional regulatory processes and enriches our understanding of their underlying mechanisms.

PurposeThe purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC).Experimental designRB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss.ResultsRB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1.ConclusionsCo-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

A new emissive guanosine analog CF3thG, constructed by a single trifluoromethylation step from the previously reported thG, displays red-shifted absorption and emission spectra compared to its precursor. The impact of solvent type and polarity on the photophysical properties of CF3thG suggests that the electronic effects of the trifluoromethyl group dominate its behavior and demonstrates its susceptibility to microenvironmental polarity changes. In vitro transcription initiations using T7 RNA polymerase, initiated with CF3thG, result in highly emissive 5'-labeled RNA transcripts, demonstrating the tolerance of the enzyme toward the analog. Viability assays with HEK293T cells displayed no detrimental effects at tested concentrations, indicating the safety of the analog for cellular applications. Live cell imaging of the free emissive guanosine analog using confocal microscopy was facilitated by its red-shifted absorption and emission and adequate brightness. Real-time live cell imaging demonstrated the release of the guanosine analog from HEK293T cells at concentration-gradient conditions, which was suppressed by the addition of guanosine.

Purpose To clarify the predominant causative plaque constituent for periprocedural myocardial injury (PMI) following percutaneous coronary intervention: (a) erythrocyte-derived materials, indicated by a high plaque-to-myocardium signal intensity ratio (PMR) at coronary atherosclerosis T1-weighted characterization (CATCH) MRI, or (b) lipids, represented by a high maximum 4-mm lipid core burden index (maxLCBI4 mm) at near-infrared spectroscopy intravascular US (NIRS-IVUS). Materials and Methods This retrospective study included consecutive patients who underwent CATCH MRI before elective NIRS-IVUS-guided percutaneous coronary intervention at two facilities. PMI was defined as post-percutaneous coronary intervention troponin T values greater than five times the upper reference limit. Multivariable analysis was performed to identify predictors of PMI. Finally, the predictive capabilities of MRI, NIRS-IVUS, and their combination were compared. Results A total of 103 lesions from 103 patients (median age, 72 years [IQR, 64-78]; 78 male patients) were included. PMI occurred in 36 lesions. In multivariable analysis, PMR emerged as the strongest predictor (P = .001), whereas maxLCBI4 mm was not a significant predictor (P = .07). When PMR was excluded from the analysis, maxLCBI4 mm emerged as the sole independent predictor (P = .02). The combination of MRI and NIRS-IVUS yielded the largest area under the receiver operating curve (0.86 [95% CI: 0.64, 0.83]), surpassing that of NIRS-IVUS alone (0.75 [95% CI: 0.64, 0.83]; P = .02) or MRI alone (0.80 [95% CI: 0.68, 0.88]; P = .30). Conclusion Erythrocyte-derived materials in plaques, represented by a high PMR at CATCH MRI, were strongly associated with PMI independent of lipids. MRI may play a crucial role in predicting PMI by offering unique pathologic insights into plaques, distinct from those provided by NIRS. Keywords: Coronary Plaque, Periprocedural Myocardial Injury, MRI, Near-Infrared Spectroscopy Intravascular US Supplemental material is available for this article. © RSNA, 2024.

SIGNIFICANCE: Spatial frequency domain imaging (SFDI) applies patterned near-infrared illumination to quantify the optical properties of subsurface tissue. The periocular region is unique due to its complex ocular adnexal anatomy. Although SFDI has been successfully applied to relatively flat in vivo tissues, regions that have significant height variations and curvature may result in optical property inaccuracies. AIM: We characterize the geometric impact of the periocular region on SFDI imaging reliability. APPROACH: SFDI was employed to measure the reduced scattering coefficient ( μ s ) and absorption coefficient ( μ a ) of the periocular region in a cast facial tissue-simulating phantom by capturing images along regions of interest (ROIs): inferior temporal quadrant (ITQ), inferior nasal quadrant (INQ), superior temporal quadrant (STQ), central eyelid margin (CEM), rostral lateral nasal bridge (RLNB), and forehead (FH). The phantom was placed on a chin rest and imaged nine times from an en face or side profile position, and the flat back of the phantom was measured 15 times. RESULTS: The measured μ a and μ s of a cast facial phantom are accurate when comparing the ITQ, INQ, STQ, and FH to its flat posterior surface. Paired t tests of ITQ, INQ, STQ, and FH μ a and μ s concluded that there is not enough evidence to suggest that imaging orientation impacted the measurement accuracy. Regions of extreme topographical variation, i.e., CEM and RLNB, did exhibit differences in measured optical properties. CONCLUSIONS: We are the first to evaluate the geometric implications of wide-field imaging along the periocular region using a solid tissue-simulating facial phantom. Results suggest that the ITQ, INQ, STQ, and FH of a generalized face have minimal impact on the SFDI measurement accuracy. Areas with heightened topographic variation exhibit measurement variability. Device and facial positioning do not appear to bias measurements. These findings confirm the need to carefully select ROIs when measuring optical properties along the periocular region.

While the primary sequences of human proteins have been cataloged for over a decade, determining how these are organized into a dynamic collection of multiprotein assemblies, with structures and functions spanning biological scales, is an ongoing venture. Systematic and data-driven analyses of these higher-order structures are emerging, facilitating the discovery and understanding of cellular phenotypes. At present, knowledge of protein localization and function has been primarily derived from manual annotation and curation in resources such as the Gene Ontology, which are biased toward richly annotated genes in the literature. Here, we envision a future powered by data-driven mapping of protein assemblies. These maps can capture and decode cellular functions through the integration of protein expression, localization, and interaction data across length scales and timescales. In this review, we focus on progress toward constructing integrated cell maps that accelerate the life sciences and translational research.

Cerebellar injury in preterm infants with central nervous system (CNS) hemorrhage results in lasting neurological deficits and an increased risk of autism. The impact of blood-induced pathways on cerebellar development remains largely unknown, so no specific treatments have been developed to counteract the harmful effects of blood after neurovascular damage in preterm infants. Here, we show that fibrinogen, a blood-clotting protein, plays a central role in impairing neonatal cerebellar development. Longitudinal MRI of preterm infants revealed that cerebellar bleeds were the most critical factor associated with poor cerebellar growth. Using inflammatory and hemorrhagic mouse models of neonatal cerebellar injury, we found that fibrinogen increased innate immune activation and impeded neurogenesis in the developing cerebellum. Fibrinogen inhibited sonic hedgehog (SHH) signaling, the main mitogenic pathway in cerebellar granule neuron progenitors (CGNPs), and was sufficient to disrupt cerebellar growth. Genetic fibrinogen depletion attenuated neuroinflammation, promoted CGNP proliferation, and preserved normal cerebellar development after neurovascular damage. Our findings suggest that fibrinogen alters the balance of SHH signaling in the neurovascular niche and may serve as a therapeutic target to mitigate developmental brain injury after CNS hemorrhage.

Cytomegalovirus (CMV) reactivation is a major complication among seropositive allogeneic hematopoietic cell transplantation recipients; however, data on CMV reactivation after chimeric antigen receptor (CAR) T-cell therapy are limited. We report the incidence and outcomes of 95 adult CMV-seropositive patients who received CAR T-cell therapy between February 2018 and February 2023. CMV outcomes were CMV reactivation (any viremia) and clinically significant CMV infection (cs-CMV). Thirty-one patients (33%) had evidence of CMV reactivation (any viremia), and 10 patients (11%) had cs-CMV. The median time from CAR T-cell infusion to CMV reactivation was 19 days (interquartile range [IQR], 9-31). The cumulative incidence of CMV (any viremia) was significantly higher among patients with grade 3 to 4 cytokine release syndrome (67 vs 28%; P = .01), and those who received corticosteroids (39 vs 21%; P = .03), anakinra (56 vs 28%; P = .02), or ≥2 immunosuppressants (41 vs 21%; P = .02). Receipt of corticosteroids (18 vs 0%; P = .004), tocilizumab (14 vs 0%; P = .04), anakinra (33 vs 7%; P = .008), and ≥2 immunosuppressants (20 vs 0%; P = .001) were all associated with cs-CMV. Receiving ≥2 immunosuppressants was associated with a twofold increase in CMV reactivation in multivariate analyses (adjusted odds ratio [aOR], 2.27; 95% confidence interval, 1.1-4.8; P = .03). Overall, the 1-year mortality was significantly higher in those with CMV reactivation (57% vs 23%; P = .001). Immunosuppression, particularly with corticosteroids, for the management of CAR T-cell toxicities, is a major risk factor for CMV reactivation.

The ODYSSEY OUTCOMES trial, comprising over 47 000 patient-years of placebo-controlled observation, demonstrated important reductions in the risk of recurrent ischaemic cardiovascular events with the monoclonal antibody to proprotein convertase subtilisin/kexin type 9 alirocumab, as well as lower all-cause death. These benefits were observed in the context of substantial and persistent lowering of low-density lipoprotein cholesterol with alirocumab compared with that achieved with placebo. The safety profile of alirocumab was indistinguishable from matching placebo except for a ∼1.7% absolute increase in local injection site reactions. Further, the safety of alirocumab compared with placebo was evident in vulnerable groups identified before randomization, such as the elderly and those with diabetes mellitus, previous ischaemic stroke, or chronic kidney disease. The frequency of adverse events and laboratory-based abnormalities was generally similar to that in placebo-treated patients. Thus, alirocumab appears to be a safe and effective lipid-modifying treatment over a duration of at least 5 years.

ObjectivePatients with relapsed or metastatic head and neck squamous cell carcinoma (HNSCC) after primary local therapy have low response rates with cetuximab, systemic chemotherapy or check point inhibitor therapy. Novel combination therapies with the potential to improve outcomes for patients with HNSCC is an area of high unmet need.MethodsThis is a phase II single-arm clinical trial of locally advanced or metastatic HNSCC patients treated with a combination of soluble EphB4-human serum albumin (sEphB4-HSA) fusion protein and pembrolizumab after platinum-based chemotherapy with up to 2 prior lines of treatment. The primary endpoints were safety and tolerability and the primary efficacy endpoint was overall response rate (ORR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). HPV status and EphrinB2 expression were evaluated for outcome.ResultsTwenty-five patients were enrolled. Median follow up was 40.4 months (range 9.8 - 40.4). There were 6 responders (ORR 24%). There were 5 responders in the 11 HPV-negative and EphrinB2 positive patients, (ORR 45%) with 2 of these patients achieving a complete response (CR). The median PFS in HPV-negative/EphrinB2 positive patients was 3.2 months (95% CI 1.1, 7.3). Median OS in HPV-negative/EphrinB2 positive patients was 10.9 months (95% CI 2.0, 13.7). Hypertension, transaminitis and fatigue were the most common toxicities.DiscussionThe combination of sEphB4-HSA and pembrolizumab has a favorable toxicity profile and favorable activity particularly among HPV-negative EphrinB2 positive patients with HNSCC.

To address the rapid evolution of artificial intelligence in medical imaging, the authors present the Checklist for Artificial Intelligence in Medical Imaging (CLAIM) 2024 Update.

Cardiorespiratory fitness and mitochondrial oxidative capacity are associated with reduced walking speed in older adults, but their impact on walking speed in older adults with diabetes has not been clearly defined. We examined differences in cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity between older adults with and without diabetes, as well as determined their relative contribution to slower walking speed in older adults with diabetes. Participants with diabetes (n = 159) had lower cardiorespiratory fitness and mitochondrial respiration in permeabilized fiber bundles compared with those without diabetes (n = 717), following adjustments for covariates including BMI, chronic comorbid health conditions, and physical activity. Four-meter and 400-m walking speeds were slower in those with diabetes. Mitochondrial oxidative capacity alone or combined with cardiorespiratory fitness mediated ∼20-70% of the difference in walking speed between older adults with and without diabetes. Additional adjustments for BMI and comorbidities further explained the group differences in walking speed. Cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity contribute to slower walking speeds in older adults with diabetes.

BackgroundIn contrast to prior research, our study presents longitudinal comparisons of the EQ-5D-5L and Patient-Reported Outcomes Measurement Information System (PROMIS) preference (PROPr) scores. This fills a gap in the literature, providing a much-needed understanding of these preference-based measures and their applications in healthcare research. Furthermore, our study provides equations to estimate one measure from the other, a tool that can significantly facilitate comparisons across studies.MethodsWe administered a health survey to 4,098 KnowledgePanel® members living in the United States. A subset of 1,256 (82% response rate) with back pain also completed the six-month follow-up survey. We then conducted thorough cross-sectional and longitudinal analyses of the two measures, including product-moment correlations between scores, associations with demographic variables, and health conditions. To estimate one measure from the other, we used ordinary least squares (OLS) regression with the baseline data from the general population.ResultsThe correlation between the EQ-5D-5L and PROPr scores was 0.69, but the intraclass correlation was only 0.34 because the PROPr had lower (less positive) mean scores on the 0 (dead) to 1 (perfect health) continuum than the EQ-5D-5L. The associations between the two preference measures and demographic variables were similar at baseline. The product-moment correlation between unstandardized beta coefficients for each preference measure regressed on 22 health conditions was 0.86, reflecting similar patterns of unique associations. Correlations of change from baseline to 6 months in the two measures with retrospective perceptions of change were similar. Adjusted variance explained in OLS regressions predicting one measure from the other was 48%. On average, the predicted values were within a half-standard deviation of the observed EQ-5D-5L and PROPr scores. The beta-binomial regression model slightly improved over the OLS model in predicting the EQ-5D-5L from the PROPr but was equivalent to the OLS model in predicting the PROPr.ConclusionDespite substantial mean differences, the EQ-5D-5L and PROPr have similar cross-sectional and longitudinal associations with other variables. We provide the OLS regression equations for use in cost-effectiveness research and meta-analyses. Future studies are needed to compare these measures with different conditions and interventions to provide more information on their relative validity.

ObjectiveDespite an increase in twin pregnancies in recent decades, the Institute of Medicine twin weight gain recommendations remain provisional and provide no guidance for the pattern or timing of weight change. We sought to characterize gestational weight change trajectory patterns and examine associations with birth outcomes in a cohort of twin pregnancies.Study designPrenatal and delivery records were examined for 320 twin pregnancies from a maternal-fetal medicine practice in Austin, TX 2011-2019. Prenatal weights for those with >1 measured weight in the first trimester and ≥3 prenatal weights were included in analyses. Trajectories were estimated to 32 weeks (mean delivery: 33.7 ± 3.3 weeks) using flexible latent class mixed models with low-rank thin-plate splines. Associations between trajectory classes and infant outcomes were analyzed using multivariable Poisson or linear regression.ResultsWeight change from prepregnancy to delivery was 15.4 ± 6.3 kg for people with an underweight body mass index, 15.4 ± 5.8 kg for healthy weight, 14.7 ± 6.9 kg for overweight, and 12.5 ± 6.4 kg for obesity. Three trajectory classes were identified: low (Class 1), moderate (Class 2), or high gain (Class 3). Class 1 (24.7%) maintained weight for 15 weeks and then gained an estimated 6.6 kg at 32 weeks. Class 2 (60.9%) exhibited steady gain with 13.5 kg predicted total gain, and Class 3 (14.4%) showed rapid gain across pregnancy with 21.3 kg predicted gain. Compared to Class 1, Class 3 was associated with higher birth weight z-score (β = 0.63, 95% confidence interval [CI]: 0.31,0.96), increased risk for large for gestational age (IRR = 5.60, 95% CI: 1.59, 19.67), and birth

IntroductionCoronary artery calcium (CAC) scans contain useful information beyond the Agatston CAC score that is not currently reported. We recently reported that artificial intelligence (AI)-enabled cardiac chambers volumetry in CAC scans (AI-CAC™) predicted incident atrial fibrillation in the Multi-Ethnic Study of Atherosclerosis (MESA). In this study, we investigated the performance of AI-CAC cardiac chambers for prediction of incident heart failure (HF).MethodsWe applied AI-CAC to 5750 CAC scans of asymptomatic individuals (52% female, White 40%, Black 26%, Hispanic 22% Chinese 12%) free of known cardiovascular disease at the MESA baseline examination (2000-2002). We used the 15-year outcomes data and compared the time-dependent area under the curve (AUC) of AI-CAC volumetry versus NT-proBNP, Agatston score, and 9 known clinical risk factors (age, gender, diabetes, current smoking, hypertension medication, systolic and diastolic blood pressure, LDL, HDL for predicting incident HF over 15 years.ResultsOver 15 years of follow-up, 256 HF events accrued. The time-dependent AUC [95% CI] at 15 years for predicting HF with AI-CAC all chambers volumetry (0.86 [0.82,0.91]) was significantly higher than NT-proBNP (0.74 [0.69, 0.77]) and Agatston score (0.71 [0.68, 0.78]) (p ​

Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.

INTRODUCTION: While it is well recognised that aging is a heterogeneous process, our understanding of the determinants of biological aging and its heterogeneity remains unclear. The San Diego Nathan Shock Center (SD-NSC) Clinical Cohort aims to establish a resource of biospecimens and extensive donor clinical data such as physical, cognitive and sensory function to support other studies that aim to explore the heterogeneity of normal human aging and its biological underpinnings. METHODS AND ANALYSIS: The SD-NSC Clinical Cohort is composed of 80 individuals across the adult human lifespan. Strict inclusion and exclusion criteria are implemented to minimise extrinsic factors that may impede the study of normal aging. Across three visits, participants undergo extensive phenotyping for collection of physical performance, body composition, cognitive function, sensory ability, mental health and haematological data. During these visits, we also collected biospecimens including plasma, platelets, peripheral blood mononuclear cells and fibroblasts for banking and future studies on aging. ETHICS AND DISSEMINATION: Ethics approval from the UC San Diego School of Medicine Institutional Review Board (IRB #201 141 SHOCK Center Clinical Cohort, PI: Molina) was obtained on 11 November 2020. Written informed consent is obtained from all participants after objectives and procedures of the study have been fully explained. Congruent with the goal of establishing a core resource, biological samples and clinical data are made available to the research community through the SD-NSC.

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value

PURPOSE: Rasmussen encephalitis (RE) is a very rare chronic neurological disorder of unilateral inflammation of the cerebral cortex. Hemispherotomy provides the best chance at achieving seizure freedom in RE patients, but with significant risks and variable long-term outcomes. The goal of this study is to utilize our multicenter pediatric cohort to characterize if differences in pathology and/or imaging characterization of RE may provide a window into post-operative seizure outcomes, which in turn could guide decision-making for parents and healthcare providers. METHODS: This multi-institutional retrospective review of medical record, imaging, and pathology samples was approved by each individual institutions review board. Data was collected from all known pediatric cases of peri-insular functional hemispherotomy from the earliest available electronic medical records. Mean follow-up time was 4.9 years. Clinical outcomes were measured by last follow-up visit using both Engel and ILAE scoring systems. Relationships between categorical and continuous variables were analyzed with Pearson correlation values. RESULTS: Twenty-seven patients met study criteria. No statistically significant correlations existed between patient imaging and pathology data. Pathology stage, MRI brain imaging stages, and a combined assessment of pathology and imaging stages showed no statistically significant correlation to post-operative seizure freedom rates. Hemispherectomy Outcome Prediction Scale scoring demonstrated seizure freedom in only 71% of patients receiving a score of 1 and 36% of patients receiving a score of 2 which were substantially lower than predicted. CONCLUSIONS: Our analysis did not find evidence for either independent or combined analysis of imaging and pathology staging being predictive for post peri-insular hemispherotomy seizure outcomes, prompting the need for other biomarkers to be explored. Our data stands in contrast to the recently proposed Hemispherectomy Outcome Prediction Scale and does not externally validate this metric for an RE cohort.

Increasing evidence suggests that urbanization is associated with higher mutation rates, which can affect the health and evolution of organisms that inhabit cities. Elevated pollution levels in urban areas can induce DNA damage, leading to de novo mutations. Studies on mutations induced by urban pollution are most prevalent in humans and microorganisms, whereas studies of non-human eukaryotes are rare, even though increased mutation rates have the potential to affect organisms and their populations in contemporary time. Our Perspective explores how higher mutation rates in urban environments could impact the fitness, ecology and evolution of populations. Most mutations will be neutral or deleterious, and higher mutation rates associated with elevated pollution in urban populations can increase the risk of cancer in humans and potentially other species. We highlight the potential for urban-driven increased deleterious mutational loads in some organisms, which could lead to a decline in population growth of a wide diversity of organisms. Although beneficial mutations are expected to be rare, we argue that higher mutation rates in urban areas could influence adaptive evolution, especially in organisms with short generation times. Finally, we explore avenues for future research to better understand the effects of urban-induced mutations on the fitness, ecology and evolution of city-dwelling organisms.

Inherited peripheral neuropathies (IPNs) are a group of diseases associated with mutations in various genes with fundamental roles in the development and function of peripheral nerves. Over the past 10 years, significant advances in identifying molecular disease mechanisms underlying axonal and myelin degeneration, acquired from cellular biology studies and transgenic fly and rodent models, have facilitated the development of promising treatment strategies. However, no clinical treatment has emerged to date. This lack of treatment highlights the urgent need for more biologically and clinically relevant models recapitulating IPNs. For both neurodevelopmental and neurodegenerative diseases, patient-specific induced pluripotent stem cells (iPSCs) are a particularly powerful platform for disease modeling and preclinical studies. In this review, we provide an update on different in vitro human cellular IPN models, including traditional two-dimensional monoculture iPSC derivatives, and recent advances in more complex human iPSC-based systems using microfluidic chips, organoids, and assembloids.

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviours and although strides have been made using genome-wide association studies to identify risk variants, most variants identified have been for nicotine consumption, rather than TUD. Here we leveraged four US biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records) in 653,790 individuals (495,005 European, 114,420 African American and 44,365 Latin American) and data from UK Biobank (ncombined = 898,680). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviours in children and hundreds of medical outcomes, including HIV infection, heart disease and pain. This work furthers our biological understanding of TUD and establishes electronic health records as a source of phenotypic information for studying the genetics of TUD.

Loneliness is a pervasive experience with adverse impacts on health and well-being. Despite its significance, notable gaps impede a full understanding of how loneliness changes across the adult life span and what factors influence these changes. To address this, we conducted a coordinated data analysis of nine longitudinal studies encompassing 128,118 participants ages 13 to 103 from over 20 countries. Using harmonized variables and models, we examined loneliness trajectories and predictors. Analyses revealed that loneliness follows a U-shaped curve, decreasing from young adulthood to midlife and increasing in older adulthood. These patterns were consistent across studies. Several baseline factors (i.e., sex, marital status, physical function, education) were linked to loneliness levels, but few moderated the loneliness trajectories. These findings highlight the dynamic nature of loneliness and underscore the need for targeted interventions to reduce social disparities throughout adulthood.

BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood. METHODS: We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses. RESULTS: Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögrens-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients. CONCLUSIONS: Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

We present the Manatee variational autoencoder model to predict transcription factor (TF) perturbation-induced transcriptomes. We demonstrate that the Manatee in silico perturbation analysis recapitulates target transcriptomic phenotypes in diverse cellular lineage transitions. We further propose the Manatee in silico screening analysis for prioritizing TF combinations targeting desired transcriptomic phenotypes.

Increased left atrial volume and decreased left atrial function have long been associated with atrial fibrillation. The availability of large-scale cardiac magnetic resonance imaging data paired with genetic data provides a unique opportunity to assess the genetic contributions to left atrial structure and function, and understand their relationship with risk for atrial fibrillation. Here, we use deep learning and surface reconstruction models to measure left atrial minimum volume, maximum volume, stroke volume, and emptying fraction in 40,558 UK Biobank participants. In a genome-wide association study of 35,049 participants without pre-existing cardiovascular disease, we identify 20 common genetic loci associated with left atrial structure and function. We find that polygenic contributions to increased left atrial volume are associated with atrial fibrillation and its downstream consequences, including stroke. Through Mendelian randomization, we find evidence supporting a causal role for left atrial enlargement and dysfunction on atrial fibrillation risk.

BackgroundInfection prevention (IP) measures are designed to mitigate the transmission of pathogens in healthcare. Using large-scale viral genomic and social network analyses, we determined if IP measures used during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic were adequate in protecting healthcare workers (HCWs) and patients from acquiring SARS-CoV-2.MethodsWe performed retrospective cross-sectional analyses of viral genomics from all available SARS-CoV-2 viral samples collected at UC San Diego Health and social network analysis using the electronic medical record to derive temporospatial overlap of infections among related viromes and supplemented with contact tracing data. The outcome measure was any instance of healthcare transmission, defined as cases with closely related viral genomes and epidemiological connection within the healthcare setting during the infection window. Between November 2020 through January 2022, 12 933 viral genomes were obtained from 35 666 patients and HCWs.ResultsAmong 5112 SARS-CoV-2 viral samples sequenced from the second and third waves of SARS-CoV-2 (pre-Omicron), 291 pairs were derived from persons with a plausible healthcare overlap. Of these, 34 pairs (12%) were phylogenetically linked: 19 attributable to household and 14 to healthcare transmission. During the Omicron wave, 2106 contact pairs among 7821 sequences resulted in 120 (6%) related pairs among 32 clusters, of which 10 were consistent with healthcare transmission. Transmission was more likely to occur in shared spaces in the older hospital compared with the newer hospital (2.54 vs 0.63 transmission events per 1000 admissions, P < .001).ConclusionsIP strategies were effective at identifying and preventing healthcare SARS-CoV-2 transmission.

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

BackgroundPediatric renal trauma is rare and lacks sufficient population-specific data to generate evidence-based management guidelines. A nonoperative approach is preferred and has been shown to be safe. However, bleeding risk assessment and management of collecting system injury are not well understood. We introduce the Multi-institutional Pediatric Acute Renal Trauma Study (Mi-PARTS), a retrospective cohort study designed to address these questions. This article describes the demographics and contemporary management of pediatric renal trauma at Level I trauma centers in the United States.MethodsRetrospective data were collected at 13 participating Level I trauma centers on pediatric patients presenting with renal trauma between 2010 and 2019. Data were gathered on demographics, injury characteristics, management, and short-term outcomes. Descriptive statistics were used to report on demographics, acute management, and outcomes.ResultsIn total, 1,216 cases were included in this study. Of all patients, 67.2% were male, and 93.8% had a blunt injury mechanism. In addition, 29.3% had isolated renal injuries, and 65.6% were high-grade (American Association for the Surgery of Trauma Grades III-V) injuries. The mean Injury Severity Score was 20.5. Most patients were managed nonoperatively (86.4%), and 3.9% had an open surgical intervention, including 2.7% having nephrectomy. Angioembolization was performed in 0.9%. Collecting system intervention was performed in 7.9%. Overall mortality was 3.3% and was only observed in patients with multiple injuries. The rate of avoidable transfer was 28.2%.ConclusionThe management and outcomes of pediatric renal trauma lack data to inform evidence-based guidelines. Nonoperative management of bleeding following renal injury is a well-established practice. Intervention for renal trauma is rare. Our findings reinforce differences from the adult population and highlights opportunities for further investigation. With data made available through Mi-PARTS, we aimed to answer pediatric specific questions, including a pediatric-specific bleeding risk nomogram, and better understanding indications for interventions for collecting system injuries.Level of evidencePrognostic and Epidemiological; Level IV.

The etiology of preeclampsia (PE), a severe complication of pregnancy with several clinical manifestations and a high incidence of maternal and fetal morbidity and mortality, remains unclear. This issue is a major hurdle for effective treatment strategies. We recently demonstrated that PE exhibits an Alzheimer-like etiology of impaired autophagy and proteinopathy in the placenta. Targeting of these pathological pathways may be a novel therapeutic strategy for PE. Stimulation of autophagy with the natural disaccharide trehalose and its lacto analog lactotrehalose in hypoxia-exposed primary human trophoblasts restored autophagy, inhibited the accumulation of toxic protein aggregates, and restored the ultrastructural features of autophagosomes and autolysosomes. Importantly, trehalose and lactotrehalose inhibited the onset of PE-like features in a humanized mouse model by normalizing autophagy and inhibiting protein aggregation in the placenta. These disaccharides restored the autophagy-lysosomal biogenesis machinery by increasing nuclear translocation of the master transcriptional regulator TFEB. RNA-seq analysis of the placentas of mice with PE indicated the normalization of the PE-associated transcriptome profile in response to trehalose and lactotrehalose. In summary, our results provide a novel molecular rationale for impaired autophagy and proteinopathy in patients with PE and identify treatment with trehalose and its lacto analog as promising therapeutic options for this severe pregnancy complication.

The key challenge in cancer treatment is prevention of metastatic disease which is therapeutically resistant and carries poor prognoses necessitating efficacious prophylactic approaches that prevent metastasis and recurrence. It is previously demonstrated that cowpea mosaic virus (CPMV) induces durable antitumor responses when used in situ, i.e., intratumoral injection. As a new direction, it is showed that CPMV demonstrates widespread effectiveness as an immunoprophylactic agent - potent efficacy is demonstrated in four metastatic models of colon, ovarian, melanoma, and breast cancer. Systemic administration of CPMV stimulates the innate immune system, enabling attack of cancer cells; processing of the cancer cells and associated antigens leads to systemic, durable, and adaptive antitumor immunity. Overall, CPMV demonstrated broad efficacy as an immunoprophylactic agent in the rejection of metastatic cancer.

COVID-19 pandemic-related traumatic stress (PRTS) symptoms are reported in various populations, but risk factors in older adults with chronic medical conditions, remain understudied. We therefore examined correlates and pre-pandemic predictors of PRTS in older adults with hypertension during COVID-19. Participants in California, aged 61-92 years (n = 95), participated in a pre-pandemic healthy aging trial and later completed a COVID-19 assessment (May to September 2020). Those experiencing ⩾1 PRTS symptom (n = 40), and those without PRTS symptoms (n = 55), were compared. The PRTS+ group had poorer mental and general health and greater impairment in instrumental activities of daily living. Pre-pandemic biomarkers of vascular inflammation did not predict increased odds of PRTS; however, greater pre-pandemic anxiety and female gender did predict PRTS during COVID-19. Our findings highlight PRTS as a threat to healthy aging in older adults with hypertension; targeted approaches are needed to mitigate this burden, particularly for females and those with pre-existing anxiety.