Decoding the transcriptomic signatures of psychological trauma in human cortex and amygdala.

Psychological trauma has profound effects on brain function and precipitates psychiatric disorders in vulnerable individuals, however, the molecular mechanisms linking trauma with psychiatric risk remain incompletely understood. Using RNA-seq data postmortem brain tissue of a cohort of 304 donors (N=136 with trauma exposure), we investigated transcriptional signatures of trauma exposures in two cortical regions (dorsolateral prefrontal cortex, and dorsal anterior cingulate cortex) and two amygdala regions (medial amygdala and basolateral amygdala) associated with stress processing and regulation. We focused on dissecting heterogeneity of traumatic experiences in these transcriptional signatures by investigating exposure to several trauma types (childhood, adulthood, complex, single acute, combat, and interpersonal traumas) and interactions with sex. Overall, amygdala regions were more vulnerable to childhood traumas, whereas cortical regions were more vulnerable to adulthood trauma (regardless of childhood experience). Using cell-type-specific expression imputation, we identified a strong transcriptional response of medial amygdala excitatory neurons to childhood trauma, which coincided with dysregulation observed in a human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons exposed to hydrocortisone. We resolved multiscale coexpression networks for each brain region and identified modules enriched in trauma signatures and whose connectivity was altered with trauma. Trauma-associated coexpression modules provide insight into coordinated functional dysregulation with different traumas and point to potential gene targets for further dissection. Together, these data provide a characterization of the long-lasting human encoding of traumatic experiences in corticolimbic regions of human brain.

Truncated cones from indenting a clamped disk.

When a simply supported thin disk is indented by a centrally applied point force, it buckles out-of-plane to form a shape dominated by two conical portions: a uniform region indenting against the support, interrupted by a smaller elevated portion detached from the support, altogether known as a "developable cone" or d-Cone. If a central circular region of the disk is clamped instead, then the buckling complexion changes markedly: The indenting region is interspersed with several detached and elevated cones, now "truncated," where their number depends on the clamping extent as well as the radius of the circular simple support. Studies of d-Cone kinematics often consider its shape as an analogous vertex, which forms by folding along hinge lines separating triangular facets. We extend this methodology by, first, showing that each truncated cone, or "t-Cone," operates as a pair of connected d-Cone vertices that fold synchronously and that their number, viz. distribution, around the indented disk stems from optimal "packaging" of the folded shape in the annular space between the clamping edge and support; furthermore, because our analysis presumes a geometrically dominant character, it captures the "saturated," i.e., final number of t-Cones, in experiments from a recent study. Our predictions agree rather well.

Tough Monolayer Silver Nanowire-Reinforced Double-Layer Graphene.

Mixed-dimensional nanomaterials composed of one-dimensional (1D) and two-dimensional (2D) nanomaterials, such as graphene-silver nanowire (AgNW) composite sandwiched structures, are promising candidates as building blocks for multifunctional structures and materials. However, their mechanical behavior and failure mechanism have not yet been fully understood. In this work, we have performed integrated experimental, theoretical, and numerical studies to explore the performance and failure modes of graphene-AgNW composite under tensile and impact loading conditions. In situ tensile tests using a nanoindenter, implemented with a push-to-pull device and a laser-induced projectile impact test system, are used to shed light on load-bearing mechanisms in graphene-AgNW composites. Multiple failure modes have been observed in both experimental setups and analyzed with numerical and theoretical models. Results show that in the tensile loading the distribution of AgNW, as characterized by the effective free length, is the key parameter determining the failure mode. As for the impact failure scenarios, compared with failure modes observed in pure graphene cases, the mechanical reinforcing effect of AgNW will transform the failure mode from a scattered tensile fracture along radial directions to a shear failure that is constrained in a relatively local domain. Theoretical analysis using shear lag modeling, Timoshenko plate theory, molecular dynamics modeling, and finite element modeling approaches are adopted to further establish the failure modes.

Electrodeposition of Polymer Networks as Conformal and Uniform Ultrathin Coatings.

Natural systems, synthetic materials, and devices almost always feature interphases that control the flow of mass and energy or stabilize interfaces between incompatible materials. With technologies transitioning to non-planar and 3D mesoscale architectures, novel deposition methods for realizing ultrathin coatings and interphases are required. Polymer networks are of particular interest for their tunable chemical and physical properties combined with their structural integrity. Here, the electrodeposition of polymer networks (EPoN) is introduced as a general approach to uniformly coat non-planar conductive materials. Conceptually, EPoN utilizes electrochemically activated crosslinkers as polymer end groups to confine their network formation exclusively to the material surface upon charge transfer, yielding a passivating and self-limiting growth of conformal and uniform coatings with tunable submicron thickness on conductive materials. EPoN is found to result in thin functional films of various polymer backbones and side group chemistries as demonstrated for poly(ether) and poly(acrylamide) based polymers as solid electrolyte and thermally responsive interphases, respectively.

Parenting stress and child behavior problems: Developmental psychopathology perspectives.

The growing base of research on parenting stress and its relation to child behavior problems has largely paralleled the emergence of developmental psychopathology as a field of inquiry. Specifically, the focus on mechanism rather than main effects has begun to elevate explanatory models in the connection between parenting stress and a variety of adverse child and parent conditions. Still, work on parenting stress is limited by conceptual confusion, the absence of attention to developmental differentiation, a focus on child-specific rather than system influences. Recent research on these parenting stress issues is briefly reviewed, highlighting studies that have illustrated developmental psychopathology perspectives. A conceptual model is offered to illustrate the complex recursive nature of connections between parenting stress, parenting behavior, parent well-being, and children's adjustment, and I make a case for the adoption of a more systemic perspective to influence the next generation of developmental psychopathology research on parenting stress.

Sex-specific post-inflammatory dysbiosis mediates chronic visceral pain in colitis.

BACKGROUND: Despite achieving endoscopic remission, over 20% of inflammatory bowel disease (IBD) patients experience chronic abdominal pain. Visceral pain and the microbiome exhibit sex-dependent interactions, while visceral pain in IBD shows a sex bias. Our aim was to evaluate whether post-inflammatory microbial perturbations contribute to visceral hypersensitivity in a sex-dependent manner. METHODS: Males, cycling females, ovariectomized, and sham-operated females were given dextran sodium sulfate to induce colitis and allowed to recover. Germ-free recipients received sex-appropriate and cross-sex fecal microbial transplants (FMT) from post-inflammatory donor mice. Visceral sensitivity was assessed by recording visceromotor responses to colorectal distention. The composition of the microbiota was evaluated via 16S rRNA gene V4 amplicon sequencing, while the metabolome was assessed using targeted (short chain fatty acids - SCFA) and semi-targeted mass spectrometry. RESULTS: Post-inflammatory cycling females developed visceral hyperalgesia when compared to males. This effect was reversed by ovariectomy. Both post-inflammatory males and females exhibited increased SCFA-producing species, but only males had elevated fecal SCFA content. FMT from post-inflammatory females transferred visceral hyperalgesia to both males and females, while FMT from post-inflammatory males could only transfer visceral hyperalgesia to males. CONCLUSIONS: Female sex, hormonal status as well as the gut microbiota play a role in pain modulation. Our data highlight the importance of considering biological sex in the evaluation of visceral pain.

Discovering genotype-phenotype relationships with machine learning and the Visual Physiology Opsin Database (VPOD).

BACKGROUND: Predicting phenotypes from genetic variation is foundational for fields as diverse as bioengineering and global change biology, highlighting the importance of efficient methods to predict gene functions. Linking genetic changes to phenotypic changes has been a goal of decades of experimental work, especially for some model gene families, including light-sensitive opsin proteins. Opsins can be expressed in vitro to measure light absorption parameters, including λmax-the wavelength of maximum absorbance-which strongly affects organismal phenotypes like color vision. Despite extensive research on opsins, the data remain dispersed, uncompiled, and often challenging to access, thereby precluding systematic and comprehensive analyses of the intricate relationships between genotype and phenotype. RESULTS: Here, we report a newly compiled database of all heterologously expressed opsin genes with λmax phenotypes that we call the Visual Physiology Opsin Database (VPOD). VPOD_1.0 contains 864 unique opsin genotypes and corresponding λmax phenotypes collected across all animals from 73 separate publications. We use VPOD data and deepBreaks to show regression-based machine learning (ML) models often reliably predict λmax, account for nonadditive effects of mutations on function, and identify functionally critical amino acid sites. CONCLUSION: The ability to reliably predict functions from gene sequences alone using ML will allow robust exploration of molecular-evolutionary patterns governing phenotype, will inform functional and evolutionary connections to an organism's ecological niche, and may be used more broadly for de novo protein design. Together, our database, phenotype predictions, and model comparisons lay the groundwork for future research applicable to families of genes with quantifiable and comparable phenotypes.

Intrapulmonary pharmacokinetics of SPR719 following oral administration of SPR720 to healthy volunteers.

SPR720 is a phosphate ester prodrug that is converted rapidly in vivo to SPR719, the active moiety, which exhibits potent in vitro activity against clinically relevant mycobacterial species including Mycobacterium avium complex (MAC) and Mycobacterium abscessus. SPR720 is in clinical development for the treatment of nontuberculous mycobacterial pulmonary disease (NTM-PD) due to MAC. This study evaluated the safety and the intrapulmonary pharmacokinetics of SPR719 in healthy volunteers. A total of 30 subjects received oral SPR720 1,000 mg once daily for 7 days followed by bronchoscopy and bronchoalveolar lavage, with blood samples collected for plasma pharmacokinetic assessments. Mean SPR719 area under the concentration-time curve from time 0 to 24 hours (AUC0-24) and maximum concentration (Cmax) for plasma, epithelial lining fluid (ELF), and alveolar macrophages (AM) were 52,418 ng·h/mL and 4,315 ng/mL, 59,880 ng·h/mL and 5,429 ng/mL, and 128,105 ng·h/mL and 13,033 ng/mL, respectively. The ratios of ELF to total plasma concentrations of SPR719 based on AUC0-24 and Cmax were 1.14 and 1.26, and the ratios of AM to total plasma concentrations of SPR719 based on AUC0-24 and Cmax were 2.44 and 3.02, respectively. When corrected for protein binding, the ratios of ELF to unbound plasma concentrations of SPR719 for AUC0-24 and Cmax were 19.87 and 21.88, and the ratios of AM to unbound plasma concentrations of SPR719 for AUC0-24 and Cmax were 42.50 and 52.53, respectively. No unexpected safety findings were observed. Results from this study of the intrapulmonary disposition of SPR719 support further investigation of SPR720 as a potential oral agent for the treatment of patients with NTM-PD.This study is registered with Clinicaltrials.gov as NCT05955586.

Investigating the feasibility of 18F-flortaucipir PET imaging in the antemortem diagnosis of primary age-related tauopathy (PART): An observational imaging-pathological study.

INTRODUCTION: Primary age-related tauopathy (PART) is characterized by neurofibrillary tangles and minimal ß-amyloid deposition, diagnosed postmortem. This study investigates 18F-flortaucipir (FTP) PET imaging for antemortem PART diagnosis. METHODS: We analyzed FTP PET scans from 50 autopsy-confirmed PART and 13 control subjects. Temporal lobe uptake was assessed both qualitatively and quantitatively. Demographic and clinicopathological characteristics and voxel-level uptake using SPM12 were compared between FTP-positive and FTP-negative cases. Intra-reader reproducibility was evaluated with Krippendorff's alpha. RESULTS: Minimal/mild and moderate FTP uptake was seen in 32% of PART cases and 62% of controls, primarily in the left inferior temporal lobe. No demographic or clinicopathological differences were found between FTP-positive and FTP-negative cases. High intra-reader reproducibility (α = 0.83) was noted. DISCUSSION: FTP PET imaging did not show a specific uptake pattern for PART diagnosis, indicating that in vivo PART identification using FTP PET is challenging. Similar uptake in controls suggests non-specific uptake in PART. HIGHLIGHTS: 18F-flortaucipir (FTP) PET scans were analyzed for diagnosing PART antemortem. 32% of PART cases had minimal/mild FTP uptake in the left inferior temporal lobe. Similar to PART FTP uptake was found in 62% of control subjects. No specific uptake pattern was found, challenging in vivo PART diagnosis.

Artistic gymnastics-specific extension of the IOC 2020 consensus statement: methods for recording and reporting of epidemiological data on injury and illness in sport.

The incidence of injuries reported in artistic gymnastics varies greatly. This is partly due to inconsistencies in defining and reporting injuries in artistic gymnastics. The objective was to develop consistent definitions and methodology for reporting injuries in artistic gymnastics. A group of medical practitioners working with international-level artistic gymnasts from America, Asia, Australia and Europe came to a consensus on recommendations for defining and reporting injuries in artistic gymnastics. Development of the consensus statement was achieved through in-person and online discussions, online surveys and post meeting electronic discussions. This consensus statement is meant to serve as an extension to the recommendations made by the IOC on injury surveillance. The statement includes specific recommendations of injury definitions, characterising activity at the time of injury, and describing injury burden in artistic gymnastics. The following consensus statement has been developed to encourage consistency of injury surveillance in artistic gymnastics. Reporting injury in a consistent manner will help understand the true burden of injury in artistic gymnastics and help guide future work in injury prevention.

Latent change-on-change between amyloid accumulation and cognitive decline.

INTRODUCTION: While the influence of cross-sectional ß-amyloid (Aß) on longitudinal changes in cognition is well established, longitudinal change-on-change between Aß and cognition is less explored. METHODS: A series of bivariate latent change score models (LCSM) examined the relationship between changes in 11C-Pittsburgh Compound-B (PiB) positron emission tomography (PET) and the Preclinical Alzheimer's Cognitive Composite-5 (PACC-5) while adjusting for covariates, including cross-sectional medial temporal lobe (MTL) tau-PET burden. We selected 352 clinically normal older participants with up to 9 years of PiB-PET and PACC-5 data from the Harvard Aging Brain Study (HABS). RESULTS: Aß accumulation was associated with subsequent cognitive decline beyond the effects of cross-sectional Aß burden. Within this model including covariates such as age, sex, and apolipoprotein ε4 (APOEε4) status, we found no evidence supporting previously published associations between cross-sectional tau-PET and cognitive intercept/slope. DISCUSSION: Short-term Aß changes are significantly associated with cognitive decline in clinically normal older adults and may eclipse the effect of cross-sectional Aß and MTL tau. HIGHLIGHTS: Aß accumulation is associated with subsequent cognitive decline. High Aß burden is not the sole metric signaling impending cognitive decline. Contrary to prior work, MTL tau-PET and cognition were not associated in our models. Models of bivariate latent Aß and cognitive change may eclipse the effects of MTL tau.

Society of Surgical Oncology Consensus Statement: Assessing the Evidence for and Utility of Gene Expression Profiling of Primary Cutaneous Melanoma.

INTRODUCTION: Gene expression profiling (GEP) of primary cutaneous melanoma aims to offer prognostic and predictive information to guide clinical care. Despite limited evidence of clinical utility, these tests are increasingly incorporated into clinical care. METHODS: A panel of melanoma experts from the Society of Surgical Oncology convened to develop recommendations regarding the use of GEP to guide management of patients with melanoma. The use of currently available GEP tests were evaluated in three clinical scenarios: (1) the utility in patient selection for sentinel lymph node biopsy; (2) the utility to guide surveillance; and (3) the utility to inform adjuvant therapy. As a basis for these recommendations, the panel performed a systematic review of the literature, including articles published from January 2012 until August 2023. RESULTS: After review of 137 articles, 50 met the inclusion criteria. These articles included evidence related to three available GEP tests: 31-GEP, CP-GEP, and 11-GEP. The consensus recommendations were finalized using a modified Delphi process. The panel found that current evidence often fails to account for known clinicopathologic risk factors and lacks high-level data. The panel recognizes that the study of GEP tests is still evolving. The integration of GEP into routine clinical practice for predicting sentinel lymph node status and patient prognosis in melanoma is therefore not currently recommended. CONCLUSION: At present, GEP should be considered primarily an investigational tool, ideally used in the context of clinical trials or specialized research settings.

Retrospective Exploration of Botulinum Toxin Injection for Pharyngoesophageal Segment Dysfunction Post-laryngectomy.

Objective: To assess our institution's experience with botulinum toxin A injection management of pharyngoesophageal (PE) segment dysfunction after laryngectomy in tracheoesophageal voice and swallowing restoration. Study Design: A retrospective review of 43 patients who had Botox as treatment for PE dysfunction. Setting: Tertiary academic center with fellowship-trained otolaryngologists. Methods: Pre- and post-injection outcomes were evaluated using chart review, and the severity of symptoms was recorded based on the subjective assessment by the patient, speech language pathologists, and the treating surgeon. Results: Forty-three patients were treated for PE dysfunction with botulinum toxin A injection. Most patients were male (n = 35, 81.4%), underwent primary cricopharnygeal myotomy (n = 36, 83.7%), and 37 (86%) had both dysphagia and speech concerns. Our injection methods included percutaneous injection by videofluoroscopy (n = 19, 44.2%), transnasal esophagoscopy (17, 40.5%), electromyography (n = 3, 7%), ultrasound (n = 1, 2.3%), or in the operating room (n = 3,7%). We found that 37 (86%) patients had subjective improvement in their symptoms, with 16 (38.1%) improving in both swallow and voice. There were no significant complications, or subjective difference in speech and swallowing outcomes by method of injection. Conclusion: Botulinum toxin A injection appears to be safe and effective for treating difficulty with speech and swallowing due to PE dysfunction after laryngectomy. Institutions should develop standard protocols for treatment and assessment.

Player and match characteristics associated with head acceleration events in elite-level men's and women's rugby union matches.

Objective: To examine the likelihood of head acceleration events (HAEs) as a function of previously identified risk factors: match time, player status (starter or substitute) and pitch location in elite-level men's and women's rugby union matches. Methods: Instrumented mouthguard data were collected from 179 and 107 players in the men's and women's games and synchronised to video-coded match footage. Head peak resultant linear acceleration (PLA) and peak resultant angular acceleration were extracted from each HAE. Field location was determined for HAEs linked to a tackle, carry or ruck. HAE incidence was calculated per player hour across PLA recording thresholds with 95% CIs estimated. Propensity was calculated as the percentage of contact events that caused HAEs across PLA recording thresholds, with a 95% CI estimated. Significance was assessed by non-overlapping 95% CIs. Results: 29 099 and 6277 HAEs were collected from 1214 and 577 player-matches in the men's and women's games. No significant differences in match quarter HAE incidence or propensity were found. Substitutes had higher HAE incidence than starters at lower PLA recording thresholds for men but similar HAE propensity. HAEs were more likely to occur in field locations with high contact event occurrence. Conclusion: Strategies to reduce HAE incidence need not consider match time or status as a substitute or starter as HAE rates are similar throughout matches, without differences in propensity between starters and substitutes. HAE incidence is proportional to contact frequency, and strategies that reduce either frequency or propensity for contact to cause head contact may be explored.

Twenty year analysis of professional men's rugby union knee injuries from the English premiership shows high rates and burden.

OBJECTIVES: To determine the rates, severity and burden of knee injuries in professional male rugby union from the English Premiership. METHODS: Injury and exposure data were captured over 20 seasons using a prospective cohort design. Knee injury incidence, days' absence and burden were recorded for each injury type and by pitch surface type for match and training. RESULTS: The rate of knee injury in matches was 9.8/1000 hours (95% CIs 9.3-10.3). Mean days lost were 50 (95% CI 46 to 53) in matches and 51 (95% CI 44 to 57) in training. In matches, medial collateral ligament injuries were the most common, while anterior cruciate ligament (ACL) injuries had the highest mean severity and burden. There was no significant change in the count of knee injuries over time; however, average severity increased significantly (annual change: 2.18 days (95% CI 1.60 to 2.77); p<0.001). The incidence of match knee injury was 44% higher on artificial pitches than grass pitches (incidence rate ratio: 1.44 (95% CI 1.21 to 1.69); p<0.01), with no significant difference in severity between surfaces. In matches, the tackle was the event most commonly associated with knee injuries for all diagnoses, except ACL injuries (running). In training, running was a more common injury event than the tackle. CONCLUSION: Knee injuries in matches are common and severe in English professional men's rugby union. Despite an increased focus on player conditioning and injury prevention throughout the study period, rates of knee injury remained stable, and resulting days' absence increased. New strategies for the prevention of knee injuries should be considered a priority.

Microscopy assessment of a fluorescence [18F] flortaucipir analog (T726) shows neuropathological overlap with 3R and 4R tau lesions.

BACKGROUND: [18F] flortaucipir (FTP) binding to paired helical filament (PHF) tau in Alzheimer's disease (AD) is well accepted. Binding to 3R and 4R tau in frontotemporal lobar degeneration (FTLD) is controversial. We aimed to investigate whether an FTP fluorescent analog (T726) can help shed light on this controversy. METHOD: We assessed T726 binding to amyloid beta (Aß) and different tau isoforms in nine subjects (one control, three with Alzheimer's disease [AD], and five with FTLD) with different 3R and 4R tauopathies using fluorescence confocal microscopy. RESULTS: T726 did not colocalize with Aß but showed significant co-localization with PHF tau in AD. We also observed some, albeit limited, co-localization of T726 with 3R and 4R tau lesions in FTLD. DISCUSSION: This study's findings support FTP binding to some 3R and 4R tau lesions in FTLD. Further studies are needed to understand the biology of why FTP binds some but not all FTLD tau lesions. HIGHLIGHTS: Flortaucipir analog (T726) showed significant co-localization with paired helical filament (PHF) tau in Alzheimer's disease (AD). Colocalization between T726 with 3R and 4R tau lesions was observed in frontotemporal lobar degeneration (FTLD). Not all 4R tau lesions bind to T726 across different FTLD brain regions.

What value do teaching hospitals provide commercial beneficiaries when in an ACO?

OBJECTIVES: The number of commercial beneficiaries cared for by accountable care organizations (ACOs) is growing, but the literature examining their trends is nascent. STUDY DESIGN: We examined commercial claims data from 2019 to 2021 to compare beneficiaries attributed to participants in Medicare Shared Savings Program ACOs with and without a major teaching hospital. METHODS: We calculated mortality and spending by setting for each ACO type by year. RESULTS: Compared with per-beneficiary rates at nonteaching ACOs, major teaching ACOs have lower mortality rates by up to 2.2 percentage points depending on the patient age group, $283 lower inpatient spending, and lower emergency department utilization in inpatient (-0.008) and outpatient (-0.013) settings, as well as $146 higher overall outpatient spending. Upward trends in mortality and beneficiary risk scores across both ACO types show disruption to health outcomes during COVID-19. CONCLUSIONS: These results provide evidence that ACOs with major teaching hospitals may be more likely to achieve the value-based goals of ACOs. Means to accomplish those goals may include avoiding higher-intensity care and supporting access to lower-cost alternatives where clinically appropriate, such as reducing inpatient and emergency department stays by delivering timely, high-quality outpatient care.

Reduced Stroke Volume and Brain Perfusion Drive Postural Hyperventilation in Postural Orthostatic Tachycardia Syndrome.

Postural hyperventilation has been implicated as a cause of postural orthostatic tachycardia syndrome (POTS), yet the precise mechanisms underlying the heightened breathing response remain unclear. This study challenges current hypotheses by revealing that exaggerated peripheral chemoreceptor activity is not the primary driver of postural hyperventilation. Instead, significant contributions from reduced stroke volume and compromised brain perfusion during orthostatic stress were identified. These findings shed light on our understanding of POTS pathophysiology, emphasizing the critical roles of systemic hemodynamic status. Further research should explore interventions targeting stroke volume and brain perfusion for more effective clinical management of POTS.

Foams with 3D Spatially Programmed Mechanics Enabled by Autonomous Active Learning on Viscous Thread Printing.

Foams are versatile by nature and ubiquitous in a wide range of applications, including padding, insulation, and acoustic dampening. Previous work established that foams 3D printed via Viscous Thread Printing (VTP) can in principle combine the flexibility of 3D printing with the mechanical properties of conventional foams. However, the generality of prior work is limited due to the lack of predictable process-property relationships. In this work, a self-driving lab is utilized that combines automated experimentation with machine learning to identify a processing subspace in which dimensionally consistent materials are produced using VTP with spatially programmable mechanical properties. In carrying out this process, an underlying self-stabilizing characteristic of VTP layer thickness is discovered as an important feature for its extension to new materials and systems. Several complex exemplars are constructed to illustrate the newly enabled capabilities of foams produced via VTP, including 1D gradient rectangular slabs, 2D localized stiffness zones on an insole orthotic and living hinges, and programmed 3D deformation via a cable-driven humanoid hand. Predictive mapping models are developed and validated for both thermoplastic polyurethane (TPU) and polylactic acid (PLA) filaments, suggesting the ability to train a model for any material suitable for material extrusion (ME) 3D printing.