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The relationship between genetic variation and gene expression in brain cell types and subtypes remains understudied. Here, we generated single-nucleus RNA sequencing data from the neocortex of 424 individuals of advanced age; we assessed the effect of genetic variants on RNA expression in cis (cis-expression quantitative trait loci) for seven cell types and 64 cell subtypes using 1.5 million transcriptomes. This effort identified 10,004 eGenes at the cell type level and 8,099 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer's disease pathology, after adjusting for APOEε4, providing mechanistic insights into both pathologies. Furthermore, only a TMEM106B variant affects the proportion of cell subtypes. Integration of these results with genome-wide association studies highlighted the targeted cell type and probable causal gene within Alzheimer's disease, schizophrenia, educational attainment and Parkinson's disease loci., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

In the setting of femoroacetabular impingement of the hip joint, paralabral cysts are well-documented sequelae. These cysts are typically associated with labral tears caused by CAM and/or pincer-type bony lesions. Synovial fluid extravasation through a tear in the labrum, similar to a popliteus cyst, leads to formation of a capsular-based cyst that is usually self-limiting. Few documented cases of these cysts causing compression of nearby neurovascular structures exist. There are several studies documenting arthroscopic decompression of these cysts, but none reporting compression of the femoral vein by a paralabral cyst resulting in deep vein thrombosis. We present the case of a large anterior paralabral cyst causing compression of the right femoral vein in a patient presenting with deep vein thrombosis and hip pain. Treatment consisted of arthroscopic decompression, followed by definitive aspiration by interventional radiology after labral repair and bipolar hip osteoplasty. The purpose of this case report was to document this rare presentation and offer learning points from our experience., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Two active, adult male patients, one with prior triceps rupture and direct repair, presented with traumatic rupture of the distal triceps tendon. MRI confirmed not only complete rupture with retraction in both, but also signal changes within the tendon, raising concern for healing potential and re-rupture. Surgical repair was performed using heavy, non-absorbable suture and suture anchors in the standard fashion, followed by augmentation with a bovine, bio-inductive collagen scaffold in order to increase tendon thickness and aid with healing capability. This technique is well described for rotator cuff repair augmentation but is a novel technique to the literature in the setting of triceps tendons repair. Both patients returned to full, preinjury activity without complication with sustained results at 3 and 3.5 years postoperatively., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Enrollment in high-quality early childhood education (ECE) improves educational and health outcomes and can mitigate racial and economic disparities. Pediatricians are encouraged to promote ECE yet lack the time and knowledge to assist families effectively. In 2016, our academic primary care center hired an ECE Navigator to promote ECE and help families enroll. Our SMART aims were to increase the number of children with facilitated referrals to high-quality ECE programs from 0 to 15 per month and to confirm enrollment on a subset to achieve an enrollment rate of 50% by December 31, 2020., Methods: We used the Institute for Healthcare Improvement's Model for Improvement. Interventions included system changes in partnership with ECE agencies (eg, interactive map of subsidized preschool options, streamlined enrollment forms), case management with families, and population-based approaches to understand families' needs and the program's overall impact. We plotted the number of monthly facilitated referrals and the percentage of referrals enrolled on run and control charts. We used standard probability-based rules to identify special causes., Results: Facilitated referrals increased from 0 to 29 per month and remained above 15. The percentage of enrolled referrals increased from 30% to 74% in 2018, then decreased to 27% in 2020 when childcare availability declined during the pandemic., Conclusions: Our innovative ECE partnership improved access to high-quality ECE. Interventions could be adopted in part or whole by other clinical practices or WIC offices to equitably improve early childhood experiences for low-income families and racial minorities., Competing Interests: Disclosures: Amy King is under contract with 4C for Children, a local childcare resource and referral agency in Cincinnati, Ohio, and Child Guidance & Family Solutions, a mental health agency in Akron, Ohio. The other authors have no conflicts of interest to declare in relation to the content of this article. This work has been supported by a grant from United Way of Greater Cincinnati (2016–2017) and the PNC Trust Organization of Cincinnati, Ohio (2018–2020)., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

The role of different cell types and their interactions in Alzheimer's disease (AD) is a complex and open question. Here, we pursued this question by assembling a high-resolution cellular map of the aging frontal cortex using single-nucleus RNA sequencing of 24 individuals with a range of clinicopathologic characteristics. We used this map to infer the neocortical cellular architecture of 638 individuals profiled by bulk RNA sequencing, providing the sample size necessary for identifying statistically robust associations. We uncovered diverse cell populations associated with AD, including a somatostatin inhibitory neuronal subtype and oligodendroglial states. We further identified a network of multicellular communities, each composed of coordinated subpopulations of neuronal, glial and endothelial cells, and we found that two of these communities are altered in AD. Finally, we used mediation analyses to prioritize cellular changes that might contribute to cognitive decline. Thus, our deconstruction of the aging neocortex provides a roadmap for evaluating the cellular microenvironments underlying AD and dementia., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Opioids are a mainstay for pain control in patients undergoing lumbar spine surgery but are associated with a high risk of dependence and significant adverse effects. Efforts continue to be made to utilize non-narcotic agents such as regional nerve block for pain control as part of a multimodal analgesia regimen. Recently, transversus abdominis plane (TAP) blocks have proven beneficial for patients undergoing lumbar fusion procedures. The purpose of this study is to evaluate the efficacy of TAP blocks for postoperative pain control and the effect on opioid consumption and hospital length of stay (LOS) in patients undergoing anterior lumbar interbody fusion (ALIF)., Methods: A retrospective review of patients undergoing elective ALIF included collection of data on demographics, LOS, pain scores using visual analog scale (VAS), opioid consumption using morphine milligram equivalents (MME) from postoperative day (POD) 0 to 5, and any complications. Patients who underwent primary ALIF or ALIF with concomitant posterolateral lumbar fusion were included., Results: A total of 99 patients met inclusion criteria; 47 had a preoperative TAP block and 52 did not. Demographic data and number of levels fused were equally distributed between the groups. The TAP group had significantly lower MME consumption postoperatively during POD 0 to 2 and 0 to 5. VAS pain scores were lower for TAP block patients on POD 3 and 4; otherwise, there was no significant difference. LOS and complication rates were not significantly different. A multiple regression analysis found male sex to be a predictor of increased postoperative MME, while age and TAP block were significant predictors of decreased MME., Conclusions: The use of TAP block for patients undergoing ALIF was associated with less cumulative MME consumption in the immediate postoperative period. TAP block may be an effective tool for reducing postoperative opioid consumption in patients undergoing ALIF., Clinical Relevance: The data in this study provide clinical relevance supporting the use of TAP blocks for patients undergoing ALIF procedures., Competing Interests: Declaration of Conflicting Interests : The authors report no conflicts of interest in this work., (This manuscript is generously published free of charge by ISASS, the International Society for the Advancement of Spine Surgery. Copyright © 2023 ISASS. To see more or order reprints or permissions, see http://ijssurgery.com.)

The deleterious effects of solar ultraviolet (UV) radiation on construction materials, especially wood and plastics, and the consequent impacts on their useful lifetimes, are well documented in scientific literature. Any future increase in solar UV radiation and ambient temperature due to climate change will therefore shorten service lifetimes of materials, which will require higher levels of stabilisation or other interventions to maintain their lifetimes at the present levels. The implementation of the Montreal Protocol and its amendments on substances that deplete the ozone layer, controls the solar UV-B radiation received on Earth. This current quadrennial assessment provides a comprehensive update on the deleterious effects of solar UV radiation on the durability of natural and synthetic materials, as well as recent innovations in better stabilising of materials against solar UV radiation-induced damage. Pertinent emerging technologies for wood and plastics used in construction, composite materials used in construction, textile fibres, comfort fabric, and photovoltaic materials, are addressed in detail. Also addressed are the trends in technology designed to increase sustainability via replacing toxic, unsustainable, legacy additives with 'greener' benign substitutes that may indirectly affect the UV stability of the redesigned materials. An emerging class of efficient photostabilisers are the nanoscale particles that include oxide fillers and nanocarbons used in high-performance composites, which provide good UV stability to materials. They also allow the design of UV-shielding fabric materials with impressive UV protection factors. An emerging environmental issue related to the photodegradation of plastics is the generation of ubiquitous micro-scale particles from plastic litter exposed to solar UV radiation., (© 2023. The Author(s).)

Microplastics (MPs) are an emerging class of pollutants in air, soil and especially in all aquatic environments. Secondary MPs are generated in the environment during fragmentation of especially photo-oxidised plastic litter. Photo-oxidation is mediated primarily by solar UV radiation. The implementation of the Montreal Protocol and its Amendments, which have resulted in controlling the tropospheric UV-B (280-315 nm) radiation load, is therefore pertinent to the fate of environmental plastic debris. Due to the Montreal Protocol high amounts of solar UV-B radiation at the Earth's surface have been avoided, retarding the oxidative fragmentation of plastic debris, leading to a slower generation and accumulation of MPs in the environment. Quantifying the impact of the Montreal Protocol in reducing the abundance of MPs in the environment, however, is complicated as the role of potential mechanical fragmentation of plastics under environmental mechanical stresses is poorly understood., (© 2023. The Author(s).)

Introduction: Surgical site infections (SSIs) are associated with patient morbidity and increased healthcare costs. Limited literature in foot and ankle surgery provides guidance about routine administration of postoperative antibiotic prophylaxis. The purpose of this study was to examine the incidence and revision surgery rates of SSI in outpatient foot and ankle surgeries in patients not receiving oral postoperative antibiotic prophylaxis., Methods: A retrospective review of all outpatient surgeries (n = 1517) conducted by a single surgeon in a tertiary referral academic center was conducted through electronic medical records. Incidence of SSI, revision surgery rate, and associated risk factors were determined. The median follow-up was 6 months., Results: Postoperative infection occurred in 2.9% (n = 44) of the surgeries conducted, with 0.9% of patients (n = 14) requiring return to the operating room. Thirty patients (2.0%) were diagnosed with simple superficial infections, which resolved with local wound care and oral antibiotics. Diabetes (adjusted odds ratio, 2.09; 95% confidence interval, 1.00 to 4.38; P = 0.049) and increasing age (adjusted odds ratio, 1.02; 95% confidence interval, 1.00 to 1.04; P = 0.016) were significantly associated with postoperative infection., Discussion: This study demonstrated low postoperative infection and revision surgery rates without the routine prescription of prophylactic postoperative antibiotics. Increasing age and diabetes are signficant risk factors for developing a postoperative infection., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

The goals for increased patient access and fast fulfillment have motivated considerable interest in autologous cell therapy manufacturing networks having multiple and geographically distributed manufacturing facilities. However, the cost of safety manufacturing capacity to mitigate supplier disruption risk-a significant risk in the emerging cell manufacturing industry-would be lower if manufacturing is centralized. In this paper, we analyze a decentralized network that has as its objective to minimize the cost of network resilience for mitigating supplier disruption by making use of the fact that bioreactors for autologous therapy manufacturing are small enough to be relocatable. We model this problem as a Markov decision process and develop efficient algorithms that are based on real-time demand data to minimize safety manufacturing capacity and determine how relocatable capacity should be distributed while satisfying resilience constraints. In case studies, based in part on data collected from a Chimeric antigen receptor T cell therapy manufacturing facility at the University of Pennsylvania, we compare decentralized network models with different heuristic algorithms. Results indicate that transshipment in a decentralized network can result in a significant reduction of required safety capacity, reducing the cost of network resilience., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Understanding the fate of plastics in the environment is of critical importance for the quantitative assessment of the biological impacts of plastic waste. Specially, there is a need to analyze in more detail the reputed longevity of plastics in the context of plastic degradation through oxidation and fragmentation reactions. Photo-oxidation of plastic debris by solar UV radiation (UVR) makes material prone to subsequent fragmentation. The fragments generated following oxidation and subsequent exposure to mechanical stresses include secondary micro- or nanoparticles, an emerging class of pollutants. The paper discusses the UV-driven photo-oxidation process, identifying relevant knowledge gaps and uncertainties. Serious gaps in knowledge exist concerning the wavelength sensitivity and the dose-response of the photo-fragmentation process. Given the heterogeneity of natural UV irradiance varying from no exposure in sediments to full UV exposure of floating, beach litter or air-borne plastics, it is argued that the rates of UV-driven degradation/fragmentation will also vary dramatically between different locations and environmental niches. Biological phenomena such as biofouling will further modulate the exposure of plastics to UV radiation, while potentially also contributing to degradation and/or fragmentation of plastics independent of solar UVR. Reductions in solar UVR in many regions, consequent to the implementation of the Montreal Protocol and its Amendments for protecting stratospheric ozone, will have consequences for global UV-driven plastic degradation in a heterogeneous manner across different geographic and environmental zones. The interacting effects of global warming, stratospheric ozone and UV radiation are projected to increase UV irradiance at the surface in localized areas, mainly because of decreased cloud cover. Given the complexity and uncertainty of future environmental conditions, this currently precludes reliable quantitative predictions of plastic persistence on a global scale., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

For centuries, society has called out for transformations to lift all of its members. While it may seem ordinary in our time for women to be dentists or dental educators, the path was neither always easy, nor has true equity been achieved. The modern transformation of dental education and dentistry creates the need for leaders to propose and develop concrete initiatives to advance the profession and benefit society. Areas to address that could lead to increased equity for women include career advancement, leadership opportunities, compensation, career satisfaction, research, and scholarly activity. Our analysis demonstrates that even though the number of full-time female faculty has increased during recent years, most positions (59.5%) at dental schools in the US are held by men (2018-2019). Males were also compensated at higher rates than their female counterparts, and female deans made 7% less in total compensation. Because disparities are evident in pay and academic pathways, new directions and strategies must be employed to ensure parity and gender equity. Facilitating the progress of women in organized dentistry requires efforts of dental academic institutions to invest resources and provide nurturing environments that promote professional performances and leadership skills for women, with these being priorities-considering the current trends that anticipate increased numbers of women in dental academia. All dentists bring their own experiences to the profession, making for rich depth and diversity. As a collective voice, we have a bright future. We can and will move forward together., (© 2022 American Dental Education Association.)

The Clinical Trial Treatment Train Ms. Christine Cissy White received a diagnosis of high-grade serous ovarian cancer in August 2019 at 52 years of age. Her experiences as a clinical trial participant and the uncertainties of living with cancer are recounted in this Patient Platform.

The Environmental Effects Assessment Panel of the Montreal Protocol under the United Nations Environment Programme evaluates effects on the environment and human health that arise from changes in the stratospheric ozone layer and concomitant variations in ultraviolet (UV) radiation at the Earth's surface. The current update is based on scientific advances that have accumulated since our last assessment (Photochem and Photobiol Sci 20(1):1-67, 2021). We also discuss how climate change affects stratospheric ozone depletion and ultraviolet radiation, and how stratospheric ozone depletion affects climate change. The resulting interlinking effects of stratospheric ozone depletion, UV radiation, and climate change are assessed in terms of air quality, carbon sinks, ecosystems, human health, and natural and synthetic materials. We further highlight potential impacts on the biosphere from extreme climate events that are occurring with increasing frequency as a consequence of climate change. These and other interactive effects are examined with respect to the benefits that the Montreal Protocol and its Amendments are providing to life on Earth by controlling the production of various substances that contribute to both stratospheric ozone depletion and climate change., (© 2022. The Author(s).)

Antioxidant signaling/communication is among the most important cellular defense and survival pathways, and the importance of redox signaling and homeostasis in aging has been well-documented. Intracellular levels of glutathione (GSH), a very important endogenous antioxidant, both govern and are governed by the Nrf2 pathway through expression of genes involved in its biosynthesis, including the subunits of the rate-limiting enzyme (glutamate cysteine ligase, GCL) in GSH production, GCLC and GCLM. Mice homozygous null for the Gclm gene are severely deficient in GSH compared to wild-type controls, expressing approximately 10% of normal GSH levels. To compensate for GSH deficiency, Gclm null mice have upregulated redox-regulated genes, and, surprisingly, are less susceptible to certain types of oxidative damage. Furthermore, young Gclm null mice display an interesting lean phenotype, resistance to high fat diet-induced diabetes and obesity, improved insulin and glucose tolerance, and decreased expression of genes involved in lipogenesis. However, the persistence of this phenotype has not been investigated into old age, which is important in light of studies which suggest aging attenuates antioxidant signaling, particularly in response to exogenous stimuli. In this work, we addressed whether aging compromises the favorable phenotype of increased antioxidant activity and improved glucose homeostasis observed in younger Gclm null mice. We present data showing that under basal conditions and in response to cadmium exposure (2 mg/kg, dosed once via intraperitoneal injection), the phenotype previously described in young (<6 months) Gclm null mice persists into old age (24+ months). We also provide evidence that transcriptional activation of the Nrf2, AMPK, and PPARγ pathways underlie the favorable metabolic phenotype observed previously in young Gclm null mice., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

RNA editing is a feature of RNA maturation resulting in the formation of transcripts whose sequence differs from the genome template. Brain RNA editing may be altered in Alzheimer's disease (AD). Here, we analyzed data from 1,865 brain samples covering 9 brain regions from 1,074 unrelated subjects on a transcriptome-wide scale to identify inter-regional differences in RNA editing. We expand the list of known brain editing events by identifying 58,761 previously unreported events. We note that only a small proportion of these editing events are found at the protein level in our proteome-wide validation effort. We also identified the occurrence of editing events associated with AD dementia, neuropathological measures and longitudinal cognitive decline in: SYT11, MCUR1, SOD2, ORAI2, HSDL2, PFKP, and GPRC5B. Thus, we present an extended reference set of brain RNA editing events, identify a subset that are found to be expressed at the protein level, and extend the narrative of transcriptomic perturbation in AD to RNA editing., (© 2021. The Author(s).)

Importance: The X chromosome represents 5% of the human genome in women and men, and its influence on cognitive aging and Alzheimer disease (AD) is largely unknown., Objective: To determine whether the X chromosome is associated with sex-specific cognitive change and tau pathology in aging and AD., Design, Setting, Participants: This study examined differential gene expression profiling of the X chromosome from an RNA sequencing data set of the dorsolateral prefrontal cortex obtained from autopsied, elderly individuals enrolled in the Religious Orders Study and Rush Memory and Aging Project joint cohorts. Samples were collected from the cohort study with enrollment from 1994 to 2017. Data were last analyzed in May 2021., Main Outcomes and Measures: The main analysis examined whether X chromosome gene expression measured by RNA sequencing of the dorsolateral prefrontal cortex was associated with cognitive change during aging and AD, independent of AD pathology and at the transcriptome-wide level in women and men. Whether X chromosome gene expression was associated with neurofibrillary tangle burden, a measure of tau pathology that influences cognition, in women and men was also explored., Results: Samples for RNA sequencing of the dorsolateral prefrontal cortex were obtained from 508 individuals (mean [SD] age at death, 88.4 [6.6] years; 315 [62.0%] were female; 197 [38.8%] had clinical diagnosis of AD at death; 293 [58.2%] had pathological diagnosis of AD at death) enrolled in the Religious Orders Study and Rush Memory and Aging Project joint cohorts and were followed up annually for a mean (SD) of 6.3 (3.9) years. X chromosome gene expression (29 genes), adjusted for age at death, education, and AD pathology, was significantly associated with cognitive change at the genome-wide level in women but not men. In the majority of identified X genes (19 genes), increased expression was associated with slower cognitive decline in women. In contrast with cognition, X chromosome gene expression (3 genes), adjusted for age at death and education, was associated with neuropathological tau burden at the genome-wide level in men but not women., Conclusions and Relevance: In this study, the X chromosome was associated with cognitive trajectories and neuropathological tau burden in aging and AD in a sex-specific manner. This is important because specific X chromosome factors could contribute risk or resilience to biological pathways of aging and AD in women, men, or both.

It has been demonstrated that elamipretide (SS-31) rescues age-related functional deficits in the heart but the full set of mechanisms behind this have yet to be determined. We investigated the hypothesis that elamipretide influences post-translational modifications to heart proteins. The S-glutathionylation and phosphorylation proteomes of mouse hearts were analyzed using shotgun proteomics to assess the effects of aging on these post-translational modifications and the ability of the mitochondria-targeted drug elamipretide to reverse age-related changes. Aging led to an increase in oxidation of protein thiols demonstrated by increased S-glutathionylation of cysteine residues on proteins from Old (24 months old at the start of the study) mouse hearts compared to Young (5-6 months old). This shift in the oxidation state of the proteome was almost completely reversed by 8 weeks of treatment with elamipretide. Many of the significant changes that occurred were in proteins involved in mitochondrial or cardiac function. We also found changes in the mouse heart phosphoproteome that were associated with age, some of which were partially restored with elamipretide treatment. Parallel reaction monitoring of a subset of phosphorylation sites revealed that the unmodified peptide reporting for Myot S231 increased with age, but not its phosphorylated form and that both phosphorylated and unphosphorylated forms of the peptide covering cMyBP-C S307 increased, but that elamipretide treatment did not affect these changes. These results suggest that changes to thiol redox state and phosphorylation status are two ways in which age may affect mouse heart function, which can be restored by treatment with elamipretide., (© 2021. American Aging Association.)

Background: Higher body mass index (BMI) is a well-known risk factor for the development of hip and knee osteoarthritis and predicts total hip arthroplasty (THA) and total knee arthroplasty (TKA) at an earlier age. The purpose of this study is to document the nationwide trends in age and obesity in primary THA and TKA throughout the obesity epidemic., Methods: A retrospective analysis of the National Inpatient Sample database was conducted on patients undergoing primary THA and TKA for primary OA between 2002 and 2017. Analysis of variance and chi-square tests were performed to examine changes in age and obesity percentage over time, respectively. Pearson correlations were used to assess the relationship between patient age, BMI, and year of surgery., Results: A total of 688,371 THA and 1,556,651 TKA were identified over the sixteen-year period. Between 2002 and 2017, the proportion of obese patients increased for both THA (7.0% to 22.7%, P < .001) and TKA (10.7% to 30.4%, P < .001). Mean age significantly decreased for both THA (66.7 to 65.9 years, P < .001) and TKA (67.6 to 66.8 years; P < .001). Over time, BMI significantly increased (THA: r = 0.221 vs. TKA: r = 0.272) and patient age decreased (THA: r = -0.031 vs. TKA: r = -0.137) for both procedures (P < .001 for all)., Conclusion: THA and TKA patients have become younger and increasingly more obese throughout the obesity epidemic, as obesity rates have tripled over this time period. The current investigation is the first to demonstrate significant trends in both age and obesity in the THA and TKA populations on a national level., Level of Evidence: III., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We previously found that the widely used disinfectants, benzalkonium chlorides (BACs), alter cholesterol and lipid homeostasis in neuronal cell lines and in neonatal mouse brains. Here, we investigate the effects of BACs on neurospheres, an in vitro three-dimensional model of neurodevelopment. Neurospheres cultured from mouse embryonic neural progenitor cells (NPCs) were exposed to increasing concentrations (from 1 to 100 nM) of a short-chain BAC (BAC C12), a long-chain BAC (BAC C16), and AY9944 (a known DHCR7 inhibitor). We found that the sizes of neurospheres were decreased by both BACs but not by AY9944. Furthermore, we observed potent inhibition of cholesterol biosynthesis at the step of DHCR7 by BAC C12 but not by BAC C16, suggesting that cholesterol biosynthesis inhibition is not responsible for the observed reduction in neurosphere growth. By using immunostaining and cell cycle analysis, we found that both BACs induced apoptosis and decreased proliferation of NPCs. To explore the mechanisms underlying their effect on neurosphere growth, we carried out RNA sequencing on neurospheres exposed to each BAC at 50 nM for 24 h, which revealed the activation of the integrated stress response by both BACs. Overall, these results suggest that BACs affect neurodevelopment by inducing the integrated stress response in a manner independent of their effects on cholesterol biosynthesis.

Accumulating evidence has suggested that the molecular transcriptional mechanism contributes to Alzheimer's disease (AD) and its endophenotypes of cognitive decline and neuropathological traits, β-amyloid (Aβ) and phosphorylated tangles (TAU). However, it is unknown what is the impact of the AD risk factors, personality characteristics assessed by the NEO Five-Factor Inventory, on the human brain's transcriptome. Using postmortem human brain samples from 466 subjects, we found that neuroticism has a significant overall impact on the brain transcriptome (omnibus P = 0.005) but not the other four personality characteristics. Focused on those cognitive decline related gene co-expressed modules, neuroticism has nominally significant associations (P < 0.05) with four neuronal modules, which are more related to PHFtau than Aβ across all eight brain regions. Furthermore, the effect of neuroticism on cognitive decline and AD might be mediated through the expression of module 7 and TAU pathology (P = 0.008). To conclude, neuroticism has a broad impact on the transcriptome of human brains, and its effect on cognitive decline and AD may be mediated through gene transcription programs related to TAU pathology.

Microglial dysfunction has been proposed as one of the many cellular mechanisms that can contribute to the development of Alzheimer's disease (AD). Here, using a transcriptional network map of the human frontal cortex, we identify five modules of co-expressed genes related to microglia and assess their role in the neuropathologic features of AD in 540 subjects from two cohort studies of brain aging. Two of these transcriptional programs-modules 113 and 114-relate to the accumulation of β-amyloid, while module 5 relates to tau pathology. We replicate these associations in brain epigenomic data and in two independent datasets. In terms of tau, we propose that module 5, a marker of activated microglia, may lead to tau accumulation and subsequent cognitive decline. We validate our model further by showing that three representative module 5 genes (ACADVL, TRABD, and VASP) encode proteins that are upregulated in activated microglia in AD.

Purpose: To determine whether change in shoulder position between internal rotation (IR) and external rotation (ER) during magnetic resonance arthrography (MRA) affects previously defined capsular measurements and to determine the utility of rotation in the diagnosis of instability., Methods: A retrospective study was conducted of patients who received a shoulder MRA with humeral IR and ER views. Patients with an arthroscopically confirmed diagnosis of instability and those with clinically stable shoulders, no history of instability, and no MRA findings of instability were identified and compared. Humeral rotation, glenoid retroversion, humeral head subluxation, capsular length, and capsular area using axial sequences of IR and ER views were recorded. Analysis compared IR, ER, and Δ capsular measurements between groups using independent t tests and univariate and multivariate regression., Results: Thirty-one subjects who were diagnosed with instability were included, along with 28 control subjects. Capsular length, capsular area, and humeral subluxations were significantly greater with ER compared with IR views (P < .001, P < .001, P < .001). Patients with instability displayed greater ER capsular length (P = .0006) and ER capsular area (P = .005) relative to controls. Multivariate logistic regression identified age, weight, sex, ER capsular length, and retroversion to be significant predictors of instability. ER capsular length independently predicts instability with 86% sensitivity and 84% specificity. Interobserver reliability using the intraclass correlation coefficient was rated good or excellent on all measurements., Conclusion: Variance in humeral rotation during shoulder MRA significantly affects capsular measurements. Rotational views increase the utility of capsular measurements when assessing for instability, particularly capsular length and capsular area. The implementation of ER positioning enhances the ability to examine capsular changes of the shoulder joint and can assist in the diagnosis of instability., Level of Evidence: III, retrospective comparative study., (Copyright © 2020 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

This assessment by the Environmental Effects Assessment Panel (EEAP) of the United Nations Environment Programme (UNEP) provides the latest scientific update since our most recent comprehensive assessment (Photochemical and Photobiological Sciences, 2019, 18, 595-828). The interactive effects between the stratospheric ozone layer, solar ultraviolet (UV) radiation, and climate change are presented within the framework of the Montreal Protocol and the United Nations Sustainable Development Goals. We address how these global environmental changes affect the atmosphere and air quality; human health; terrestrial and aquatic ecosystems; biogeochemical cycles; and materials used in outdoor construction, solar energy technologies, and fabrics. In many cases, there is a growing influence from changes in seasonality and extreme events due to climate change. Additionally, we assess the transmission and environmental effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for the COVID-19 pandemic, in the context of linkages with solar UV radiation and the Montreal Protocol.

Objective: To test the association between physical function and the social environment in multiple sclerosis (MS), we quantified personal social networks., Methods: In this cross-sectional study, we analyzed data from 2 academic MS centers, with center 1 serving as a discovery group and center 2 as the extension group. We performed a meta-analysis of the centers to extend the analysis. We used responses from a questionnaire to map the structure and health habits of participants' social networks as well as the NIH Patient-Reported Outcomes Measurement Information System (PROMIS) physical function scale (0-100, mean 50 for US general population) as the primary outcome. We applied multivariable models to test the association between network metrics and physical function., Results: The discovery cohort included 263 patients with MS: 81% were women, 96% non-Hispanic European, 78% had relapsing MS, average age was 50 (12.4) years, and mean disease duration was 17 (12.3) years. The extension group included 163 patients, who were younger, more racially diverse, and less physically disabled, and had shorter disease duration. In the meta-analysis, higher network constraint, a measure of tightly bound networks, was associated with worse physical function (β = -0.163 ± 0.047, p < 0.001), while larger network effective size, a measure of clustered groups in the network, correlated with better physical function (β = 0.134 ± 0.046, p = 0.003)., Conclusions: Our study highlights personal networks as an important environmental factor associated with physical function in MS. Patients with close-knit networks had worse function than those with more open networks. Longitudinal studies are warranted to evaluate a causal relationship between network structure and physical impairment., (© 2020 American Academy of Neurology.)

Genetic mechanisms underlying age-related cognitive decline and dementia remain poorly understood. Here, we take advantage of the Diversity Outbred mouse population to utilize quantitative trait loci mapping and identify Dlgap2 as a positional candidate responsible for modifying working memory decline. To evaluate the translational relevance of this finding, we utilize longitudinal cognitive measures from human patients, RNA expression from post-mortem brain tissue, data from a genome-wide association study (GWAS) of Alzheimer's dementia (AD), and GWAS results in African Americans. We find an association between Dlgap2 and AD phenotypes at the variant, gene and protein expression, and methylation levels. Lower cortical DLGAP2 expression is observed in AD and is associated with more plaques and tangles at autopsy and faster cognitive decline. Results will inform future studies aimed at investigating the cross-species role of Dlgap2 in regulating cognitive decline and highlight the benefit of using genetically diverse mice to prioritize novel candidates., Competing Interests: Declaration of Interests C.C.K. and S.M.N. have filed a related patent application. The other authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

A major sex difference in Alzheimer's disease (AD) is that men with the disease die earlier than do women. In aging and preclinical AD, men also show more cognitive deficits. Here, we show that the X chromosome affects AD-related vulnerability in mice expressing the human amyloid precursor protein (hAPP), a model of AD. XY-hAPP mice genetically modified to develop testicles or ovaries showed worse mortality and deficits than did XX-hAPP mice with either gonad, indicating a sex chromosome effect. To dissect whether the absence of a second X chromosome or the presence of a Y chromosome conferred a disadvantage on male mice, we varied sex chromosome dosage. With or without a Y chromosome, hAPP mice with one X chromosome showed worse mortality and deficits than did those with two X chromosomes. Thus, adding a second X chromosome conferred resilience to XY males and XO females. In addition, the Y chromosome, its sex-determining region Y gene ( Sry ), or testicular development modified mortality in hAPP mice with one X chromosome such that XY males with testicles survived longer than did XY or XO females with ovaries. Furthermore, a second X chromosome conferred resilience potentially through the candidate gene Kdm6a , which does not undergo X-linked inactivation. In humans, genetic variation in KDM6A was linked to higher brain expression and associated with less cognitive decline in aging and preclinical AD, suggesting its relevance to human brain health. Our study suggests a potential role for sex chromosomes in modulating disease vulnerability related to AD., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Here, we perform a genome-wide screen for variants that regulate the expression of gene co-expression modules in the aging human brain; we discover and replicate such variants in the TMEM106B and RBFOX1 loci. The TMEM106B haplotype is known to influence the accumulation of TAR DNA-binding protein 43 kDa (TDP-43) proteinopathy, and the haplotype's large-scale transcriptomic effects include the dysregulation of lysosomal genes and alterations in synaptic gene splicing that are also seen in the pathophysiology of TDP-43 proteinopathy. Further, a variant near GRN, another TDP-43 proteinopathy susceptibility gene, shows concordant effects with the TMEM106B haplotype. Leveraging neuropathology data from the same participants, we also show that TMEM106B and APOE-amyloid-β effects converge to alter myelination and lysosomal gene expression, which then contributes to TDP-43 accumulation. These results advance our mechanistic understanding of the TMEM106B TDP-43 risk haplotype and uncover a transcriptional program that mediates the converging effects of APOE-amyloid-β and TMEM106B on TDP-43 aggregation in older adults., Competing Interests: Declaration of Interests P.L.D. serves on a scientific advisory board for Neuroimmunology Newco, Roche, Biogen, and Celgene; has a sponsored research agreement with Biogen and Roche; and has fellowship funding through Genentech, outside the submitted work. All other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

This assessment, by the United Nations Environment Programme (UNEP) Environmental Effects Assessment Panel (EEAP), one of three Panels informing the Parties to the Montreal Protocol, provides an update, since our previous extensive assessment (Photochem. Photobiol. Sci., 2019, 18, 595-828), of recent findings of current and projected interactive environmental effects of ultraviolet (UV) radiation, stratospheric ozone, and climate change. These effects include those on human health, air quality, terrestrial and aquatic ecosystems, biogeochemical cycles, and materials used in construction and other services. The present update evaluates further evidence of the consequences of human activity on climate change that are altering the exposure of organisms and ecosystems to UV radiation. This in turn reveals the interactive effects of many climate change factors with UV radiation that have implications for the atmosphere, feedbacks, contaminant fate and transport, organismal responses, and many outdoor materials including plastics, wood, and fabrics. The universal ratification of the Montreal Protocol, signed by 197 countries, has led to the regulation and phase-out of chemicals that deplete the stratospheric ozone layer. Although this treaty has had unprecedented success in protecting the ozone layer, and hence all life on Earth from damaging UV radiation, it is also making a substantial contribution to reducing climate warming because many of the chemicals under this treaty are greenhouse gases.

Doxorubicin is a widely used cancer therapeutic, but its effectiveness is limited by cardiotoxic side effects. Evidence suggests cardiotoxicity is due not to doxorubicin, but rather its metabolite, doxorubicinol. Identification of the enzymes responsible for doxorubicinol formation is important in developing strategies to prevent cardiotoxicity. In this study, the contributions of three murine candidate enzymes to doxorubicinol formation were evaluated: carbonyl reductase (Cbr) 1, Cbr3, and thioredoxin reductase 1 (Tr1). Analyses with purified proteins revealed that all three enzymes catalyzed doxorubicin-dependent NADPH oxidation, but only Cbr1 and Cbr3 catalyzed doxorubicinol formation. Doxorubicin-dependent NADPH oxidation by Tr1 was likely due to redox cycling. Subcellular fractionation results showed that doxorubicin-dependent redox cycling activity was primarily microsomal, whereas doxorubicinol-forming activity was exclusively cytosolic, as were all three enzymes. An immunoclearing approach was used to assess the contributions of the three enzymes to doxorubicinol formation in the complex milieu of the cytosol. Immunoclearing Cbr1 eliminated 25% of the total doxorubicinol-forming activity in cytosol, but immunoclearing Cbr3 had no effect, even in Tr1 null livers that overexpressed Cbr3. The immunoclearing results constituted strong evidence that Cbr1 contributed to doxorubicinol formation in mouse liver but that enzymes other than Cbr1 also played a role, a conclusion supported by ammonium sulfate fractionation results, which showed that doxorubicinol-forming activity was found in fractions that contained little Cbr1. In conclusion, the results show that Cbr1 accounts for 25% of the doxorubicinol-forming activity in mouse liver cytosol but that the majority of the doxorubicinol-forming activity remains unidentified. SIGNIFICANCE STATEMENT: Earlier studies suggested carbonyl reductase (Cbr) 1 plays a dominant role in converting chemotherapeutic doxorubicin to cardiotoxic doxorubicinol, but a new immunoclearing approach described herein shows that Cbr1 accounts for only 25% of the doxorubicinol-forming activity in mouse liver cytosol, that two other candidate enzymes-Cbr3 and thioredoxin reductase 1-play no role, and that the majority of the activity remains unidentified. Thus, targeting Cbr1 is necessary but not sufficient to eliminate doxorubicinol-associated cardiotoxicity; identification of the additional doxorubicinol-forming activity is an important next challenge., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

Anaphylaxis is a life-threatening condition with a known effective prehospital intervention: parenteral epinephrine. The National Association of EMS Physicians (NAEMSP) advocates for emergency medical services (EMS) providers to be allowed to carry and administer epinephrine. Some states constrain epinephrine administration by basic life support (BLS) providers to administration using epinephrine auto-injectors (EAIs), but the cost and supply of EAIs limits the ability of some EMS agencies to provide epinephrine for anaphylaxis. This literature review and consensus report describes the extant literature and the practical and policy issues related to non-EAI administration of epinephrine for anaphylaxis, and serves as a supplementary resource document for the revised NAEMSP position statement on the use of epinephrine in the out-of-hospital treatment of anaphylaxis, complementing (but not replacing) prior resource documents. The report concludes that there is some evidence that intramuscular injection of epinephrine drawn up from a vial or ampule by appropriately trained EMS providers-without limitation to specific certification levels-is safe, facilitates timely treatment of patients, and reduces costs.

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

CpG-related single nucleotide polymorphisms (CGS) have the potential to perturb DNA methylation; however, their effects on Alzheimer disease (AD) risk have not been evaluated systematically. We conducted a genome-wide association study using a sliding-window approach to measure the combined effects of CGSes on AD risk in a discovery sample of 24 European ancestry cohorts (12,181 cases, 12,601 controls) from the Alzheimer's Disease Genetics Consortium (ADGC) and replication sample of seven European ancestry cohorts (7,554 cases, 27,382 controls) from the International Genomics of Alzheimer's Project (IGAP). The potential functional relevance of significant associations was evaluated by analysis of methylation and expression levels in brain tissue of the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP), and in whole blood of Framingham Heart Study participants (FHS). Genome-wide significant (p < 5 × 10 -8 ) associations were identified with 171 1.0 kb-length windows spanning 932 kb in the APOE region (top p < 2.2 × 10 -308 ), five windows at BIN1 (top p = 1.3 × 10 -13 ), two windows at MS4A6A (top p = 2.7 × 10 -10 ), two windows near MS4A4A (top p = 6.4 × 10 -10 ), and one window at PICALM (p = 6.3 × 10 -9 ). The total number of CGS-derived CpG dinucleotides in the window near MS4A4A was associated with AD risk (p = 2.67 × 10 -10 ), brain DNA methylation (p = 2.15 × 10 -10 ), and gene expression in brain (p = 0.03) and blood (p = 2.53 × 10 -4 ). Pathway analysis of the genes responsive to changes in the methylation quantitative trait locus signal at MS4A4A (cg14750746) showed an enrichment of methyltransferase functions. We confirm the importance of CGS in AD and the potential for creating a functional CpG dosage-derived genetic score to predict AD risk., (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

All-polyethylene tibial (APT) implants were incorporated into the initial design of the first total knee arthroplasty (TKA) systems. Since then, a dynamic shift has taken place and metal-backed tibial (MBT) implants have become the gold standard in TKA. This has mostly been due to the theoretical advantages of intraoperative flexibility and improved biomechanics in addition to the heavy influence of device manufacturers. MBT implant comes not only with a higher cost but also with potential for complications such as osteolysis, backside wear, and thinning of the polyethylene insert, which were not previously seen with APT implant. The majority of studies comparing APT and MBT implants have shown no difference in clinical outcomes and survivorship. Newer studies from the past decade have begun highlighting the economic advantages of APT implant, especially in patients undergoing primary, uncomplicated TKA. Use of APT implants in younger patients and those with a body mass index > 35 has not been extensively studied, but the existing literature suggests the use of APT implant in these cohorts to be equally as acceptable. With modern implant design and instrumentation, rising utilization of TKA along with current and future economic strain on health care, the increased use of APT implant could result in massive savings without sacrificing positive patient outcomes., Competing Interests: Dr. Friedman reports grants and personal fees from Exactech, outside the submitted work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Sarcopenia and exercise intolerance are major contributors to reduced quality of life in the elderly for which there are few effective treatments. We tested whether enhancing mitochondrial function and reducing mitochondrial oxidant production with SS-31 (elamipretide) could restore redox balance and improve skeletal muscle function in aged mice. Young (5 mo) and aged (26 mo) female C57BL/6Nia mice were treated for 8-weeks with 3 mg/kg/day SS-31. Mitochondrial function was assessed in vivo using 31 P and optical spectroscopy. SS-31 reversed age-related decline in maximum mitochondrial ATP production (ATPmax) and coupling of oxidative phosphorylation (P/O). Despite the increased in vivo mitochondrial capacity, mitochondrial protein expression was either unchanged or reduced in the treated aged mice and respiration in permeabilized gastrocnemius (GAS) fibers was not different between the aged and aged+SS-31 mice. Treatment with SS-31 also restored redox homeostasis in the aged skeletal muscle. The glutathione redox status was more reduced and thiol redox proteomics indicated a robust reversal of cysteine S-glutathionylation post-translational modifications across the skeletal muscle proteome. The gastrocnemius in the age+SS-31 mice was more fatigue resistant with significantly greater mass compared to aged controls. This contributed to a significant increase in treadmill endurance compared to both pretreatment and untreated control values. These results demonstrate that the shift of redox homeostasis due to mitochondrial oxidant production in aged muscle is a key factor in energetic defects and exercise intolerance. Treatment with SS-31 restores redox homeostasis, improves mitochondrial quality, and increases exercise tolerance without an increase in mitochondrial content. Since elamipretide is currently in clinical trials these results indicate it may have direct translational value for improving exercise tolerance and quality of life in the elderly., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Here we report a vertically integrated in vitro - in silico study that aims to elucidate the molecular initiating events involved in the induction of oxidative stress (OS) by seven diverse chemicals (cumene hydroperoxide, t-butyl hydroperoxide, hydroquinone, t-butyl hydroquinone, bisphenol A, Dinoseb, and perfluorooctanoic acid). To that end, we probe the relationship between chemical properties, cell viability, glutathione (GSH) depletion, and antioxidant gene expression. Concentration-dependent effects on cell viability were assessed by MTT assay in two Hepa-1 derived mouse liver cell lines: a control plasmid vector transfected cell line (Hepa-V), and a cell line with increased glutamate-cysteine ligase (GCL) activity and GSH content (CR17). Changes to intracellular GSH content and mRNA expression levels for the Nrf2-driven antioxidant genes Gclc, Gclm, heme oxygenase-1 ( Hmox1), and NADPH quinone oxidoreductase-1 ( Nqo1) were monitored after sublethal exposure to the chemicals. In silico models of covalent and redox reactivity were used to rationalize differences in activity of quinones and peroxides. Our findings show CR17 cells were generally more resistant to chemical toxicity and showed markedly attenuated induction of OS biomarkers; however, differences in viability effects between the two cell lines were not the same for all chemicals. The results highlight the vital role of GSH in protecting against oxidative stress-inducing chemicals as well as the importance of probing molecular initiating events in order to identify chemicals with lower potential to cause oxidative stress.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10 -7 ), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

We report on a study of the ultraviolet (UV)-induced degradation on optical grade polytetrafluoroethylene (PTFE) and ceramic diffuser samples. Long-term UV exposure may significantly alter the reflectance and lead to an error in the calibration of optical instruments. A large integrating sphere was used to irradiate the samples for 334.7 days at an irradiance level of 194.9   W / m 2 . Samples were qualified and measured for reflectance factor, bidirectional reflectance distribution function, and fluorescence, before and after the exposure, and at 12-week intervals during the exposure. This study revealed significant differences between the aging behavior of ceramic and PTFE samples.

Background: The UNC5C rs3846455G allele has been linked to poor cognitive resilience against age-related neuropathologies, but this association remains to be replicated, and the allele's effect on hippocampal neurodegeneration needs to be examined., Objective: To further validate the association between rs3846455G and faster cognitive decline, especially among cognitively normal older adults, and to assess whether rs3846455G predicts accelerated hippocampal volume loss in older adults., Methods: We assessed participants in the Harvard Aging Brain Study (HABS), a longitudinal cohort study of older adults who were clinically normal at baseline. To avoid bias from population admixture, analyses were limited to participants of European descent with longitudinal neuroimaging data (n = 174). Linear mixed effect models were used to examine the effect of rs3846455G on longitudinal change of the Preclinical Alzheimer Cognitive Composite (PACC) and MRI-measured bilateral hippocampal volume, adjusting for baseline amyloid-β (Aβ) measured by the cortical Pittsburgh Compound B PET distributed volume ratio. We also tested whether hippocampal atrophy mediates the association between rs3846455G and greater PACC decline through a mediation analysis., Results: rs3846455G was associated with greater PACC decline (β= -0.087/year, 95% CI -0.169 to -0.005, p = 0.039) after controlling for baseline Aβ. Further, rs3846455G predicted accelerated hippocampal atrophy after controlling for baseline Aβ (β= -57.3 mm3/year, 95% CI -102.8 to -11.9, p = 0.014). The association between rs3846455G and greater PACC decline was partially mediated by accelerated hippocampal atrophy (mediated effect (relative scale) = -0.014, 95% CI -0.032 to -6.0×10-4, p = 0.039)., Conclusion: UNC5C rs3846455G predicts greater cognitive decline and accelerated hippocampal atrophy in clinically normal older adults.

Counseling professionals and graduate students (N = 117) recruited online read a randomly assigned one-paragraph vignette about either a nonrational or rational suicide involving an imaginary loved one. Then, they completed the Grief Experiences Questionnaire (GEQ) about how they would feel. The nonrational suicide group expected significantly more search for explanation than the rational suicide group but was not significantly different on the other six GEQ subscales. All participants expected few distressing reactions to either vignette, suggesting a one-paragraph vignette may not be sufficient to induce the kind of grief many experience when a loved one dies by suicide.

Social networks are conduits of support, information, and health behavior flows. Existing measures of social networks used in clinical research are typically summative scales of social support or artificially truncated networks of ≤ 5 people. Here, we introduce a quantitative social network assessment tool on a secure open-source web platform, readily deployable in large-scale clinical studies. The tool maps an individual's personal network, including specific persons, their relationships to each other, and their health habits. To demonstrate utility, we used the tool to measure the social networks of 1493 persons at risk of multiple sclerosis. We examined each person's social network in relation to self-reported neurological disability. We found that the characteristics of persons surrounding the participant, such as negative health behaviors, were strongly associated with the individual's functional disability. This quantitative assessment reveals the key elements of individuals' social environments that could be targeted in clinical trials.

Background: Transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy in older adults frequently coexists with Alzheimer's disease pathology and hippocampal sclerosis. It is unclear whether there is a link between APOE ε4 and TDP-43 proteinopathy, and the role of APOE ε4 in the association of TDP-43 proteinopathy with hippocampal sclerosis remains to be examined. We investigated the relationships of TDP-43 proteinopathy and hippocampal sclerosis with APOE ε4., Methods: We used data from two community-based cohort studies of ageing and dementia: the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). A battery of cognitive tests examining multiple cognitive domains is given to ROS-MAP participants each year, and a measure of annual global cognitive function for each participant is derived by averaging Z scores of these tests. The final clinical diagnosis is assigned after death by a neurologist using all available clinical data without access to post-mortem pathology. Amyloid-β, paired helical filament tau, Lewy bodies, TDP-43, and hippocampal sclerosis were microscopically evaluated in the midbrain, medial temporal, and neocortical regions that capture the progression of each neuropathology. TDP-43 proteinopathy topographic stage was recorded as an ordinal variable, and TDP-43 burden was defined by averaging a semi-quantitative six-point scale across six brain regions. The relationships among APOE ε4, TDP-43 proteinopathy, and hippocampal sclerosis were tested with regression models controlled for sex and age at death, and they were further explored with a mediation analysis using the quasi-Bayesian Monte Carlo method., Findings: ROS began data collection in 1994, and MAP began data collection in 1997. The data included in this study were analysed from Jan 16, 2017, to July 12, 2017. When analysis began in January, 2017, a total of 1059 ROS-MAP participants who were deceased had APOE genotype and complete pathological measures for amyloid-β, paired helical filament tau, and TDP-43 proteinopathy stage. After excluding 15 participants with other pathological diagnoses, 1044 participants, 1042 of whom also had measures of Lewy body pathology, were included in this study (470 from ROS and 574 from MAP). APOE ε4 count was associated with higher TDP-43 proteinopathy stage (odds ratio [OR] 2·0, 95% CI 1·6-2·6; p=1·9 × 10 -9 ) and TDP-43 burden (0·40, 0·28-0·52; p=1·2 × 10 -10 ). Amyloid-β, paired helical filament tau, or Lewy body pathology did not fully explain this association. APOE ε4 increased the odds of hippocampal sclerosis (OR 2·1, 95% CI 1·4-3·0; p=1·7 × 10 -4 ); this effect was largely mediated by TDP-43 burden (mediated effect p<1·0 × 10 -4 ) but not directly by APOE ε4 (direct effect p=0·40). APOE ε4 was associated with worse global cognition proximate to death even after adjusting for amyloid-β and paired helical filament tau (estimated effect -0·18, 95% CI -0·31 to -0·04; p=0·010), but this association was attenuated by additionally adjusting for TDP-43 burden (-0·09, -0·22 to 0·04; p=0·18)., Interpretation: APOE ε4 seems to increase TDP-43 burden, and this effect in turn was associated with higher odds of hippocampal sclerosis, a pathology potentially downstream of TDP-43 proteinopathy. TDP-43 proteinopathy contributes to the detrimental effect of APOE ε4 on late-life cognition through mechanisms independent of Alzheimer's disease pathology, and future research should consider that TDP-43 proteinopathy might be an integral component of APOE-related neurodegeneration., Funding: US National Institute on Aging and Alzheimer's Association., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

We initiated the systematic profiling of the dorsolateral prefrontal cortex obtained from a subset of autopsied individuals enrolled in the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP), which are jointly designed prospective studies of aging and dementia with detailed, longitudinal cognitive phenotyping during life and a quantitative, structured neuropathologic examination after death. They include over 3,322 subjects. Here, we outline the first generation of data including genome-wide genotypes (n=2,090), whole genome sequencing (n=1,179), DNA methylation (n=740), chromatin immunoprecipitation with sequencing using an anti-Histone 3 Lysine 9 acetylation (H3K9Ac) antibody (n=712), RNA sequencing (n=638), and miRNA profile (n=702). Generation of other omic data including ATACseq, proteomic and metabolomics profiles is ongoing. Thanks to its prospective design and recruitment of older, non-demented individuals, these data can be repurposed to investigate a large number of syndromic and quantitative neuroscience phenotypes. The many subjects that are cognitively non-impaired at death also offer insights into the biology of the human brain in older non-impaired individuals.

Introduction: Concerns have been raised regarding occupational exposure to engineered nanomaterials (ENMs). Potential impacts on lung function from inhalation exposures are of concern as the lung is a sensitive ENM target in animals. Epidemiological data suggest that occupational exposure to ENMs may impact respiratory and cardiovascular health. Quantum dots (QDs) are ENMs with outstanding semiconductor and fluorescent properties with uses in biomedicine and electronics. QDs are known to induce inflammation and cytotoxicity in rodents and high dose exposures impact lung function 2 weeks after exposure. However, effects of mouse strain and the temporality of QD effects on lung function at more occupationally relevant doses have not been well-established., Objective: We evaluated the impact of QD exposure on respiratory mechanics in C57BL/6J and A/J mice. Previous work found a greater initial inflammatory response to QD exposure in A/J mice compared to C57BL/6J mice. Thus, we hypothesized that A/J mice would be more sensitive to QD-induced effects on lung mechanics., Methods: C57BL/6J and A/J mice were exposed to 6 μg/kg Cd equivalents of amphiphilic polymer-coated Cd/Se core, ZnS shell QDs via oropharyngeal aspiration. Lung mechanics were measured using forced oscillation, and inflammation was characterized by neutrophils and cytokines in bronchoalveolar lavage fluid., Results: Both strains showed signs of QD-induced acute lung inflammation. However, lung mechanics were impacted by QD exposure in A/J mice only., Conclusions: Our findings suggest that susceptibility to QDs and similar ENM-induced changes in lung function may depend at least in part on genetic background.