Single-base tiled screen unveils design principles of PspCas13b for potent and off-target-free RNA silencing.

The development of precise RNA-editing tools is essential for the advancement of RNA therapeutics. CRISPR (clustered regularly interspaced short palindromic repeats) PspCas13b is a programmable RNA nuclease predicted to offer superior specificity because of its 30-nucleotide spacer sequence. However, its design principles and its on-target, off-target and collateral activities remain poorly characterized. Here, we present single-base tiled screening and computational analyses that identify key design principles for potent and highly selective RNA recognition and cleavage in human cells. We show that the de novo design of spacers containing guanosine bases at precise positions can greatly enhance the catalytic activity of inefficient CRISPR RNAs (crRNAs). These validated design principles (integrated into an online tool, https://cas13target.azurewebsites.net/ ) can predict highly effective crRNAs with ~90% accuracy. Furthermore, the comprehensive spacer-target mutagenesis revealed that PspCas13b can tolerate only up to four mismatches and requires ~26-nucleotide base pairing with the target to activate its nuclease domains, highlighting its superior specificity compared to other RNA or DNA interference tools. On the basis of this targeting resolution, we predict an extremely low probability of PspCas13b having off-target effects on other cellular transcripts. Proteomic analysis validated this prediction and showed that, unlike other Cas13 orthologs, PspCas13b exhibits potent on-target activity and lacks collateral effects.

Trends in the administration of COVID-19 vaccines with other vaccines in the United States reported to V-safe during December 14, 2020-May 19, 2023.

Introduction COVID-19 vaccines may be administered with other vaccines during the same healthcare visit. COVID-19 monovalent (Fall 2021) and bivalent (Fall 2022) vaccine recommendations coincided with annual seasonal influenza vaccination. Data describing the frequency of the co-administration of COVID-19 vaccines with other vaccines are limited. Methods We used V-safe, a voluntary smartphone-based U.S. safety surveillance system established by the CDC, to describe trends in the administration of COVID-19 vaccines with other vaccines reported to V-safe during December 14, 2020 - May 19, 2023. Results Of the 21 million COVID-19 vaccinations reported to V-safe, 2.2% (459,817) were administered with at least 1 other vaccine. Co-administration most frequently occurred during the first week of October 2023 (27,092; 44.1%). Most reports of co-administration included influenza vaccine (393,003; 85.5%). Co-administration was most frequently reported for registrants aged 6 months-6 years (4,872; 4.4%). Conclusion Reports of co-administration to V-safe peaked during October 2023, when influenza vaccination most often occurs, possibly reflecting increased opportunities for multiple vaccinations and greater acceptability of the co-administration of COVID-19 vaccine with other vaccines, especially influenza vaccine.

A predominately pulmonary activation of complement in a mouse model of severe COVID-19.

Evidence from in vitro studies and observational human disease data suggest the complement system plays a significant role in SARS-CoV-2 pathogenesis, although how complement dysregulation develops in patients with severe COVID-19 is unknown. Here, using a mouse-adapted SARS-CoV-2 virus (SARS2-N501YMA30) and a mouse model of severe COVID-19, we identify significant serologic and pulmonary complement activation following infection. We observed C3 activation in airway and alveolar epithelia, and in pulmonary vascular endothelia. Our evidence suggests that while the alternative pathway is the primary route of complement activation, components of both the alternative and classical pathways are produced locally by respiratory epithelial cells following infection, and increased in primary cultures of human airway epithelia in response to cytokine exposure. This locally generated complement response appears to precede and subsequently drive lung injury and inflammation. Results from this mouse model recapitulate findings in humans, which suggest sex-specific variance in complement activation, with predilection for increased C3 activity in males, a finding that may correlate with more severe disease. Our findings indicate that complement activation is a defining feature of severe COVID-19 in mice and lay the foundation for further investigation into the role of complement in COVID-19.

snRNA-seq of human cutaneous neurofibromas before and after selumetinib treatment implicates role of altered Schwann cell states, inter-cellular signaling, and extracellular matrix in treatment response.

Neurofibromatosis Type 1 (NF1) is caused by loss of function variants in the NF1 gene. Most patients with NF1 develop skin lesions called cutaneous neurofibromas (cNFs). Currently the only approved therapeutic for NF1 is selumetinib, a mitogen -activated protein kinase (MEK) inhibitor. The purpose of this study was to analyze the transcriptome of cNF tumors before and on selumetinib treatment to understand both tumor composition and response. We obtained biopsy sets of tumors both pre- and on- selumetinib treatment from the same individuals and were able to collect sets from four separate individuals. We sequenced mRNA from 5844 nuclei and identified 30,442 genes in the untreated group and sequenced 5701 nuclei and identified 30,127 genes in the selumetinib treated group. We identified and quantified distinct populations of cells (Schwann cells, fibroblasts, pericytes, myeloid cells, melanocytes, keratinocytes, and two populations of endothelial cells). While we anticipated that cell proportions might change with treatment, we did not identify any one cell population that changed significantly, likely due to an inherent level of variability between tumors. We also evaluated differential gene expression based on drug treatment in each cell type. Ingenuity pathway analysis (IPA) was also used to identify pathways that differ on treatment. As anticipated, we identified a significant decrease in ERK/MAPK signaling in cells including Schwann cells but most specifically in myeloid cells. Interestingly, there is a significant decrease in opioid signaling in myeloid and endothelial cells; this downward trend is also observed in Schwann cells and fibroblasts. Cell communication was assessed by RNA velocity, Scriabin, and CellChat analyses which indicated that Schwann cells and fibroblasts have dramatically altered cell states defined by specific gene expression signatures following treatment (RNA velocity). There are dramatic changes in receptor-ligand pairs following treatment (Scriabin), and robust intercellular signaling between virtually all cell types associated with extracellular matrix (ECM) pathways (Collagen, Laminin, Fibronectin, and Nectin) is downregulated after treatment. These response specific gene signatures and interaction pathways could provide clues for understanding treatment outcomes or inform future therapies.

Variability in zoobenthic blue carbon storage across a southern polar gradient.

The seabed of the Antarctic continental shelf hosts most of Antarctica's known species, including taxa considered indicative of vulnerable marine ecosystems (VMEs). Nonetheless, the potential impact of climatic and environmental change, including marine icescape transition, on Antarctic shelf zoobenthos, and their blue carbon-associated function, is still poorly characterised. To help narrow knowledge gaps, four continental shelf study areas, spanning a southern polar gradient, were investigated for zoobenthic (principally epi-faunal) carbon storage (a component of blue carbon), and potential environmental influences, employing a functional group approach. Zoobenthic carbon storage was highest at the two southernmost study areas (with a mean estimate of 41.6 versus 7.2 g C m-2) and, at each study area, increased with morphotaxa richness, overall faunal density, and VME indicator density. Functional group mean carbon content varied with study area, as did each group's percentage contribution to carbon storage and faunal density. Of the environmental variables explored, sea-ice cover and primary production, both likely to be strongly impacted by climate change, featured in variable subsets most highly correlating with assemblage and carbon storage (by functional groups) structures. The study findings can underpin biodiversity- and climate-considerate marine spatial planning and conservation measures in the Southern Ocean.

Variation in Androgen Deprivation Therapy Use Among Men With Intermediate-Risk Prostate Cancer: Results From a Statewide Radiation Oncology Quality Consortium.

PURPOSE: For men with intermediate-risk prostate cancer treated with definitive therapy, the addition of androgen deprivation therapy (ADT) reduces the risk of distant metastasis and cancer-related mortality. However, the absolute benefit of ADT varies by baseline cancer risk. Estimates of prognosis have improved over time, and little is known about ADT decision making in the modern era. We sought to characterize variability and identify factors associated with intended ADT use within the Michigan Radiation Oncology Quality Consoritum (MROQC). MATERIALS AND METHODS: Patients with localized prostate cancer undergoing definitive radiation therapy were enrolled from June 9, 2020, to June 26, 2023 (n = 815). Prospective data were collected using standardized patient, physician, and physicist forms. Intended ADT use was prospectively defined and was the primary outcome. Associations with patient, tumor, and practice-related factors were tested with multivariable analyses. Random intercept modeling was used to estimate facility-level variability. RESULTS: Five hundred seventy patients across 26 facilities were enrolled with intermediate-risk disease. ADT was intended for 46% of men (n = 262/570), which differed by National Comprehensive Cancer Network favorable intermediate-risk (23.5%, n = 38/172) versus unfavorable intermediate-risk disease (56.3%, n = 224/398; P < .001). After adjusting for the statewide case mix, the predicted probability of intended ADT use varied significantly across facilities, ranging from 15.4% (95% CI, 5.4%-37.0%) to 71.7% (95% CI, 57.0%-82.9%), with P < .01. Multivariable analyses showed that grade group 3 (OR, 4.60 [3.20-6.67]), ≥50% positive cores (OR, 2.15 [1.43-3.25]), and prostate-specific antigen 10 to 20 (OR, 1.87 [1.24-2.84]) were associated with ADT use. Area under the curve was improved when incorporating MRI adverse features (0.76) or radiation treatment variables (0.76), but there remained significant facility-level heterogeneity in all models evaluated (P < .05). CONCLUSIONS: Within a state-wide consortium, there is substantial facility-level heterogeneity in intended ADT use for men with intermediate-risk prostate cancer. Future efforts are necessary to identify patients who will benefit most from ADT and to develop strategies to standardize appropriate use.

Human intestinal stromal cells promote homeostasis in normal mucosa but inflammation in Crohn's disease in a retinoic acid-deficient manner.

Intestinal stromal cells (SCs), which synthesize the extracellular matrix that gives the mucosa its structure, are newly appreciated to play a role in mucosal inflammation. Here we show that human intestinal vimentin+CD90+SMA- SCs synthesize retinoic acid (RA) at levels equivalent to intestinal epithelial cells, a function in the human intestine previously attributed exclusively to epithelial cells. Crohn's disease SCs (Crohn's SCs), however, synthesized markedly less RA than SCs from healthy intestine (Normal SCs). We also show that microbe-stimulated Crohn's SCs, which are more inflammatory than stimulated Normal SCs, induced less RA-regulated differentiation of mucosal DCS (circulating pre-DCs and monocyte-derived DCs), leading to the generation of more potent inflammatory IFN-γhi/IL-17hi T cells than Normal SCs. Explaining these results, Crohn's SCs expressed more DHRS3, a retinaldehyde reductase that inhibits retinol conversion to retinal, and thus synthesized less RA than Normal SCs. These findings uncover a microbe-SC-DC crosstalk in which luminal microbes induce Crohn's disease SCs to initiate and perpetuate inflammation through impaired synthesis of RA.

3D-Printing Multi-Component Multi-Domain Supramolecular Gels with Differential Conductivity.

We report the use of wet-spinning to 3D-print gels from low-molecular-weight gelators (LMWGs) based on the 1,3:2,4-dibenzylidenesorbitol (DBS) scaffold. Gel stripes assembled from DBS-CONHNH2 and DBS-COOH are printed, and their conductivities assessed. Printed gels based on DBS-CONHNH2 can be loaded with Au(III), which is reduced in situ to form embedded gold nanoparticles (AuNPs). The conductivity of these gels increases because of electron transport mediated by the AuNPs, whereas the conductivity of DBS-COOH, which does not promote AuNP formation, remains lower. We then fabricate multi-component gel patterns comprised of spatially well-defined domains of printed DBS-CONHNH2/AuNP (higher conductivity) and DBS-COOH (lower conductivity) resulting in soft multi-domain materials with differential conductivity. Such materials have future prospects in applications such as soft nanoelectronics or tissue engineering.

Improving IVF Utilization with Patient-Centric Artificial Intelligence-Machine Learning (AI/ML): A Retrospective Multicenter Experience.

Objectives: In vitro fertilization (IVF) has the potential to give babies to millions more people globally, yet it continues to be underutilized. We established a globally applicable and locally adaptable IVF prognostics report and framework to support patient-provider counseling and enable validated, data-driven treatment decisions. This study investigates the IVF utilization rates associated with the usage of machine learning, center-specific (MLCS) prognostic reports (the Univfy® report) in provider-patient pre-treatment and IVF counseling. Methods: We used a retrospective cohort comprising 24,238 patients with new patient visits (NPV) from 2016 to 2022 across seven fertility centers in 17 locations in seven US states and Ontario, Canada. We tested the association of Univfy report usage and first intra-uterine insemination (IUI) and/or first IVF usage (a.k.a. conversion) within 180 days, 360 days, and "Ever" of NPV as primary outcomes. Results: Univfy report usage was associated with higher direct IVF conversion (without prior IUI), with odds ratios (OR) 3.13 (95% CI 2.83, 3.46), 2.89 (95% CI 2.63, 3.17), and 2.04 (95% CI 1.90, 2.20) and total IVF conversion (with or without prior IUI), OR 3.41 (95% CI 3.09, 3.75), 3.81 (95% CI 3.49, 4.16), and 2.78 (95% CI 2.59, 2.98) in 180-day, 360-day, and Ever analyses, respectively; p < 0.05. Among patients with Univfy report usage, after accounting for center as a factor, older age was a small yet independent predictor of IVF conversion. Conclusions: Usage of a patient-centric, MLCS-based prognostics report was associated with increased IVF conversion among new fertility patients. Further research to study factors influencing treatment decision making and real-world optimization of patient-centric workflows utilizing the MLCS reports is warranted.

Single-Line LiDAR Localization via Contribution Sampling and Map Update Technology.

Localization based on single-line lidar is widely used in various robotics applications, such as warehousing, service, transit, and construction, due to its high accuracy, cost-effectiveness, and minimal computational requirements. However, challenges such as LiDAR degeneration and frequent map changes persist in hindering its broader adoption. To address these challenges, we introduce the Contribution Sampling and Map-Updating Localization (CSMUL) algorithm, which incorporates weighted contribution sampling and dynamic map-updating methods for robustness enhancement. The weighted contribution sampling method assigns weights to each map point based on the constraints within degenerate environments, significantly improving localization robustness under such conditions. Concurrently, the algorithm detects and updates anomalies in the map in real time, addressing issues related to localization drift and failure when the map changes. The experimental results from real-world deployments demonstrate that our CSMUL algorithm achieves enhanced robustness and superior accuracy in both degenerate scenarios and dynamic map conditions. Additionally, it facilitates real-time map adjustments and ensures continuous positioning, catering to the needs of dynamic environments.

Postexposure prophylaxis for occupational exposure to selected pathogens for healthcare personnel.

PURPOSE OF REVIEW: Timely postexposure prophylaxis is important after an occupational exposure. Here we review select organisms, exposure opportunities in the healthcare setting, and postexposure prophylaxis regimens. RECENT FINDINGS: Needlestick injuries pose a risk of exposure to bloodborne pathogens, such as HIV, Hepatitis B, and Hepatitis C. Risk mitigation strategies should be reexamined in light of newer vaccines and therapeutics. Increased vaccine hesitancy and vaccine denialisms may foster the re-emergence of some infections that have become extremely uncommon because of effective vaccines. With increasing occurrences of zoonotic infections and the ease of global spread as evidenced by COVID-19 and mpox, healthcare exposures must also consider risks related to emerging and re-emerging infectious diseases. SUMMARY: Early recognition and reporting of occupational exposures to pathogens with available postexposure prophylaxis is key to mitigating the risk of transmission. Providers should be able to evaluate the exposure and associated risks to provide prompt and appropriate postexposure prophylaxis.

Long-term duration and safety of Radiesse (+) for the treatment of jawline.

BACKGROUND: Calcium hydroxyapatite (CaHA)-carboxymethylcellulose (CMC)+ has unique properties that make it optimal for lifting, contouring, and defining the jawline. This long-term follow-up of a randomized, multicenter, rater-blinded trial reports efficacy and safety of CaHA-CMC(+) through 48 and up to 60 weeks post-treatment. METHODS: Eligible patients were randomized (2:1) to the treatment or the control/delayed treatment group to receive CaHA-CMC(+) injections in both jawlines. While touch-ups were permitted 4 weeks post-treatment for both groups, only the treatment group was eligible for optional retreatment after 48 weeks. The primary outcome was ≥1-point improvement on both jawlines on the Merz Jawline Assessment Scale (MJAS); secondary endpoints included the Subject Global Aesthetic Improvement Scale (SGAIS) among others. Post hoc analysis included pooling up to 48-week data from the combined treatment and control/delayed groups and 60-week data for the treatment group. RESULTS: Overall, 175 received treatment. MJAS responder rates were 77.9%, 78.7%, and 62.9% at 12, 24, and 48 weeks post-treatment, respectively. Responder rate on the MJAS at 60 weeks was 74.6% for those who received retreatment and 43.5% for those patients who received only the initial and touchup treatments. SGAIS scores demonstrated 93.4%, 85.6%, and 68.5% of patients rated themselves very much improved after 12, 24, and 48 weeks, respectively. Adverse events consisted of procedure or CaHA-CMC(+)-related events that were mostly resolved and overwhelmingly mild. CONCLUSIONS: CaHA-CMC(+) produced clinically meaningful and long-lasting improvements in jawline contour and was well tolerated in patients through 60 weeks. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03583359.

Use of phosphotyrosine-containing peptides to target SH2 domains: Antagonist peptides of the Crk/CrkL-p130Cas axis.

Protein-protein interactions between SH2 domains and segments of proteins that include a post-translationally phosphorylated tyrosine residue (pY) underpin numerous signal transduction cascades that allow cells to respond to their environment. Dysregulation of the writing, erasing, and reading of these posttranslational modifications is a hallmark of human disease, notably cancer. Elucidating the precise role of the SH2 domain-containing adaptor proteins Crk and CrkL in tumor cell migration and invasion is challenging because there are no specific and potent antagonists available. Crk and CrkL SH2s interact with a region of the docking protein p130Cas containing 15 potential pY-containing tetrapeptide motifs. This chapter summarizes recent efforts toward peptide antagonists for this Crk/CrkL-p130Cas interaction. We describe our protocol for recombinant expression and purification of Crk and CrkL SH2s for functional assays and our procedure to determine the consensus binding motif from the p130Cas sequence. To develop a more potent antagonist, we employ methods often associated with structure-based drug design. Computational docking using Rosetta FlexPepDock, which accounts for peptides having a greater number of conformational degrees of freedom than small organic molecules that typically constitute libraries, provides quantitative docking metrics to prioritize candidate peptides for experimental testing. A battery of biophysical assays, including fluorescence polarization, differential scanning fluorimetry and saturation transfer difference nuclear magnetic resonance spectroscopy, were employed to assess the candidates. In parallel, GST pulldown competition assays characterized protein-protein binding in vitro. Taken together, our methodology yields peptide antagonists of the Crk/CrkL-p130Cas axis that will be used to validate targets, assess druggability, foster in vitro assay development, and potentially serve as lead compounds for therapeutic intervention.

The importance of public engagement in clinical xenotransplantation.

Over the past several decades, significant scientific progress in xenotransplantation has brought the field to the threshold of clinical trials. In the past 3 years in the United States, experimental pig kidney and heart xenotransplantation have been performed on human subjects recently declared dead by neurological criteria (decedents). In addition, two pig heart transplants have been carried out in living patients under the United States Food and Drug Administration's expanded access guidelines. However, though there has been a flurry of activity there remain unanswered questions regarding how the public views xenotransplantation, what concerns may exist, and how to address these concerns in a meaningful way. This paper aims to underscore the importance of public engagement in xenotransplantation, emphasizing the ongoing need for studies to assess public opinions. The current evidence on public engagement studies is reviewed and gaps in our understanding are identified. We propose practical steps to advance this field. Additional studies to determine the extent of racial/ethnic differences in attitudes to xenotransplantation should be conducted. Empirical and descriptive analysis of certain religious viewpoints-especially minority faiths-would be valuable. As public engagement is an important aspect of public acceptance of novel research that is accompanied by risk, we suggest that xenotransplantation biotechnology companies might consider leading the way in funding this research.

Routine MR Imaging Protocol and Standardization in Central Nervous System Demyelinating Diseases.

Standardized MR imaging protocols are important for the diagnosis and monitoring of patients with multiple sclerosis (MS) and the appropriate use of MR imaging in routine clinical practice. Advances in using MR imaging to establish an earlier diagnosis of MS, safety concerns regarding intravenous gadolinium-based contrast agents, and the value of spinal cord MR imaging for diagnostic, prognostic, and monitoring purposes suggest a changing role of MR imaging for the management and care of MS patients. The MR imaging protocol emphasizes 3 dimensional acquisitions for optimal comparison over time.

Malignant Melanoma: An Overview, New Perspectives, and Vitamin D Signaling.

Melanoma, originating through malignant transformation of melanin-producing melanocytes, is a formidable malignancy, characterized by local invasiveness, recurrence, early metastasis, resistance to therapy, and a high mortality rate. This review discusses etiologic and risk factors for melanoma, diagnostic and prognostic tools, including recent advances in molecular biology, omics, and bioinformatics, and provides an overview of its therapy. Since the incidence of melanoma is rising and mortality remains unacceptably high, we discuss its inherent properties, including melanogenesis, that make this disease resilient to treatment and propose to use AI to solve the above complex and multidimensional problems. We provide an overview on vitamin D and its anticancerogenic properties, and report recent advances in this field that can provide solutions for the prevention and/or therapy of melanoma. Experimental papers and clinicopathological studies on the role of vitamin D status and signaling pathways initiated by its active metabolites in melanoma prognosis and therapy are reviewed. We conclude that vitamin D signaling, defined by specific nuclear receptors and selective activation by specific vitamin D hydroxyderivatives, can provide a benefit for new or existing therapeutic approaches. We propose to target vitamin D signaling with the use of computational biology and AI tools to provide a solution to the melanoma problem.

Mutations in nonstructural proteins essential for pathogenicity in SARS-CoV-2-infected mice.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has resulted in substantial morbidity and mortality. The basis of severe disease in humans is difficult to determine without the use of experimental animal models. Mice are resistant to infection with ancestral strains of SARS-CoV-2, although many variants that arose later in the pandemic were able to directly infect mice. In almost all cases, viruses that naturally infected mice or were engineered to enable mouse infection required mouse passage to become virulent. In most cases, changes in structural and nonstructural changes occurred during mouse adaptation. However, the mechanism of increased virulence in mice is not understood. Here, using a recently described strain of mouse-adapted SARS-CoV-2 (rSARS2-MA30N501Y), we engineered a series of recombinant viruses that expressed a subset of the mutations present in rSARS2-MA30N501Y. Mutations were detected in the spike protein and in three nonstructural proteins (nsp4, nsp8, and nsp9). We found that infection of mice with recombinant SARS-CoV-2 expressing only the S protein mutations caused very mild infection. Addition of the mutations in nsp4 and nsp8 was required for complete virulence. Of note, all these recombinant viruses replicated equivalently in cultured cells. The innate immune response was delayed after infection with virulent compared to attenuated viruses. Further, using a lineage tracking system, we found that attenuated virus was highly inhibited in the ability to infect the parenchyma, but not the airway after infection. Together, these results indicate that mutations in both the S protein and nonstructural proteins are required for maximal virulence during mouse adaptation.IMPORTANCEUnderstanding the pathogenesis of coronavirus disease 2019 (COVID-19) requires the study of experimental animals after infection with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). For this purpose, several mouse-adapted SARS-CoV-2 strains have been developed. Here, using a strain of mouse-adapted virus that causes a range of diseases ranging from mild to severe, we show that mutations in both a structural protein [spike (S) protein] and nonstructural proteins are required for maximal virulence. Thus, changes in the S protein, the most widely studied viral protein, while required for mouse adaptation, are not sufficient to result in a virulent virus.

Assessing the Use of Radiographs Alone to Determine Air Force Dental Readiness Classification.

INTRODUCTION: The Air Force Dental Service is responsible for ensuring that airmen are dentally ready to support military operations worldwide by delivering top-tier dental care. As the military healthcare landscape undergoes significant changes, the Air Force Dental Service has explored innovative approaches to dental care delivery. One consideration involves the potential use of radiographs as the primary tool for assessing service members' dental conditions, specifically focusing on identifying nondeployable conditions and periodontal health. MATERIALS AND METHODS: Providers who previously participated as examiners in the 2018 Air Force Recruit Oral Health Study were recruited to re-evaluate randomly selected de-identified records, this time making assessments exclusively based on radiographs. Their evaluations included Dental Readiness Classification (DRC) determinations, total caries counts, and Periodontal Screening and Recording (PSR) index scores, providers also rated their confidence in these conclusions using a 5-point Likert scale. The study then computed sensitivity and specificity to assess the diagnostic performance of providers using radiographs only compared to the original study results that use the gold standard of radiographs with a clinical examination. RESULTS: Providers exceled at ruling out most DRC 3 conditions, with specificities surpassing 70%. Positively identifying those with DRC 3, particularly radiographically identifying periodontal conditions posed challenges with computed sensitivity rates as low as 8%. Discrepancies in PSR scores also accentuated limitations in relying solely on radiographs, where provider's radiographically determined PSR scores that matched less than one third of the time. In general, providers had low to very low confidence in their assessments. CONCLUSIONS: The study strongly cautions against relying solely on radiographs for determining the dental health of U.S. Air Force personnel. While providers effectively ruled out the absence of certain conditions, the challenge of positively identifying DRC 3 conditions poses significant risks to oral health if such a workflow was utilized. Particularly, the high probability of false negatives would be detrimental to the operational readiness of military personnel. Therefore, results support the continued use of radiographic and clinical examinations for comprehensive dental exams.

Accelerated Aging after Traumatic Brain Injury: An ENIGMA Multi-Cohort Mega-Analysis.

OBJECTIVE: The long-term consequences of traumatic brain injury (TBI) on brain structure remain uncertain. Given evidence that a single significant brain injury event increases the risk of dementia, brain-age estimation could provide a novel and efficient indexing of the long-term consequences of TBI. Brain-age procedures use predictive modeling to calculate brain-age scores for an individual using structural magnetic resonance imaging (MRI) data. Complicated mild, moderate, and severe TBI (cmsTBI) is associated with a higher predicted age difference (PAD), but the progression of PAD over time remains unclear. We sought to examine whether PAD increases as a function of time since injury (TSI) and if injury severity and sex interacted to influence this progression. METHODS: Through the ENIGMA Adult Moderate and Severe (AMS)-TBI working group, we examine the largest TBI sample to date (n = 343), along with controls, for a total sample size of n = 540, to replicate and extend prior findings in the study of TBI brain age. Cross-sectional T1w-MRI data were aggregated across 7 cohorts, and brain age was established using a similar brain age algorithm to prior work in TBI. RESULTS: Findings show that PAD widens with longer TSI, and there was evidence for differences between sexes in PAD, with men showing more advanced brain age. We did not find strong evidence supporting a link between PAD and cognitive performance. INTERPRETATION: This work provides evidence that changes in brain structure after cmsTBI are dynamic, with an initial period of change, followed by relative stability in brain morphometry, eventually leading to further changes in the decades after a single cmsTBI. ANN NEUROL 2024.

Absence of nonfatal suicidal behavior preceding suicide death reveals differences in clinical risks.

Nonfatal suicidality is the most robust predictor of suicide death. However, only ~10% of those who survive an attempt go on to die by suicide. Moreover, ~50% of suicide deaths occur in the absence of prior known attempts, suggesting risks other than nonfatal suicide attempt need to be identified. We studied data from 4,000 population-ascertained suicide deaths and 26,191 population controls to improve understanding of risks leading to suicide death. This study included 2,253 suicide deaths and 3,375 controls with evidence of nonfatal suicidality (SUI_SI/SB and CTL_SI/SB) from diagnostic codes and natural language processing of electronic health records notes. Characteristics of these groups were compared to 1,669 suicides with no prior nonfatal SI/SB (SUI_None) and 22,816 controls with no lifetime suicidality (CTL_None). The SUI_None and CTL_None groups had fewer diagnoses and were older than SUI_SI/SB and CTL_SI/SB. Mental health diagnoses were far less common in both the SUI_None and CTL_None groups; mental health problems were less associated with suicide death than with presence of SI/SB. Physical health diagnoses were conversely more often associated with risk of suicide death than with presence of SI/SB. Pending replication, results indicate highly significant clinical differences among suicide deaths with versus without prior nonfatal SI/SB.