Subjective cognitive concerns, APOE ε4, PTSD symptoms, and risk for dementia among older veterans.

BACKGROUND: Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with self-reported problems with cognition as well as risk for Alzheimer's disease and related dementias (ADRD). Overlapping symptom profiles observed in cognitive disorders, psychiatric disorders, and environmental exposures (e.g., head injury) can complicate the detection of early signs of ADRD. The interplay between PTSD, head injury, subjective (self-reported) cognitive concerns and genetic risk for ADRD is also not well understood, particularly in diverse ancestry groups. METHODS: Using data from the U.S. Department of Veterans Affairs (VA) Million Veteran Program (MVP), we examined the relationship between dementia risk factors (APOE ε4, PTSD, TBI) and subjective cognitive concerns (SCC) measured in individuals of European (n = 140,921), African (n = 15,788), and Hispanic (n = 8,064) ancestry (EA, AA, and HA, respectively). We then used data from the VA electronic medical record to perform a retrospective survival analysis evaluating PTSD, TBI, APOE ε4, and SCC and their associations with risk of conversion to ADRD in Veterans aged 65 and older. RESULTS: PTSD symptoms (B = 0.50-0.52, p < 1E-250) and probable TBI (B = 0.05-0.19, p = 1.51E-07 - 0.002) were positively associated with SCC across all three ancestry groups. APOE ε4 was associated with greater SCC in EA Veterans aged 65 and older (B = 0.037, p = 1.88E-12). Results of Cox models indicated that PTSD symptoms (hazard ratio [HR] = 1.13-1.21), APOE ε4 (HR = 1.73-2.05) and SCC (HR = 1.18-1.37) were positively associated with risk for ADRD across all three ancestry groups. In the EA group, probable TBI also contributed to increased risk of ADRD (HR = 1.18). CONCLUSIONS: The findings underscore the value of SCC as an indicator of ADRD risk in Veterans 65 and older when considered in conjunction with other influential genetic, clinical, and demographic risk factors.

Combined Tibial Deflexion Osteotomy and Anterior Cruciate Ligament Reconstruction Improves Knee Function and Stability: A Systematic Review.

IMPORTANCE: Patients with excessive posterior tibial slope (PTS) may have higher risks of anterior cruciate ligament (ACL) reconstruction (ACL-R) failure, and clinical outcomes after revision ACL-R procedures are typically poor. OBJECTIVE: To perform a systematic review of the literature summarizing the clinical and radiological outcomes of the surgical treatment of ACL insufficiency in the setting of excessive PTS using a tibial deflexion osteotomy combined with ACL-R. EVIDENCE REVIEW: A systematic review of the literature was performed using PubMed, Cochrane Library, and OVID Medline databases from 1990 to present. Inclusion criteria were: studies of outcomes of isolated tibial deflexion osteotomies performed with primary or revision ACL-R in the English language. Data extracted included study demographic information, type of tibial deflexion osteotomy and concomitant procedures, radiological outcomes, patient reported outcome scores, and postoperative complications FINDINGS: Six studies, with 133 knees were identified. All included studies were retrospective case series, with a weighted mean follow-up of 3.39 years. In 106 of 133 (79.7%) knees, tibial deflexion osteotomy was performed concomitantly with an ACL-R, whereas in 27 of 133 (20.3%) knees the procedures were staged. 22, 45, and 66 of 133 knees (16.5%, 33.8%, and 49.6%) underwent primary, 1st revision, and 2nd or greater revision ACL-R, respectively. 3 of 133 (2.25%) knees demonstrated recurrent ACL graft failure at final follow-up. On average, PTS decreased from 15.2 degrees preoperatively to 7.1 degrees postoperatively. Mean International Knee Documentation Committee (IKDC), Lysholm, and Tegner scores increased from 42.5, 46.4, and 4.2 preoperatively to 71.8, 89.0, and 6.7 postoperatively. CONCLUSIONS: The results of this review suggest that combined ACL-R and tibial deflexion osteotomy may be effective in decreasing PTS and improving knee function and stability. STUDY DESIGN: Systematic Review; Level of evidence 4.

Water, Soil, Noise, and Light Pollution: JACC Focus Seminar, Part 2.

Various forms of pollution carry a substantial burden with respect to increasing the risk of causing and exacerbating noncommunicable diseases, especially cardiovascular disease. The first part of this 2-part series on pollution and cardiovascular disease provided an overview of the impact of global warming and air pollution. This second paper provides an overview of the impact of water, soil, noise, and light pollution on the cardiovascular system. This review discusses the biological mechanisms underlying these effects and potential environmental biometrics of exposure. What is clear from both these pollution papers is that significant efforts and redoubled urgency are needed to reduce the sources of pollution in our environment, to incorporate environmental risk factors into medical education, to provide resources for research, and, ultimately, to protect those who are particularly vulnerable and susceptible.

Environmentally Not So Friendly: Global Warming, Air Pollution, and Wildfires: JACC Focus Seminar, Part 1.

Environmental stresses are increasingly recognized as significant risk factors for adverse health outcomes. In particular, various forms of pollution and climate change are playing a growing role in promoting noncommunicable diseases, especially cardiovascular disease. Given recent trends, global warming and air pollution are now associated with substantial cardiovascular morbidity and mortality. As a vicious cycle, global warming increases the occurrence, size, and severity of wildfires, which are significant sources of airborne particulate matter. Exposure to wildfire smoke is associated with cardiovascular disease, and these effects are underpinned by mechanisms that include oxidative stress, inflammation, impaired cardiac function, and proatherosclerotic effects in the circulation. In the first part of a 2-part series on pollution and cardiovascular disease, this review provides an overview of the impact of global warming and air pollution, and because of recent events and emerging trends specific attention is paid to air pollution caused by wildfires.

The effect of factors from different time points on psychological readiness following ACL reconstruction.

OBJECTIVE: The purpose of this study was to examine factors correlated with psychological readiness to return to activity after ACLR. DESIGN: cross sectional study. SETTING: controlled laboratory. PARTICIPANTS: 164 patients (82 M/82 F, 22.5 ± 8.9yr, 171.6 ± 11.0 cm, 77.4 ± 18.6 kg, 8.6 ± 3.4 months post-ACLR) participated in this study after a primary, isolated, and uncomplicated ACLR. MAIN OUTCOME MEASURES: ACL Return to Sport Index (ACL-RSI). RESULTS: ACL-RSI scores demonstrated a weak positive correlation with activity level at the time of injury and a fair positive correlation with activity level at the time of post-operative testing (p-values: 0.004, <0.001). ACL-RSI scores showed a statistically significant fair negative correlation with pain and a moderate negative correlation with kinesiophobia during rehabilitation (p-values: <0.001, <0.001). There was no statistical significance between ACL-RSI and the surgical variables (p-value range: 0.10-0.61). CONCLUSIONS: Outcomes from testing during postoperative rehabilitation were most correlated with psychological readiness to return to activity after ACLR. Increased pain and kinesiophobia were associated with a decreased psychological readiness. Increased activity level prior to injury and activity level at the time of testing during rehabilitation were both correlated with increased psychological readiness. Psychological readiness to return to activity may need to be customized based on potentially modifiable patient-specific factors during the post-operative rehabilitation.

Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood.

The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) included the central nucleus of the amygdala, hippocampal dentate gyrus, and medial prefrontal cortex (mPFC). Genes and exons within the mPFC carried most disease signals replicated across two independent cohorts. Pathways pointed to immune function, neuronal and synaptic regulation, and stress hormones. Multiomic factor and gene network analyses provided the underlying genomic structure. Single nucleus RNA sequencing in dorsolateral PFC revealed dysregulated (stress-related) signals in neuronal and non-neuronal cell types. Analyses of brain-blood intersections in >50,000 UK Biobank participants were conducted along with fine-mapping of the results of PTSD and MDD genome-wide association studies to distinguish risk from disease processes. Our data suggest shared and distinct molecular pathology in both disorders and propose potential therapeutic targets and biomarkers.

Intravital Two-Photon Microscopy of the Transplanted Mouse Lung.

Complications after lung transplantation are largely related to the host immune system responding to the graft. Such immune responses are regulated by crosstalk between donor and recipient cells. A better understanding of these processes relies on the use of preclinical animal models and is aided by an ability to study intra-graft immune cell trafficking in real-time. Intravital two-photon microscopy can be used to image tissues and organs for depths up to several hundred microns with minimal photodamage, which affords a great advantage over single-photon confocal microscopy. Selective use of transgenic mice with promoter-specific fluorescent protein expression and/or adoptive transfer of fluorescent dye-labeled cells during intravital two-photon microscopy allows for the dynamic study of single cells within their physiologic environment. Our group has developed a technique to stabilize mouse lungs, which has enabled us to image cellular dynamics in naïve lungs and orthotopically transplanted pulmonary grafts. This technique allows for detailed assessment of cellular behavior within the vasculature and in the interstitium, as well as for examination of interactions between various cell populations. This procedure can be readily learned and adapted to study immune mechanisms that regulate inflammatory and tolerogenic responses after lung transplantation. It can also be expanded to the study of other pathogenic pulmonary conditions.

More People, More Active, More Often for Heart Health - Taking Action on Physical Activity.

Physical inactivity is a leading contributor to increased cardiovascular morbidity and mortality. Almost 500 million new cases of preventable noncommunicable diseases (NCDs) will occur globally between 2020 and 2030 due to physical inactivity, costing just over US$300 billion, or around US$ 27 billion annually (WHO 2022). Active adults can achieve a reduction of up to 35% in risk of death from cardiovascular disease. Physical activity also helps in moderating cardiovascular disease risk factors such as high blood pressure, unhealthy weight and type 2 diabetes. For people with cardiovascular disease, hypertension, type 2 diabetes and many cancers, physical activity is an established and evidence-based part of treatment and management. For children and young people, physical activity affords important health benefits. Physical activity can also achieve important cross-sector goals. Increased walking and cycling can reduce journeys by vehicles, air pollution, and traffic congestion and contribute to increased safety and liveability in cities.

A Practical Approach to Using the Genomic Standards Consortium MIxS Reporting Standard for Comparative Genomics and Metagenomics.

Comparative analysis of (meta)genomes necessitates aggregation, integration, and synthesis of well-annotated data using standards. The Genomic Standards Consortium (GSC) collaborates with the research community to develop and maintain the Minimum Information about any (x) Sequence (MIxS) reporting standard for genomic data. To facilitate the use of the GSC's MIxS reporting standard, we provide a description of the structure and terminology, how to navigate ontologies for required terms in MIxS, and demonstrate practical usage through a soil metagenome example.

NCI Resources for Cancer Immunoprevention Research.

Cancer prevention and early detection, the first two of the eight primary goals of the National Cancer Plan released in April 2023, are at the forefront of the nation's strategic efforts to reduce cancer incidence and mortality. The Division of Cancer Prevention (DCP) of the NCI is the federal government's principal component devoted to promoting and supporting innovative cancer prevention research. Recent advances in tumor immunology, cancer immunotherapy, and vaccinology strongly suggest that the host immune system can be effectively harnessed to elicit protective immunity against the development of cancer, that is, cancer immunoprevention. Cancer immunoprevention may be most effective if the intervention is given before or early in the carcinogenic process while the immune system remains relatively uncompromised. DCP has increased the emphasis on immunoprevention research in recent years and continues to expand program resources and interagency collaborations designed to facilitate research in the immunoprevention field. These resources support a wide array of basic, translational, and clinical research activities, including discovery, development, and validation of biomarkers for cancer risk assessment and early detection (Early Detection Research Network), elucidation of biological and pathophysiological mechanistic determinants of precancer growth and its control (Translational and Basic Science Research in Early Lesions), spatiotemporal multiomics characterization of precancerous lesions (Human Tumor Atlas Network/Pre-Cancer Atlas), discovery of immunoprevention pathways and immune targets (Cancer Immunoprevention Network), and preclinical and clinical development of novel agents for immunoprevention and interception (Cancer Prevention-Interception Targeted Agent Discovery Program, PREVENT Cancer Preclinical Drug Development Program, and Cancer Prevention Clinical Trials Network).

An integrated metagenomic, metabolomic and transcriptomic survey of Populus across genotypes and environments.

Bridging molecular information to ecosystem-level processes would provide the capacity to understand system vulnerability and, potentially, a means for assessing ecosystem health. Here, we present an integrated dataset containing environmental and metagenomic information from plant-associated microbial communities, plant transcriptomics, plant and soil metabolomics, and soil chemistry and activity characterization measurements derived from the model tree species Populus trichocarpa. Soil, rhizosphere, root endosphere, and leaf samples were collected from 27 different P. trichocarpa genotypes grown in two different environments leading to an integrated dataset of 318 metagenomes, 98 plant transcriptomes, and 314 metabolomic profiles that are supported by diverse soil measurements. This expansive dataset will provide insights into causal linkages that relate genomic features and molecular level events to system-level properties and their environmental influences.

Feeling our place in the world: an active inference account of self-esteem.

Self-esteem, the evaluation of one's own worth or value, is a critical aspect of psychological well-being and mental health. In this paper, we propose an active inference account of self-esteem, casting it as a sociometer or an inferential capacity to interpret one's standing within a social group. This approach allows us to explore the interaction between an individual's self-perception and the expectations of their social environment.When there is a mismatch between these perceptions and expectations, the individual needs to adjust their actions or update their self-perception to better align with their current experiences. We also consider this hypothesis in relation with recent research on affective inference, suggesting that self-esteem enables the individual to track and respond to this discrepancy through affective states such as anxiety or positive affect. By acting as an inferential sociometer, self-esteem allows individuals to navigate and adapt to their social environment, ultimately impacting their psychological well-being and mental health.

Comparison of Three Preharvest Sampling Strategies to Monitor Pathogens in Cattle Lairage Areas.

The objective of this study was to compare preharvest monitoring strategies by evaluating three different sampling methods in the lairage area to determine pathogen recovery for each sampling method and incoming pathogen prevalence from the cattle to inform in-plant decision making. Samples were gathered over a 5-month period, from February to June 2022, at a harvesting and processing facility located in Eastern Nebraska. Sampling methods included (i) fecal pats, (ii) boot swabs, and (iii) MicroTally swab. A total of 329 samples were collected over the study period (fecal pats: n = 105, boot swabs: n = 104, and MicroTally swabs: n = 120). Specific media combinations, an incubation temperature of 42°C, and incubation timepoints (18-24 h) were utilized for each matrix and the prevalence of Salmonella, Escherichia coli O157:H7, and six non-O157 Shiga-toxin producing E. coli (STEC) was evaluated using the BAX system Real-Time PCR assay. Overall, results from the study concluded that boot swabs were an effective sampling method for pathogen detection in the cattle lairage area. Boot swabs (97.1%) were statistically more likely to detect for Salmonella (p < 0.05) when compared to fecal pats (67.6%) and MicroTally swab (77.5%) methods. For E. coli O157:H7 and STEC - O26, O121, O45, and O103 prevalence, boot swabs were significantly better at detecting for these pathogens (p < 0.05) than MicroTally swabs (OR = 3.16 - 11.95) and a comparable sampling method to fecal pats (OR = 0.93 - 2.01, p > 0.05). Lastly, all three sampling methods detected a very low prevalence for E. coli O111 and O145; therefore, no further analysis was conducted. The boot swab sampling method was strongly favored because they require little training to implement, are inexpensive, and they do not require much sampling labor; therefore, would be a simple and effective sampling method to implement within the industry to evaluate pathogen prevalence preharvest.

An EWAS of dementia biomarkers and their associations with age, African ancestry, and PTSD.

BACKGROUND: Large-scale cohort and epidemiological studies suggest that PTSD confers risk for dementia in later life but the biological mechanisms underlying this association remain unknown. This study examined this question by assessing the influences of PTSD, APOE ε4 genotypes, DNA methylation, and other variables on the age- and dementia-associated biomarkers Aß40, Aß42, GFAP, NfL, and pTau-181 measured in plasma. Our primary hypothesis was that PTSD would be associated with elevated levels of these markers. METHODS: Analyses were based on data from a PTSD-enriched cohort of 849 individuals. We began by performing factor analyses of the biomarkers, the results of which identified a two-factor solution. Drawing from the ATN research framework, we termed the first factor, defined by Aß40 and Aß42, "Factor A" and the second factor, defined by GFAP, NfL and pTau-181, "Factor TN." Next, we performed epigenome-wide association analyses (EWAS) of the two-factor scores. Finally, using structural equation modeling (SEM), we evaluated (a) the influence of PTSD, age, APOE ε4 genotype and other covariates on levels of the ATN factors, and (b) tested the mediating influence of the EWAS-significant DNAm loci on these associations. RESULTS: The Factor A EWAS identified one significant locus, cg13053408, in FANCD2OS. The Factor TN analysis identified 3 EWAS-significant associations: cg26033520 near ASCC1, cg23156469 in FAM20B, and cg15356923 in FAM19A4. The SEM showed age to be related to both factors, more so with Factor TN (ß = 0.581, p < 0.001) than Factor A (ß = 0.330, p < 0.001). Genotype-determined African ancestry was associated with lower Factor A (ß = 0.196, p < 0.001). Contrary to our primary hypothesis, we found a modest negative bivariate correlation between PTSD and the TN factor scores (r = - 0.133, p < 0.001) attributable primarily to reduced levels of GFAP (r = - 0.128, p < 0.001). CONCLUSIONS: This study identified novel epigenetic associations with ATN biomarkers and demonstrated robust age and ancestral associations that will be essential to consider in future efforts to develop the clinical applications of these tests. The association between PTSD and reduced GFAP, which has been reported previously, warrants further investigation.

A conserved gastropod withdrawal circuit in Biomphalaria glabrata, an intermediate host for schistosomiasis.

Neuronal signals mediated by the biogenic amine serotonin (5-HT) underlie critical survival strategies across the animal kingdom. This investigation examined serotonin-like immunoreactive neurons in the cerebral ganglion of the panpulmonate snail Biomphalaria glabrata, a major intermediate host for the trematode parasite Schistosoma mansoni. Five neurons comprising the cerebral serotonergic F (CeSF) cluster of B. glabrata shared morphological characteristics with neurons that contribute to withdrawal behaviors in numerous heterobranch species. The largest member of this group, designated CeSF-1, projected an axon to the tentacle, a major site of threat detection. Intracellular recordings demonstrated repetitive activity and electrical coupling between the bilateral CeSF-1 cells. In semi-intact preparations, the CeSF-1 cells were not responsive to cutaneous stimuli but did respond to photic stimuli. A large FMRF-NH2-like immunoreactive neuron, termed C2, was also located on the dorsal surface of each cerebral hemiganglion near the origin of the tentacular nerve. C2 and CeSF-1 received coincident bouts of inhibitory synaptic input. Moreover, in the presence of 5-HT they both fired rhythmically and in phase. As the CeSF and C2 cells of Biomphalaria share fundamental properties with neurons that participate in withdrawal responses in Nudipleura and Euopisthobranchia, our observations support the proposal that features of this circuit are conserved in the Panpulmonata.NEW & NOTEWORTHY Neuronal signals mediated by the biogenic amine serotonin underlie critical survival strategies across the animal kingdom. This investigation identified a group of serotonergic cells in the panpulmonate snail Biomphalaria glabrata that appear to be homologous to neurons that mediate withdrawal responses in other gastropod taxa. It is proposed that an ancient withdrawal circuit has been highly conserved in three major gastropod lineages.

Biomechanical comparison of composite and cadaveric humeri models in experiments on operated humeral shaft fractures.

A study was undertaken to determine how well contacting fracture fragments of composite bone replicated the behavior of fracture fragments in real bone. Ten composite and ten real humeral diaphyses were transected and reconstructed with limited-contact dynamic-compression plates. Two screws were placed on each side of the transection site and a calibrated electronic sensor sheet was placed between the imitated fracture fragments. After insertion of the distal screws, pressure measurements were made during insertion of the first proximal screw in compression mode, during insertion of the second screw in compression mode after loosening the first screw, and finally after retightening the first screw. The process was repeated after bending the plate. The contact area, the net compression force and the average compressive stress were computed and statistically compared. The composite bone and cadaveric bone differed in contact area and compressive stress but not in net compressive force. Plate bending did not produce a significant difference between composite and cadaveric bone. The results indicate that composite bone does not reproduce all the local fracture fragment conditions so that hardware testing in composite bone should proceed carefully. A gap between fracture fragments as is often used in comminuted fracture tests may remain as the most appropriate situation for fracture hardware testing.

Sterile kidney tissue injury induces neutrophil swarming in lung alveolar capillaries.

Sterile tissue injury, such as by acute kidney injury, is common in the clinic and frequently associated with respiratory compromise and hypoxemia. We previously described signaling components released by the injured kidney that drive a remote inflammatory response in the lung. How this caused the resultant hypoxemia remained unclear. Here, we report that sterile kidney tissue injury induces rapid intravascular "neutrophil train" formation in lung capillaries, a novel form of neutrophil swarming. Rapid swarming is enhanced by decreased deformability of circulating neutrophils that impedes their lung capillary passage. Classical lung monocytes are required for neutrophil train formation and release CXCL2 to attract and retain stiffened neutrophils in lung capillaries which reduces capillary perfusion. We thus discovered a novel feature of kidney-lung crosstalk after sterile kidney tissue injury, capillary perfusion deficits that lead to reduced oxygenation despite proper alveolar function and ventilation, unlike in infectious inflammatory lung processes, such as bacterial pneumonia.

Digital Being: social media and the predictive mind.

Social media is implicated today in an array of mental health concerns. While concerns around social media have become mainstream, little is known about the specific cognitive mechanisms underlying the correlations seen in these studies or why we find it so hard to stop engaging with these platforms when things obviously begin to deteriorate for us. New advances in computational neuroscience, however, are now poised to shed light on this matter. In this paper, we approach the phenomenon of social media addiction through the lens of the active inference framework. According to this framework, predictive agents like us use a 'generative model' of the world to predict our own incoming sense data and act to minimize any discrepancy between the prediction and incoming signal (prediction error). In order to live well and be able to act effectively to minimize prediction error, it is vital that agents like us have a generative model, which not only accurately reflects the regularities of our complex environment but is also flexible and dynamic and able to stay accurate in volatile and turbulent circumstances. In this paper, we propose that some social media platforms are a spectacularly effective way of warping an agent's generative model and of arresting the model's ability to flexibly track and adapt to changes in the environment. We go on to investigate cases of digital tech, which do not have these adverse effects and suggest-based on the active inference framework-some ways to understand why some forms of digital technology pose these risks, while others do not.