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MicroCT-based finite element models were used to compute power law relations for uniaxial compressive yield stress versus bone volume fraction for 78 cores of human trabecular bone from five anatomic sites. The leading coefficient of the power law for calcaneus differed from those for most of the other sites (

Recess provides many physical, mental, and social benefits for students; however, the most recent systematic review examining the benefits of recess was conducted over a decade ago. The purpose of this paper was to determine the current benefits of school recess by conducting an updated systematic review of the literature.Multiple databases were systematically examined to find articles fitting the following inclusionary criteria: (a) school recess, (b) all schooling before college, and (c) recess benefits of any kind. Research was limited to literature published between June 2009 and July 2020.Nine studies were included in this review. The majority of studies examined elementary-aged students. Seven studies were conducted in the United States, and 2 studies were conducted internationally. Recess provided school-aged children academic and cognitive benefits, behavioral and emotional benefits, physical benefits, and social benefits.Providing recess for all school levels positively impacts the whole child; there was no literature implicating negative impacts of recess.Schools can improve overall student health and belonging by redesigning and/or implementing daily recess.

Background Eastern equine encephalitis virus is a mosquito-borne alphavirus responsible for unpredictable outbreaks of severe neurologic disease in animals and humans. While most human infections are asymptomatic or clinically nonspecific, a minority of patients develops encephalitic disease, a devastating illness with a mortality rate of ≥30%. No treatments are known to be effective. Eastern equine encephalitis virus infection is rare in the United States, with an annual average nationwide incidence of 7 cases between 2009 and 2018. However, in 2019, 38 cases were confirmed nationwide, including 10 in Michigan. Methods Data from 8 cases identified by a regional network of physicians in southwest Michigan were abstracted from clinical records. Clinical imaging and histopathology were aggregated and reviewed. Results Patients were predominantly older adults (median age, 64 years), and all were male. Results of initial arboviral cerebrospinal fluid serology were frequently negative, and diagnosis was not made until a median of 24.5 days (range, 13–38 days) after presentation, despite prompt lumbar punctures in all patients. Imaging findings were dynamic and heterogeneous, with abnormalities of the thalamus and/or basal ganglia, and prominent pons and midbrain abnormalities were displayed in 1 patient. Six patients died, 1 survived the acute illness with severe neurologic sequelae, and 1 recovered with mild sequelae. A limited postmortem examination revealed diffuse meningoencephalitis, neuronophagia, and focal vascular necrosis. Conclusions Eastern equine encephalitis is a frequently fatal condition whose diagnosis is often delayed, and for which no effective treatments are known. Improved diagnostics are needed to facilitate patient care and encourage the development of treatments.

Supplementary Figures 1-5, Table 1 from DNA Damage Signaling in Hematopoietic Cells: A Role for Mre11 Complex Repair of Topoisomerase Lesions

The Mre11 complex promotes DNA double-strand break repair and regulates DNA damage signaling via activation of the ataxia-telangiectasia mutated (ATM) kinase. The hypermorphic Rad50S allele encodes a variant of Rad50, a member of the Mre11 complex. Cells expressing Rad50S experience constitutive ATM activation, which leads to precipitous apoptotic attrition in hematopoietic cells. In this study, we show that ATM activation by the Rad50S-containing Mre11 complex enhances the proliferation of LSK cells, a population consisting of hematopoietic stem cells and multipotent progenitor cells. In Rad50S/S mice, enhanced LSK proliferation triggers apoptotic attrition. This phenotype is mitigated when Rad50S/S is combined with mutations that alter either LSK cell quiescence (myeloid elf-1–like factor/ELF4–deficient mice) or hematopoietic differentiation (p21- and p27-deficient mice), indicating that the LSK population is a primary target of Rad50S pathology. We show that cells from Rad50S/S mice are hypersensitive to camptothecin, a topoisomerase I inhibitor that causes DNA damage primarily during DNA replication. On this basis, we propose that apoptotic attrition of Rad50S/S hematopoietic cells results from enhanced proliferation in the context of topoisomerase-associated DNA damage. Impairment of apoptosis in Rad50S/S mice promotes hematopoietic malignancy, suggesting that primitive hematopoietic cells serve as a reservoir of potentially oncogenic lesions in Rad50S/S mice. These data provide compelling evidence that the Mre11 complex plays a role in the metabolism of topoisomerase lesions in mammals, and further suggest that such lesions can accumulate in primitive hematopoietic cells and confer significant oncogenic potential. [Cancer Res 2008;68(7):2186–93]

Introduction Prehospital identification of large vessel occlusion (LVO) ischemic stroke using stroke scoring tools based upon physical exam findings is highly user‐dependent and associated with poor specificity. Measurement of the “headpulse” by cranial accelerometry has been previously shown to reliably identify LVO in a hospitalized group of suspected stroke patients, but the utility of this technology in the prehospital environment remains unclear. The EPISODE‐PS‐COVID study was designed to evaluate the use of a novel triaxial cranial accelerometry device (Harmony, MindRhythm, Inc.) for predicting LVO using prehospital data. Methods Paramedics from multiple emergency medical services (EMS) agencies were trained in placement of the Harmony device. Patients suspected of LVO stroke by EMS personnel received placement of the non‐invasive headband device in the field, and prehospital data were collected over a 3‐minute period prior to hospital arrival. Headpulse data were then compared to clinical data collected during a subsequent emergency department (ED) and hospital visit, including results of brain computed tomography angiogram (CTA) as the gold standard for LVO diagnosis. Patients were consented for inclusion in the study after hospital arrival, utilizing a delayed consent model, as approved by the local institutional review board (IRB). Los Angeles Motor Scale (LAMS) scores were also calculated by prehospital providers for comparison with headpulse measurements. Results A total of 377 enrollments were made at six participating hospitals over a period of 18 months (April 2021 – September 2022), including 92 subjects with recordings free of technical recording errors who were able to provide informed consent for use of their data. Nine (9.8%) subjects were confirmed to have LVO by subsequent CTA, while 15 (16.3%) were diagnosed with non‐LVO ischemic stroke, seven (7.6%) with intracranial hemorrhage, and 61 (66.3%) with stroke mimics. The Harmony device algorithm correctly identified seven of nine LVO strokes, resulting in 78% sensitivity, as well as 82 of 83 non‐LVO diagnoses (99% specificity, p Conclusions Data from this pilot study suggest that the Harmony device has a sensitivity and specificity that may be non‐inferior to the LAMS score when tested in an undifferentiated population of suspected stroke patients. Although the sample size is underpowered to test for superiority, enrollment in the trial is ongoing. A blinded, pivotal trial will begin soon. The use of a non‐invasive device to detect LVO has substantial implications for prehospital LVO stroke management, including the potential for improved triage and improved outcomes for patients with LVO stroke, without delaying care for non‐LVO stroke patients.

Introduction Traditionally, larger lesions of laryngeal verrucous carcinoma are treated with surgical excision, with definitive radiotherapy generally reserved for smaller lesions. However, data utilizing modern databases is limited. Objective The authors sought to assess, utilizing the National Cancer Database, whether overall survival for patients with laryngeal verrucous carcinoma was equivalent when treated with definitive radiotherapy versus definitive surgery. Methods A retrospective cohort study was conducted utilizing the National Cancer Database. All cases of laryngeal verrucous carcinoma within the National Cancer Database between 2006 and 2014 were reviewed. Patients with T1–T3 (American Joint Commission on Cancer 7th Edition) laryngeal verrucous carcinoma were included and stratified by treatment modality. Demographics, treatment, and survival data were analyzed. Results A total of 392 patients were included. Two hundred and fifty patients underwent surgery and 142 received radiotherapy. The two groups differed in age, transition of care, clinical T stage, and clinical stages. There was no significant difference in survival between T1–T3 lesions treated with surgery or radiotherapy (p = 0.32). Age, comorbidities, insurance status, and clinical T stage impacted overall hazard on multivariate analysis (p Conclusion Overall survival is equivalent for patients with clinical T1 and clinical T2 laryngeal verrucous carcinoma treated with primary radiotherapy versus primary surgery. Thus, radiotherapy should be considered as a non-inferior treatment modality for certain patients with laryngeal verrucous carcinoma.

Heterocyclic nonacetamide ligands are used as positron emission tomography (PET) imaging agents of the synaptic vesicle glycoprotein 2A (SV2A), with potential applications in the diagnosis of various neuropsychiatric diseases. To date, the main synthetic strategy to access these optically active compounds has involved the racemic synthesis of a late-stage intermediate followed by the separation of the enantiomers. Here, we describe the use of iminium organocatalysis for the asymmetric synthesis of SynVesT-1, an important PET imaging agent of SV2A. The key step involved the conjugate addition of nitromethane with a cinnamaldehyde in the presence of the Jørgensen–Hayashi catalyst using the Merck dual acid cocatalyst system. Pinnick-type oxidation and esterification of the adduct was then followed by chemoselective nitro group reduction and cyclization using nickel borate. N-Alkylation of the resulting lactam then completed the seven-step synthesis of SynVesT-1. This approach was amenable for the synthesis of an organotin analogue, which following copper(II)-mediated fluoro-destannylation allowed rapid access to [18F]SynVesT-1.

Purpose To provide a comprehensive assessment of the novel 18 kDa translocator protein (TSPO) radiotracer, [18F]LW223, kinetics in the heart and brain when using a simplified imaging approach. Methods Naive adult rats and rats with surgically induced permanent coronary artery ligation received a bolus intravenous injection of [18F]LW223 followed by 120 min PET scanning with arterial blood sampling throughout. Kinetic modelling of PET data was applied to estimated rate constants, total volume of distribution (VT) and binding potential transfer corrected (BPTC) using arterial or image-derived input function (IDIF). Quantitative bias of simplified protocols using IDIF versus arterial input function (AIF) and stability of kinetic parameters for PET imaging data of different length (40–120 min) were estimated. Results PET outcome measures estimated using IDIF significantly correlated with those derived with invasive AIF, albeit with an inherent systematic bias. Truncation of the dynamic PET scan duration to less than 100 min reduced the stability of the kinetic modelling outputs. Quantification of [18F]LW223 uptake kinetics in the brain and heart required the use of different outcome measures, with BPTC more stable in the heart and VT more stable in the brain. Conclusion Modelling of [18F]LW223 PET showed the use of simplified IDIF is acceptable in the rat and the minimum scan duration for quantification of TSPO expression in rats using kinetic modelling with this radiotracer is 100 min. Carefully assessing kinetic outcome measures when conducting a systems level as oppose to single-organ centric analyses is crucial. This should be taken into account when assessing the emerging role of the TSPO heart-brain axis in the field of PET imaging.

Background Lithium is a first-line pharmacotherapy for the treatment of bipolar disorder, but long-term use is associated with nephrotoxicity. However, as dialysis effectively eliminates lithium, it remains a pharmacotherapeutic option for patients on dialysis. This systematic review seeks to evaluate the dosing, safety, efficacy, and monitoring of lithium in patients receiving dialysis. Method A PubMed database search performed May 5th, 2020, identified 535 article titles. After exclusion criteria were applied, a total of 15 articles were included in this systematic review. Results In 18 patients receiving dialysis, lithium was primarily used for the treatment of mood disorders. The majority of patients received 300–900 mg lithium carbonate thrice-weekly following dialysis, but several alternative lithium salts and dosing strategies were utilized. The pharmacokinetic properties of lithium in dialysis are not well understood and can be complicated by a serum lithium “rebound effect” following dialysis, due to a two-compartment volume of distribution. Additionally, presence of residual diuresis in some patients may be reason to administer lithium more frequently than thrice-weekly following dialysis. Lithium was shown to be an effective pharmacotherapy in all patients, with many demonstrating rapid improvement after drug initiation. Five patients experienced an adverse event on lithium, but only one patient required lithium discontinuation. Conclusion Lithium may be used in patients on dialysis, with close monitoring of pre-dialysis serum lithium concentrations for at least two weeks after treatment initiation, followed by a lower frequency after stabilization to ensure therapeutic concentrations and reduce toxicity risk.

We reviewed advances over the past 3 years in assessment of fracture risk based on CT scans, considering methods that use finite element models, machine learning, or a combination of both.Several studies have demonstrated that CT-based assessment of fracture risk, using finite element modeling or biomarkers derived from machine learning, is equivalent to currently used clinical tools. Phantomless calibration of CT scans for bone mineral density enables accurate measurements from routinely taken scans. This opportunistic use of CT scans for fracture risk assessment is facilitated by high-quality automated segmentation with deep learning, enabling workflows that do not require user intervention. Modeling of more realistic and diverse loading conditions, as well as improved modeling of fracture mechanisms, has shown promise to enhance our understanding of fracture processes and improve the assessment of fracture risk beyond the performance of current clinical tools. CT-based screening for fracture risk is effective and, by analyzing scans that were taken for other indications, could be used to expand the pool of people screened, therefore improving fracture prevention. Finite element modeling and machine learning both provide valuable tools for fracture risk assessment. Future approaches should focus on including more loading-related aspects of fracture risk.

The positron emission tomography imaging agents cis- and trans-4-[18F]fluoro-l-proline are used for the detection of numerous diseases such as pulmonary fibrosis and various carcinomas. These imaging agents are typically prepared by nucleophilic fluorination of 4-hydroxy-l-proline derivatives, with [18F]fluoride, followed by deprotection. Although effective radiofluorination reactions have been developed, the overall radiosynthesis process is suboptimal due to deprotection methods that are performed manually, require multiple steps, or involve harsh conditions. Here we describe the development of two synthetic routes that allow access to precursors, which undergo highly selective radiofluorination reactions and rapid deprotection, under mild acidic conditions. These methods were found to be compatible with automation, avoiding manual handling of radioactive intermediates.

Osteoporosis, characterized by low bone mineral density (BMD), is the most common complex disease affecting bone and constitutes a major societal health problem. Genome-wide association studies (GWASs) have identified over 1100 associations influencing BMD. It has been shown that perturbations to long noncoding RNAs (lncRNAs) influence BMD and the activities of bone cells; however, the extent to which lncRNAs are involved in the genetic regulation of BMD is unknown. Here, we combined the analysis of allelic imbalance (AI) in human acetabular bone fragments with a transcriptome-wide association study (TWAS) and expression quantitative trait loci (eQTL) colocalization analysis using data from the Genotype-Tissue Expression (GTEx) project to identify lncRNAs potentially responsible for GWAS associations. We identified 27 lncRNAs in bone that are located in proximity to a BMD GWAS association and harbor single-nucleotide polymorphisms (SNPs) demonstrating AI. Using GTEx data we identified an additional 31 lncRNAs whose expression was associated (false discovery rate [FDR] correction 0.05) with BMD through TWAS and had a colocalizing eQTL (regional colocalization probability [RCP] 0.1). The 58 lncRNAs are located in 43 BMD associations. To further support a causal role for the identified lncRNAs, we show that 23 of the 58 lncRNAs are differentially expressed as a function of osteoblast differentiation. Our approach identifies lncRNAs that are potentially responsible for BMD GWAS associations and suggest that lncRNAs play a role in the genetics of osteoporosis. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Purpose To determine the potential effectiveness of a novel 10-week manualised Practical Body Image therapy (PBI) with mirror exposure (ME), when used as an adjuvant to an intensive treatment package (TAU) in adolescent inpatients with Anorexia Nervosa (AN). To evaluate the effectiveness of ME in an adolescent population. Methods Using a randomised control design, 40 girls aged 11–17 years with AN were assigned to PBI with TAU (n = 20) and TAU alone (n = 20). Both groups completed self-report measures of body image at week 1 and week 10 of the study to measure the potential effectiveness of PBI. The PBI group completed measures at week 7 to evaluate the ME component. Results 31 participants completed the study; 16 TAU, 15 PBI. PBI participants had greater improvement in all outcomes than TAU participants. Medium effect sizes were seen for self-reported weight concern, body image avoidance in terms of clothing and body image anxiety. ME produced effect sizes in self-reported body image avoidance in terms of clothing and grooming that were greater than 0.40, n = 14. Conclusion The findings demonstrate that PBI supports an intensive inpatient treatment package and addresses elements of negative body image. PBI was beneficial for addressing body image dissatisfaction with improvements in weight concerns, body image avoidance and physical appearance trait anxiety following the ME component. The magnitude of the effect sizes is comparable to previous studies. Positive qualitative feedback indicated the intervention was acceptable to users. PBI is a promising new adjuvant treatment for AN. EMB Rating Level I: randomized controlled trial.

Visual Abstract, Myocardial infarction (MI) is one of the leading causes of death worldwide, and inflammation is central to tissue response and patient outcomes. The 18-kDa translocator protein (TSPO) has been used in PET as an inflammatory biomarker. The aims of this study were to screen novel, fluorinated, TSPO radiotracers for susceptibility to the rs6971 genetic polymorphism using in vitro competition binding assays in human brain and heart; assess whether the in vivo characteristics of our lead radiotracer, 18F-LW223, are suitable for clinical translation; and validate whether 18F-LW223 can detect macrophage-driven inflammation in a rat MI model. Methods: Fifty-one human brain and 29 human heart tissue samples were screened for the rs6971 polymorphism. Competition binding assays were conducted with 3H-PK11195 and the following ligands: PK11195, PBR28, and our novel compounds (AB5186 and LW223). Naïve rats and mice were used for in vivo PET kinetic studies, radiometabolite studies, and dosimetry experiments. Rats underwent permanent coronary artery ligation and were scanned using PET/CT with an invasive input function at 7 d after MI. For quantification of PET signal in the hypoperfused myocardium, K1 (rate constant for transfer from arterial plasma to tissues) was used as a surrogate marker of perfusion to correct the binding potential for impaired radiotracer transfer from plasma to tissue (BPTC). Results: LW223 binding to TSPO was not susceptible to the rs6971 genetic polymorphism in human brain and heart samples. In rodents, 18F-LW223 displayed a specific uptake consistent with TSPO expression, a slow metabolism in blood (69% of parent at 120 min), a high plasma free fraction of 38.5%, and a suitable dosimetry profile (effective dose of 20.5–24.5 μSv/MBq). 18F-LW223 BPTC was significantly higher in the MI cohort within the infarct territory of the anterior wall relative to the anterior wall of naïve animals (32.7 ± 5.0 vs. 10.0 ± 2.4 cm3/mL/min, P ≤ 0.001). Ex vivo immunofluorescent staining for TSPO and CD68 (macrophage marker) resulted in the same pattern seen with in vivo BPTC analysis. Conclusion: 18F-LW223 is not susceptible to the rs6971 genetic polymorphism in in vitro assays, has favorable in vivo characteristics, and is able to accurately map macrophage-driven inflammation after MI.

We thank Jack Suess and Damian Doyle (UMBC Division of Information Technology)for their enthusiastic cooperation. Thanks to Richard Baldwin and Travis Scheponik for helpful comments. This project was supported in part by the National Science Foundation under SFS grants 1241576 and 1753681. Sherman was also supported by the National Science Foundation under SFS capacity grant 1819521 and by the U.S. Department of Defense under CAE-R grant H98230-17-1-0349 and CySP grants H98230-17-1-0387 and H98230-18-0321.

Background: The exact relationship between the different TCF7L2 gene polymorphisms and the development of diabetic nephropathy (DN) remains unclear. Objective: To investigate the association of TCF7L2 rs12255372 (G/T) gene polymorphism and diabetic nephropathy (DN) in patients with type 2 diabetes (T2D). Methods: 100 patients with T2D (50 patients without DN and 50 patients with DN) and 50 age and sex-matched healthy controls (HC) were enrolled in the study. Genotyping for the rs12255372 (G>T) polymorphism in the TCF7L2 gene was performed by real-time PCR. Results: The rs12255372 polymorphism showed a statistically significant difference between HC and patients with and without DN in both the genotype and allele frequency. However, the rs12255372 polymorphism genotype or allele frequency was not statistically different between patients with DN and those patients without DN. The G allele was found to be higher in patients and the T allele was higher in HC suggesting that the G allele was the risk allele for developing T2D &DN and that the T allele was protective. Conclusion: rs12255372 TCF7L2 gene polymorphism was strongly associated with type 2 diabetes mellitus and DN. The association between rs12255372 polymorphism and DN was a mere reflection of a complicated diabetes mellitus rather than a direct independent association.

The spatial heterogeneity in trabecular bone density within the vertebral centrum is associated with vertebral strength and could explain why volumetric bone mineral density (vBMD) exhibits low sensitivity in identifying fracture risk. This study evaluated whether the heterogeneity and spatial distribution of trabecular vBMD are associated with prevalent vertebral fracture. We examined the volumetric quantitative computed tomography (QCT) scans of the L3 vertebra in 148 participants in the Framingham Heart Study Multidetector CT study. Of these individuals, 37 were identified as cases of prevalent fracture, and 111 were controls, matched on sex and age with three controls per case. vBMD was calculated within 5-mm contiguous cubic regions of the centrum. Two measures of heterogeneity were calculated: (i) interquartile range (IQR); and (ii) quartile coefficient of variation (QCV). Ratios in the spatial distributions of the trabecular vBMD were also calculated: anterior/posterior, central/outer, superior/mid-transverse, and inferior/mid-transverse. Heterogeneity and spatial distributions were compared between cases and controls using Wilcoxon rank sum tests and t tests and tested for association with prevalent fractures with conditional logistic regressions independent of integral vBMD. Prevalent fracture cases had lower mean ± SD integral vBMD (134 ± 38 versus165 ± 42 mg/cm3 , p < .001), higher QCV (0.22 ± 0.13 versus 0.17 ± 0.09, p = .003), and lower anterior/posterior rBMD (0.65 ± 0.13 versus 0.78 ± 0.16, p < .001) than controls. QCV was positively associated with increased odds of prevalent fracture (OR 1.61; 95% CI, 1.04 to 2.49; p = .034), but this association was not independent of integral vBMD (p = .598). Increased anterior/posterior trabecular vBMD ratio was associated with decreased odds of prevalent fracture independent of integral vBMD (OR 0.38; 95% CI, 0.20 to 0.71; p = .003). In conclusion, increased trabecular vBMD in the anterior versus posterior centrum, but not trabecular vBMD heterogeneity, was associated with decreased risk of prevalent fracture independent of integral vBMD. Regional measurements of trabecular vBMD could aid in determining the risk and underlying mechanisms of vertebral fracture. © 2019 American Society for Bone and Mineral Research.

Circulichnis is a well-known ichnogenus demonstrating broad stratigraphic and geographic distribution with known habitats spanning from deep-marine to terrestrial environments. Although commonly small in size, a recent discovery in Central Texas demonstrates a much larger early member of this ichnogenus. Compared to previous identifications of Circulichnis, the findings presented herein express a larger trace string width exceeding the average for this ichnogenus. This expansion in morphometric parameters emphasizes the importance of overall dimensions in ichnospecies descriptions in concert with descriptive taxonomy.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele. © 2022. The Author(s).

Instrumented vehicles record driver behavior and performance as it occurs in the real world. Driving simulators also capture performance, but in conditions meant to approximate the real world. It is unclear the extent to which simulators elicit performance that is comparable to the real world. This study compared driving performance measures that were collected behind the wheel (BTW) of a truck in the real world and from a truck-driving simulator. Both the road and simulator trucks were instrumented with the same data collection equipment and recorded the same driving performance measures. Comparison of overall scores on the road and range tests by test method (BTW and simulator) found test scores differed as a function of test method for drivers trained in a real truck, and in range tests for drivers trained in the simulator. Non-parametric tests indicated the mean rate of lane departures was significantly different between BTW and simulator road tests (p = 0.01); the lane departure rate per minute was 250% greater in the simulator than on the actual road (0.48 vs. 0.19, respectively). Significant differences in scores and measures between BTW and simulator testing indicates that simulation may not be an appropriate platform for testing on-road performance.

Time is a central element of the sexual dimorphic patterns of development, pathology, and aging of the skeleton. Because the transcriptome is a representation of the phenome, we hypothesized that both sex and sex-specific temporal, transcriptomic differences in bone tissues over an 18-month period would be informative to the underlying molecular processes that lead to postnatal sexual dimorphism. Regardless of age, sex-associated changes of the whole bone transcriptomes were primarily associated not only with bone but also vascular and connective tissue ontologies. A pattern-based approach used to screen the entire Gene Expression Omnibus (GEO) database against those that were sex-specific in bone identified two coordinately regulated gene sets: one related to high phosphate-induced aortic calcification and one induced by mechanical stimulation in bone. Temporal clustering of the transcriptome identified two skeletal tissue-associated, sex-specific patterns of gene expression. One set of genes, associated with skeletal patterning and morphology, showed peak expression earlier in females. The second set of genes, associated with coupled remodeling, had quantitatively higher expression in females and exhibited a broad peak between 3 to 12 months, concurrent with the animals' reproductive period. Results of phenome-level structural assessments of the tibia and vertebrae, and in vivo and in vitro analysis of cells having osteogenic potential, were consistent with the existence of functionally unique, skeletogenic cell populations that are separately responsible for appositional growth and intramedullary functions. These data suggest that skeletal sexual dimorphism arises through sex-specific, temporally different processes controlling morphometric growth and later coupled remodeling of the skeleton during the reproductive period of the animal. © 2021 The Authors.

As a precursor to type 2 diabetes mellitus (T2D), obesity adversely alters bone cell functions, causing decreased bone quality. Currently, the mechanisms leading to alterations in bone quality in obesity and subsequently T2D are largely unclear. Emerging evidence suggests that long noncoding RNAs (lncRNAs) participate in a vast repertoire of biological processes and play essential roles in gene expression and posttranscriptional processes. Mechanistically, the expression of lncRNAs is implicated in pathogenesis surrounding the aggregation or alleviation of human diseases. To investigate the functional link between specific lncRNA and obesity-associated poor bone quality and elucidate the molecular mechanisms underlying the interaction between the two, we first assessed the structure of the bones in a diet-induced obese (DIO) mouse model. We found that bone microarchitecture markedly deteriorated in the DIO mice, mainly because of aberrant remodeling in the bone structure. The results of in vitro mechanistic experiments supported these observations. We then screened mRNAs and lncRNAs from DIO bones and functionally identified a specific lncRNA, Gm15222. Further analyses demonstrated that Gm15222 promotes osteogenesis and inhibits the expression of adipogenesis-related genes in DIO via recruitment of lysine demethylases KDM6B and KDM4B, respectively. Through this epigenetic pathway, Gm15222 modulates histone methylation of osteogenic genes. In addition, Gm15222 showed a positive correlation with the expression of a neighboring gene, BMP4. Together, the results of this study identified and provided initial characterization of Gm15222 as a critical epigenetic modifier that regulates osteogenesis and has potential roles in targeting the pathophysiology of bone disease in obesity and potential T2D.

Global warming and rising energy demands have increased renewable energy (RE) usage globally. Wind energy has become the most technologically advanced renewable energy source. Wind turbines (WTs) must ride through faults to ensure power system stability. On the flip side, permanent magnet synchronous generators (PMSG)-based wind turbine power plants (WTPPs) are susceptible to grid voltage fluctuations and require extra regulations to maintain regular operations. Due to recent changes in grid code standards, it has become vital to explore alternate fault ride-through (FRT) methods to ensure their capabilities. This research will ensure that FRT solutions available via the Web of Science (WoS) database are vetted and compared in hardware retrofitting, internal software control changes, and hybrid techniques. In addition, a bibliometric analysis is provided, which reveals an ever-increasing volume of works dedicated to the topic. After that, a literature study of FRT techniques for PMSG WTs is carried out, demonstrating the evolution of these techniques over time. This paper concludes that additional research is required to enhance FRT capabilities in PMSG wind turbines and that further attention to topics, such as machine learning tools and the combination of FRT and wind power smoothing approaches, should arise in the following years.

ObjectivesThis systematic review addresses the question “Is any job better than no job?” Specifically, it compares health and well-being outcomes in those who are unemployed with those who are in jobs that could be considered poor or low quality and the impact of any movement between them.MethodWe conducted a systematic review following a PROSPERO-registered protocol (CRD42020182794). Medline, Embase, PsycINFO, HMIC, ASSIA, TRIP, Google Scholar and 10 websites were searched in April 2020 and again in May 2021 without date limits. Two reviewers working independently screened search results against the inclusion/exclusion criteria. A checklist for quantitative studies reporting correlations was used to critically appraise articles included at full text. We undertook synthesis without meta-analysis (narrative synthesis) and explored a range of variables (for example, study design and quality, type of outcome measure) that we considered might have an impact on the association between exposure and outcome.ResultsWe included 25 studies reported in 30 journal articles. All 25 studies involved secondary analysis of data from national cohorts, including six from the UK. The most frequent outcomes reported were measures of mental well-being. There was considerable heterogeneity across included studies in terms of design, population, definition of poor/bad or low quality job and outcome types and measures. Overall the quality of the included studies was moderate. The evidence base is inconsistent. There are studies that suggested either labour market position might be preferable, but a number of studies found no statistically significant difference. Cohort and case- control studies looking at mental well-being outcomes showed some support for a poor job being better than unemployment. However, we did not find sufficient numbers of well-designed studies showing a strong association to support a causal relationship. Most included study designs were unable to distinguish whether changes in employment status occurred before a change in outcome. Three studies looking at employment transitions found that moving to a poor job from unemployment was not associated with improved mental health, but moving from a poor job to unemployment was associated with a deterioration.ConclusionEvidence that better health and well-being outcomes are more likely to be associated with a poor/bad or low quality job than with unemployment is inconsistent. Studies conducted in the UK suggest that a poor job is not significantly associated with better health and well-being outcomes than unemployment. The studies we identified do not allow us to distinguish whether this lack of association is the result of a state welfare regime preventing some of the worst ills associated with unemployment, or a reflection of job quality. The evidence base has significant limitations in study design and conduct. In summary, the evidence we found suggests it is not safe to assume that, in the UK, any job will lead to better health and well-being outcomes than unemployment.

Osteoporosis, characterized by low bone mineral density (BMD), is the most common complex disease affecting bone and constitutes a major societal health problem. Genome-wide association studies (GWASs) have identified over 1100 associations influencing BMD. It has been shown that perturbations to long non-coding RNAs (lncRNAs) influence BMD and the activities of bone cells; however, the extent to which lncRNAs are involved in the genetic regulation of BMD is unknown. Here, we combined the analysis of allelic imbalance (AI) in human acetabular bone fragments with a transcriptome-wide association study (TWAS) and expression quantitative trait loci (eQTL) colocalization analysis using data from the Genotype-Tissue Expression (GTEx) project to identify lncRNAs potentially responsible for GWAS associations. We identified 27 lncRNAs in bone that are located in proximity to a BMD GWAS association and harbor SNPs demonstrating AI. Using GTEx data we identified an additional 31 lncRNAs whose expression was associated (FDR correction0.1). The 58 lncRNAs are located in 43 BMD associations. To further support a causal role for the identified lncRNAs, we show that 23 of the 58 lncRNAs are differentially expressed as a function of osteoblast differentiation. Our approach identifies lncRNAs that are potentially responsible for BMD GWAS associations and suggest that lncRNAs play a role in the genetics of osteoporosis.

Advancements in additive manufacturing have enabled design and fabrication of materials and structures not previously realizable. In particular, the design space of composite materials and structures has vastly expanded, and the resulting size and complexity has challenged traditional design methodologies, such as brute force exploration and one factor at a time (OFAT) exploration, to find optimum or tailored designs. To address this challenge, supervised machine learning approaches have emerged to model the design space using curated training data; however, the selection of the training data is often determined by the user. In this work, we develop and utilize a Reinforcement learning (RL)-based framework for the design of composite structures which avoids the need for user-selected training data. For a 5 × 5 composite design space comprised of soft and compliant blocks of constituent material, we find that using this approach, the model can be trained using 2.78% of the total design space consists of 225 design possibilities. Additionally, the developed RL-based framework is capable of finding designs at a success rate exceeding 90%. The success of this approach motivates future learning frameworks to utilize RL for the design of composites and other material systems.

Genome-wide association studies (GWASs) for bone mineral density (BMD) have identified over 1,100 associations to date. However, identifying causal genes implicated by such studies has been challenging. Recent advances in the development of transcriptome reference datasets and computational approaches such as transcriptome-wide association studies (TWASs) and expression quantitative trait loci (eQTL) colocalization have proven to be informative in identifying putatively causal genes underlying GWAS associations. Here, we used TWAS/eQTL colocalization in conjunction with transcriptomic data from the Genotype-Tissue Expression (GTEx) project to identify potentially causal genes for the largest BMD GWAS performed to date. Using this approach, we identified 512 genes as significant (Bonferroni PPP6R3, the gene with the strongest support from our analysis which was not previously implicated in the regulation of BMD, for further investigation. We observed that Ppp6r3 deletion in mice decreased BMD. In this work, we provide an updated resource of putatively causal BMD genes and demonstrate that PPP6R3 is a putatively causal BMD GWAS gene. These data increase our understanding of the genetics of BMD and provide further evidence for the utility of combined TWAS/colocalization approaches in untangling the genetics of complex traits.