A novel induced pluripotent stem cell model of schwann cell differentiation reveals NF2 -related gene regulatory networks of the extracellular matrix.

Schwann cells are vital to development and maintenance of the peripheral nervous system and their dysfunction has been implicated in a range of neurological and neoplastic disorders, including NF2 -related schwannomatosis. We have developed a novel human induced pluripotent stem cell (hiPSC) model for the study of Schwann cell differentiation in health and disease. We performed transcriptomic, immunofluorescence, and morphological analysis of hiPSC derived Schwann cell precursors (SPCs) and terminally differentiated Schwann-like cells (SLCs) representing distinct stages of development. To further validate our findings, we performed integrated, cross-species analyses across multiple external datasets at bulk and single cell resolution. Our hiPSC model of Schwann cell development shared overlapping gene expression signatures with human amniotic mesenchymal stem cell (hAMSCs) derived SLCs and in vivo mouse models, but also revealed unique features that may reflect species-specific aspects of Schwann cell biology. Moreover, we have identified gene co-expression modules that are dynamically regulated during hiPSC to SLC differentiation associated with ear and neural development, cell fate determination, the NF2 gene, and extracellular matrix (ECM) organization. By cross-referencing results between multiple datasets and analyses, we have identified potential new genes that are related to NF2 for further study including: ANXA1, CDH6, COL1A1, COL8A1, MFAP5, IGFBP5, FGF1, AHNAK, CDKN2B, LOX, CAV1 , and CAV2 . Our hiPSC model further provides a tractable platform for studying Schwann cell development in the context of human disease.

Ventromedial hypothalamic nucleus subset stimulates tissue thermogenesis via preoptic area outputs.

OBJECTIVE: Hypothalamic signals potently stimulate energy expenditure by engaging peripheral mechanisms to restore energy homeostasis. Previous studies have identified several critical hypothalamic sites (e.g. preoptic area (POA) and ventromedial hypothalamic nucleus (VMN)) that could be part of an interconnected neurocircuit that controls tissue thermogenesis and essential for body weight control. However, the key neurocircuit that can stimulate energy expenditure has not yet been established. METHODS: Here, we investigated the downstream mechanisms by which VMN neurons stimulate adipose tissue thermogenesis. We manipulated subsets of VMN neurons acutely as well as chronically and studied its effect on tissue thermogenesis and body weight control, using Sf1Cre and Adcyap1Cre mice and measured physiological parameters under both high-fat diet and standard chow diet conditions. To determine the node efferent to these VMN neurons, that is involved in modulating energy expenditure, we employed electrophysiology and optogenetics experiments combined with measurements using tissue-implantable temperature microchips. RESULTS: Activation of the VMN neurons that express the steroidogenic factor 1 (Sf1; VMNSf1 neurons) reduced body weight, adiposity and increased energy expenditure in diet-induced obese mice. This function is likely mediated, at least in part, by the release of the pituitary adenylate cyclase-activating polypeptide (PACAP; encoded by the Adcyap1 gene) by the VMN neurons, since we previously demonstrated that PACAP, at the VMN, plays a key role in energy expenditure control. Thus, we then shifted focus to the subpopulation of VMNSf1 neurons that contain the neuropeptide PACAP (VMNPACAP neurons). Since the VMN neurons do not directly project to the peripheral tissues, we traced the location of the VMNPACAP neurons' efferents. We identified that VMNPACAP neurons project to and activate neurons in the caudal regions of the POA whereby these projections stimulate tissue thermogenesis in brown and beige adipose tissue. We demonstrated that selective activation of caudal POA projections from VMNPACAP neurons induces tissue thermogenesis, most potently in negative energy balance and activating these projections lead to some similar, but mostly unique, patterns of gene expression in brown and beige tissue. Finally, we demonstrated that the activation of the VMNPACAP neurons' efferents that lie at the caudal POA are necessary for inducing tissue thermogenesis in brown and beige adipose tissue. CONCLUSIONS: These data indicate that VMNPACAP connections with the caudal POA neurons impact adipose tissue function and are important for induction of tissue thermogenesis. Our data suggests that the VMNPACAP → caudal POA neurocircuit and its components are critical for controlling energy balance by activating energy expenditure and body weight control.

-A machine learning model to predict surgical site infection after surgery of lower extremity fractures.

PURPOSE: This study aimed to develop machine learning algorithms for identifying predictive factors associated with the risk of postoperative surgical site infection in patients with lower extremity fractures. METHODS: A machine learning analysis was conducted on a dataset comprising 1,579 patients who underwent surgical fixation for lower extremity fractures to create a predictive model for risk stratification of postoperative surgical site infection. We evaluated different clinical and demographic variables to train four machine learning models (neural networks, boosted generalised linear model, naïve bayes, and penalised discriminant analysis). Performance was measured by the area under the curve score, Youdon's index and Brier score. A multivariate adaptive regression splines (MARS) was used to optimise predictor selection. RESULTS: The final model consisted of five predictors. (1) Operating room time, (2) ankle region, (3) open injury, (4) body mass index, and (5) age. The best-performing machine learning algorithm demonstrated a promising predictive performance, with an area under the ROC curve, Youdon's index, and Brier score of 77.8%, 62.5%, and 5.1%-5.6%, respectively. CONCLUSION: The proposed predictive model not only assists surgeons in determining high-risk factors for surgical site infections but also empowers patients to closely monitor these factors and take proactive measures to prevent complications. Furthermore, by considering the identified predictors, this model can serve as a reference for implementing preventive measures and reducing postoperative complications, ultimately enhancing patient outcomes. However, further investigations involving larger datasets and external validations are required to confirm the reliability and applicability of our model.

A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma.

By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC+ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma.

Primate conservation: A public issue?

Nonhuman primates (primates) are one of the most endangered mammalian taxa in the world. In the Global North, primates are considered exotic species and, as such, humans' impact on primate conservation and responsibility to protect primates is often ignored. This view differs from the spectrum of relations and attitudes of humans that live in connection to primates, which can include viewing these animals as culturally/religiously significant, cohabitors of forests, nuisances, or sources of protein. While conservationists argue that primates deserve our protection, the conservation crisis facing primates is rarely framed as a public issue, in contrast to other global crises, such as climate change. However, over half of the world's human population lives within 100 km of primate habitat. Thus, humans and primates share the same environments. We suggest leveraging a holistic approach, such as One Health, that considers the interconnectedness of primates, humans, and their shared environments, through the lens of public anthropology. By approaching primate conservation as an intersectional issue that affects and is affected by humans, researchers and conservationists can identify strategies that simultaneously protect primates and address global inequities that frequently affect people in primate range countries. Reflexive research practices further allow academics to consider the broader impact of their ecological research through means such as publicly accessible dissemination of results, equitable capacity-building of high-quality personnel in primate range countries, and social activism. The use of inter-, multi-, and transdisciplinary concepts and methodology can address the intersectional challenges associated with implementing ethical and sustainable primate conservation measures.

Timing of intraoperative neurophysiological monitoring (IONM) recovery and clinical recovery after termination of pediatric spinal deformity surgery due to loss of IONM signals.

BACKGROUND CONTEXT: Intraoperative neurophysiological monitoring (IONM) is used to reduce the risk of spinal cord injury during pediatric spinal deformity surgery. Significant reduction and/or loss of IONM signals without immediate recovery may lead the surgeon to acutely abort the case. The timing of when monitorable signals return remains largely unknown. PURPOSE: The goal of this study was to investigate the correlation between IONM signal loss, clinical examination, and subsequent normalization of IONM signals after aborted pediatric spinal deformity surgery to help determine when it is safe to return to the operating room. STUDY DESIGN/SETTING: This is a multicenter, multidisciplinary, retrospective study of pediatric patients (< 18 years old) undergoing spinal deformity surgery whose surgery was aborted due to a significant reduction or loss of IONM potentials. PATIENT SAMPLE: Sixty-six patients less than 18 years old who underwent spinal deformity surgery that was aborted due to IONM signal loss were enrolled into the study. OUTCOME MEASURES: IONM data, operative reports, and clinical examinations were investigated to determine the relationship between IONM loss, clinical examination, recovery of IONM signals, and clinical outcome. METHODS: Information regarding patient demographics, deformity type, clinical history, neurologic and ambulation status, operative details, IONM information (e.g., quality of loss [SSEPs, MEPs], laterality, any recovery of signals, etc.), intra-operative wake-up test, post-operative neurologic exam, post-operative imaging, and time to return to the operating were all collected. All factors were analyzed and compared with univariate and multivariate analysis using appropriate statistical analysis. RESULTS: Sixty-six patients were enrolled with a median age of 13 years [IQR 11-14], and the most common sex was female (42/66, 63.6%). Most patients had idiopathic scoliosis (33/66, 50%). The most common causes of IONM loss were screw placement (27/66, 40.9%) followed by rod correction (19/66, 28.8%). All patients had either complete bilateral (39/66, 59.0%), partial bilateral (10/66, 15.2%) or unilateral (17/66, 25.8%) MEP loss leading to termination of the case. Overall, when patients were returned to the operating room two weeks postoperatively, nearly 75% (40/55) had monitorable IONM signals. Univariate analysis demonstrated that bilateral SSEP loss (p = 0.019), bilateral SSEP and MEP loss (p = 0.022) and delayed clinical neurologic recovery (p = 0.008) were significantly associated with having unmonitorable IONM signals at repeat surgery. Multivariate regression analysis demonstrated that delayed clinical neurologic recovery (> 72 hours) was significantly associated with unmonitorable IONM signals when returned to the operating room (p=0.006). All patients ultimately made a full neurologic recovery. CONCLUSIONS: In children whose spinal deformity surgery was aborted due to intraoperative IONM loss, there was a strong correlation between combined intraoperative SSEP/MEP loss, the magnitude of IONM loss, the timing of clinical recovery, and the time of electrophysiological IONM recovery. The highest likelihood of having a prolonged postoperative neurological deficit and undetectable IONM signals upon return to the OR occurs with bilateral complete loss of SSEPs and MEPs.

Accelerated epigenetic age is associated with whole-brain functional connectivity and impaired cognitive performance in older adults.

While chronological age is a strong predictor for health-related risk factors, it is an incomplete metric that fails to fully characterize the unique aging process of individuals with different genetic makeup, neurodevelopment, and environmental experiences. Recent advances in epigenomic array technologies have made it possible to generate DNA methylation-based biomarkers of biological aging, which may be useful in predicting a myriad of cognitive abilities and functional brain network organization across older individuals. It is currently unclear which cognitive domains are negatively correlated with epigenetic age above and beyond chronological age, and it is unknown if functional brain organization is an important mechanism for explaining these associations. In this study, individuals with accelerated epigenetic age (i.e. AgeAccelGrim) performed worse on tasks that spanned a wide variety of cognitive faculties including both fluid and crystallized intelligence (N = 103, average age = 68.98 years, 73 females, 30 males). Additionally, fMRI connectome-based predictive models suggested a mediating mechanism of functional connectivity on epigenetic age acceleration-cognition associations primarily in medial temporal lobe and limbic structures. This research highlights the important role of epigenetic aging processes on the development and maintenance of healthy cognitive capacities and function of the aging brain.

Multiscale Modeling of Plutonium Radiation Chemistry in Nitric Acid Solutions. 1. Cobalt-60 Gamma Irradiation of Pu(IV).

Careful manipulation of the plutonium oxidation states is essential in the study and utilization of its rich redox chemistry. To achieve this level of control, a comprehensive mechanistic understanding of radiation-induced plutonium redox chemistry is critical due to the unavoidable exposure of plutonium to ionizing radiation fields, both inherent and from in-process applications. To this end, we have developed an experimentally evaluated multiscale computer model for the prediction of gamma radiation-induced Pu(IV) redox chemistry in concentrated nitric acid solutions (1.0, 3.0, and 6.0 M). Under these acidic, aqueous solution conditions, cobalt-60 gamma irradiation afforded marginal net conversion of Pu(IV) to Pu(VI), the extent of which was dependent on the concentration of HNO3 and absorbed gamma dose. Multiscale calculations, which are in excellent agreement with experimental data, indicate that this observation is due to a combination of inherent plutonium disproportionation reactions and several radiation-induced processes, including redox cycling between Pu(IV) and Pu(III), as achieved by the reduction of Pu(IV) by nitrous acid and hydrogen peroxide, the oxidation of Pu(III) by nitrate and hydroxyl radicals, and the sequential oxidation of Pu(IV) to Pu(V) and Pu(VI) by the remaining available yield of nitrate radicals.

Nationwide Case-Control Analysis of Merkel Cell Carcinoma and Associated Skin Cancer Comorbidities: An Examination of the All of Us Database.

Introduction Merkel cell carcinoma is an aggressive neuroendocrine tumor that is related to immunosuppression and the Merkel cell polyomavirus. It is more common on the head and neck and has been associated with other skin malignancies such as basal cell carcinoma, squamous cell carcinoma, and melanoma. However, there has never been a nationwide investigation that quantifies Merkel cell carcinoma's connection with these subgroups. Methods Utilizing the National Institutes of Health's All of Us open-access database, a retrospective study was conducted by filtering for Merkel cell carcinoma through the International Classification of Diseases, 9th and 10th Clinical Modification codes 209.* and C4A.*, respectively. This led to the inclusion of 41 patients in the study, with each instance compared to four control patients without merkel cell carcinoma, matched by age, race, and gender. The data's demographics and skin cancer co-morbidities were collected and evaluated with odds ratios and 95% confidence intervals using Wald's method. Results In patients with merkel cell carcinoma, a statistically significant gradient of increasing risk for developing basal cell carcinoma (Odds Ratio, 11.63; 95% Confidence Interval, 4.30-31.45; P < 0.0001), squamous cell carcinoma (Odds Ratio, 15.09; 95% Confidence Interval, 3.87-58.84; P = 0.0001), and melanoma (Odds Ratio, 27.94; 95% Confidence Interval, 3.26-239.48; P = 0.0024) was observed. The race/ethnicity demographics showed that 85.4% of the patients were white, and they were at the highest risk of developing merkel cell carcinoma. However, the study has limitations, such as the inability to identify the stage of merkel cell carcinoma among patients and the lack of consideration for other confounding variables. Conclusion The study examines the link between merkel cell carcinoma and other skin malignancies, underscoring the need for more national research to better understand the underlying causes that contribute to this link. The findings also indicate the possibility of sample bias in the All of Us database, emphasizing the need to assess the patient population's representativeness in such investigations.

Improving ecosystem health in highly altered river basins: a generalized framework and its application to the Mississippi-Atchafalaya River Basin.

Continued large-scale public investment in declining ecosystems depends on demonstrations of "success". While the public conception of "success" often focuses on restoration to a pre-disturbance condition, the scientific community is more likely to measure success in terms of improved ecosystem health. Using a combination of literature review, workshops and expert solicitation we propose a generalized framework to improve ecosystem health in highly altered river basins by reducing ecosystem stressors, enhancing ecosystem processes and increasing ecosystem resilience. We illustrate the use of this framework in the Mississippi-Atchafalaya River Basin (MARB) of the central United States (U.S.), by (i) identifying key stressors related to human activities, and (ii) creating a conceptual ecosystem model relating those stressors to effects on ecosystem structure and processes. As a result of our analysis, we identify a set of landscape-level indicators of ecosystem health, emphasizing leading indicators of stressor removal (e.g., reduced anthropogenic nutrient inputs), increased ecosystem function (e.g., increased water storage in the landscape) and increased resilience (e.g., changes in the percentage of perennial vegetative cover). We suggest that by including these indicators, along with lagging indicators such as direct measurements of water quality, stakeholders will be better able to assess the effectiveness of management actions. For example, if both leading and lagging indicators show improvement over time, then management actions are on track to attain desired ecosystem condition. If, however, leading indicators are not improving or even declining, then fundamental challenges to ecosystem health remain to be addressed and failure to address these will ultimately lead to declines in lagging indicators such as water quality. Although our model and indicators are specific to the MARB, we believe that the generalized framework and the process of model and indicator development will be valuable in an array of altered river basins.

Can cyclone exposure explain behavioural and demographic variation among lemur species?

Madagascar has a harsh and stochastic climate because of regular natural disturbances. This history of regular cyclones has been hypothesised to have directed evolutionary changes to lemur behaviour and morphology that make them more resilient to sudden environmental change. These adaptations may include: small group sizes, high degrees of energy-conserving behaviours, generalist habitat use, small home ranges, small body size, and a limited number of frugivorous species. To date, however, no one has tested how variation in cyclone exposure across Madagascar is associated with variation in these resilience traits. In this study, we created a detailed cyclone impact map for Madagascar using Koppen-Geiger climate class, historical cyclone tracks, the Saffir Class of cyclone and hurricane intensity, and precipitation data. We also used existing literature to calculate a resilience score for 26 lemur species for which data existed on resilience traits. Our cyclone impact map was then overlaid on known geographic ranges of these species and compared to resilience score while controlling for phylogenetic non-independence and spatial autocorrelation. We found no association between cyclone impact in a lemur range and their resilience score. When assessing traits individually, however, we found that cyclone impact was positively associated with body size, suggesting that the more impacted a species is by cyclones the smaller they are. We also found cyclone impact to be negatively associated with frugivory, with species in higher impact zones eating more fruit. While unexpected, this could reflect an increased production in fruit in tree fall gaps following cyclones. While we did not find a pattern between cyclone impact and behavioural resilience in lemurs, we suggest a similar study at a global scale across all primates would allow for more taxonomic variation and reveal larger patterns key to understanding past and future vulnerability to natural disturbances in primates.

Effect of f-element complexation on the radiolysis of 2-ethylhexylphosphonic acid mono-2-ethylhexyl ester (HEH[EHP]).

A systematic study of the impact on the chemical reactivity of the oxidising n-dodecane radical cation (RH˙+) with f-element complexed 2-ethylhexylphosphonic acid mono-2-ethylhexyl ester (HEH[EHP]) has been undertaken utilizing time-resolved electron pulse radiolysis/transient absorption spectroscopy and high-level quantum mechanical calculations. Lanthanide ion complexed species, [Ln((HEH[EHP])2)3], exhibited vastly increased reactivity (over 10× faster) in comparison to the non-complexed ligand in n-dodecane solvent, whose rate coefficient was k = (4.66 ± 0.22) × 109 M-1 s-1. Similar reactivity enhancement was also observed for the corresponding americium ion complex, k = (5.58 ± 0.30) × 1010 M-1 s-1. The vastly increased reactivity of these f-element complexes was not due to simple increased diffusion-control of these reactions; rather, enhanced hole transfer mechanisms for the complexes were calculated to become energetically more favourable. Interestingly, the observed reactivity trend with lanthanide ion size was not linear; instead, the rate coefficients showed an initial increase (Lu to Yb) followed by a decrease (Tm to Ho), followed by another increase (Dy to La). This behaviour was excellently predicted by the calculated reaction volumes of these complexes. Complementary cobalt-60 gamma irradiations for select lanthanide complexes demonstrated that the measured kinetic differences translated to increased ligand degradation at steady-state timescales, affording ∼38% increase in ligand loss of a 1 : 1 [La((HEH[EHP])2)3] : HEH[EHP] ratio system.

The Training and Tapering Practices of Highland Games Heavy Event Athletes.

ABSTRACT: Winwood, PW, Keogh, JW, Travis, SK, Grieve, I, and Pritchard, HJ. The training and tapering practices of Highland Games heavy event athletes. J Strength Cond Res 38(3): e116-e124, 2024-This study provides the first empirical evidence of how Highland Games heavy event athletes train and taper for Highland Games competitions. Athletes (n = 169) (mean ± SD: age 40.8 ± 10.7 years, height 181.2 ± 9.5 cm, weight 107.2 ± 23.0 kg, 18.8 ± 10.3 years of general resistance training, and 8.1 ± 6.9 years of competitive Highland Games experience) completed a self-reported 4-page online survey on training and tapering practices. Analysis by sex (male and female) and competitive standard (local or regional, national, and international) was conducted. Seventy-eight percent (n = 132) of athletes reported that they used a taper. Athletes stated that their taper length was 5.2 ± 3.5 days, with the step (36%) and linear tapers (33%) being the most performed. Athletes reported that their highest training volume and intensity were 5.5 and 3.8 weeks out (respectively) from competition, and all training ceased 2.4 ± 1.4 days before competition. Training volume decreased during the taper by 34%. Athletes typically stated that, tapering was performed to achieve recovery, peak performance, and injury prevention; training intensity, frequency, and duration stayed the same or decreased; game-specific training increased with reductions in traditional exercises; the caber toss, weight for height, and heavy weight throw were performed further out from competition than other events; muscular power and strength were the most common types of training performed; static stretching, foam rolling, and massage were strategies used in the taper; and poor tapering occurred because of life/work circumstances, lack of sleep/rest, or training too heavy/hard. These results may aid Highland Games athletes to optimize training and tapering variables leading to improved performances.

Identification of type 2 diabetes- and obesity-associated human ß-cells using deep transfer learning.

Diabetes affects >10% of adults worldwide and is caused by impaired production or response to insulin, resulting in chronic hyperglycemia. Pancreatic islet ß-cells are the sole source of endogenous insulin and our understanding of ß-cell dysfunction and death in type 2 diabetes (T2D) is incomplete. Single-cell RNA-seq data supports heterogeneity as an important factor in ß-cell function and survival. However, it is difficult to identify which ß-cell phenotypes are critical for T2D etiology and progression. Our goal was to prioritize specific disease-related ß-cell subpopulations to better understand T2D pathogenesis and identify relevant genes for targeted therapeutics. To address this, we applied a deep transfer learning tool, DEGAS, which maps disease associations onto single-cell RNA-seq data from bulk expression data. Independent runs of DEGAS using T2D or obesity status identified distinct ß-cell subpopulations. A singular cluster of T2D-associated ß-cells was identified; however, ß-cells with high obese-DEGAS scores contained two subpopulations derived largely from either non-diabetic or T2D donors. The obesity-associated non-diabetic cells were enriched for translation and unfolded protein response genes compared to T2D cells. We selected DLK1 for validation by immunostaining in human pancreas sections from healthy and T2D donors. DLK1 was heterogeneously expressed among ß-cells and appeared depleted from T2D islets. In conclusion, DEGAS has the potential to advance our holistic understanding of the ß-cell transcriptomic phenotypes, including features that distinguish ß-cells in obese non-diabetic or lean T2D states. Future work will expand this approach to additional human islet omics datasets to reveal the complex multicellular interactions driving T2D.

Multiple lines of evidence point to pesticides as stressors affecting invertebrate communities in small streams in five United States regions.

Multistressor studies were performed in five regions of the United States to assess the role of pesticides as stressors affecting invertebrate communities in wadable streams. Pesticides and other chemical and physical stressors were measured in 75 to 99 streams per region for 4 weeks, after which invertebrate communities were surveyed (435 total sites). Pesticides were sampled weekly in filtered water, and once in bed sediment. The role of pesticides as a stressor to invertebrate communities was assessed by evaluating multiple lines of evidence: toxicity predictions based on measured pesticide concentrations, multivariate models and other statistical analyses, and previously published mesocosm experiments. Toxicity predictions using benchmarks and species sensitivity distributions and statistical correlations suggested that pesticides were present at high enough concentrations to adversely affect invertebrate communities at the regional scale. Two undirected techniques-boosted regression tree models and distance-based linear models-identified which pesticides were predictors of (respectively) invertebrate metrics and community composition. To put insecticides in context with known, influential covariates of invertebrate response, generalized additive models were used to identify which individual pesticide(s) were important predictors of invertebrate community condition in each region, after accounting for natural covariates. Four insecticides were identified as stressors to invertebrate communities at the regional scale: bifenthrin, chlordane, fipronil and its degradates, and imidacloprid. Fipronil was particularly important in the Southeast region, and imidacloprid, bifenthrin, and chlordane were important in multiple regions. For imidacloprid, bifenthrin, and fipronil, toxicity predictions were supported by mesocosm experiments that demonstrated adverse effects on naïve aquatic communities when dosed under controlled conditions. These multiple lines of evidence do not prove causality-which is challenging in the field under multistressor conditions-but they make a strong case for the role of insecticides as stressors adversely affecting invertebrate communities in streams within the five sampled regions.

Wear of Third-Generation Cross-Linked Polyethylene in Primary Total Hip Arthroplasty: A 10-Year Analysis.

BACKGROUND: Sequential modifications to the manufacturing process of highly cross-linked polyethylene (HXLPE) have improved the wear resistance and implant survival of these liners in total hip arthroplasty (THA). However, no study has examined the long-term (mean 10 year) wear rates and clinical outcomes of third-generation HXLPE in THA. The aim of our study was to report the longest-to-date analysis of wear rates and clinical outcomes of a third-generation HXLPE liner. METHODS: A series of 133 THAs using a specific HXLPE acetabular liner were retrospectively evaluated. Linear and volumetric wear rates were determined using a validated radiographic technique and clinical outcomes were analyzed. Multivariate analyses were performed to determine risk factors for accelerated wear. RESULTS: At a mean follow-up of 10.4 years (range, 8 to 13.4), the mean linear wear rate was 0.0172 mm/year and the mean volumetric wear rate was 16.99 mm3/year. There were no instances of osteolysis or mechanical failures at any time point and there was a 100% acetabular component survival rate. Younger age and use of offset liners were independent risk factors for increased wear (P < .01 for both). CONCLUSIONS: Our series of a third-generation HXLPE demonstrated very low wear rates and excellent implant survival at a mean of 10.4 years following primary THA. Future comparative studies at the 15- and 20-year follow-up timepoints are necessary to determine if such findings translate to true improvements in the tribological properties and longevity of these liners when compared to previous generations of HXLPE liners.

Advantages of model averaging of species sensitivity distributions used for regulating produced water discharges.

Produced water (PW) generated by Australian offshore oil and gas activities is typically discharged to the ocean after treatment. These complex mixtures of organic and inorganic compounds can pose significant environmental risk to receiving waters, if not managed appropriately. Oil and gas operators in Australia are required to demonstrate that environmental impacts of their activity are managed to levels that are as low as reasonably practicable, for example, through risk assessments comparing predicted no-effect concentrations (PNECs) with predicted environmental concentrations of PW. Probabilistic species sensitivity distribution (SSD) approaches are increasingly being used to derive PW PNECs and subsequently calculating dilutions of PW (termed "safe" dilutions) required to protect a nominated percentage of species in the receiving environment (e.g., 95% and 99% or PC95 and PC99, respectively). Limitations associated with SSDs include fitting a single model to small (six to eight species) data sets, resulting in large uncertainty (very wide 95% confidence limits) in the region associated with PC99 and PC95 results. Recent advances in SSD methodology, in the form of model averaging, claim to overcome some of these limitations by applying the average model fit of multiple models to a data set. We assessed the advantages and limitations of four different SSD software packages for determining PNECs for five PWs from a gas and condensate platform off the North West Shelf of Australia. Model averaging reduced occurrences of extreme uncertainty around PC95 and PC99 values compared with single model fitting and was less prone to the derivation of overly conservative PC99 and PC95 values that resulted from lack of fit to single models. Our results support the use of model averaging for improved robustness in derived PNEC and subsequent "safe" dilution values for PW discharge management and risk assessment. In addition, we present and discuss the toxicity of PW considering the paucity of such information in peer-reviewed literature. Integr Environ Assess Manag 2024;20:498-517. © 2023 Commonwealth Scientific and Industrial Research Organisation. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Persistent mucus plugs in proximal airways are consequential for airflow limitation in asthma.

BACKGROUNDInformation about the size, airway location, and longitudinal behavior of mucus plugs in asthma is needed to understand their role in mechanisms of airflow obstruction and to rationally design muco-active treatments.METHODSCT lung scans from 57 patients with asthma were analyzed to quantify mucus plug size and airway location, and paired CT scans obtained 3 years apart were analyzed to determine plug behavior over time. Radiologist annotations of mucus plugs were incorporated in an image-processing pipeline to generate size and location information that was related to measures of airflow.RESULTSThe length distribution of 778 annotated mucus plugs was multimodal, and a 12 mm length defined short ("stubby", ≤12 mm) and long ("stringy", >12 mm) plug phenotypes. High mucus plug burden was disproportionately attributable to stringy mucus plugs. Mucus plugs localized predominantly to airway generations 6-9, and 47% of plugs in baseline scans persisted in the same airway for 3 years and fluctuated in length and volume. Mucus plugs in larger proximal generations had greater effects on spirometry measures than plugs in smaller distal generations, and a model of airflow that estimates the increased airway resistance attributable to plugs predicted a greater effect for proximal generations and more numerous mucus plugs.CONCLUSIONPersistent mucus plugs in proximal airway generations occur in asthma and demonstrate a stochastic process of formation and resolution over time. Proximal airway mucus plugs are consequential for airflow and are in locations amenable to treatment by inhaled muco-active drugs or bronchoscopy.TRIAL REGISTRATIONClinicaltrials.gov; NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01716494, and NCT01760915.FUNDINGAstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Sanofi-Genzyme-Regeneron, and TEVA provided financial support for study activities at the Coordinating and Clinical Centers beyond the third year of patient follow-up. These companies had no role in study design or data analysis, and the only restriction on the funds was that they be used to support the SARP initiative.

ACR Appropriateness Criteria® Incidentally Detected Indeterminate Pulmonary Nodule.

Incidental pulmonary nodules are common. Although the majority are benign, most are indeterminate for malignancy when first encountered making their management challenging. CT remains the primary imaging modality to first characterize and follow-up incidental lung nodules. This document reviews available literature on various imaging modalities and summarizes management of indeterminate pulmonary nodules detected incidentally. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Moon-forming impactor as a source of Earth's basal mantle anomalies.

Seismic images of Earth's interior have revealed two continent-sized anomalies with low seismic velocities, known as the large low-velocity provinces (LLVPs), in the lowermost mantle1. The LLVPs are often interpreted as intrinsically dense heterogeneities that are compositionally distinct from the surrounding mantle2. Here we show that LLVPs may represent buried relics of Theia mantle material (TMM) that was preserved in proto-Earth's mantle after the Moon-forming giant impact3. Our canonical giant-impact simulations show that a fraction of Theia's mantle could have been delivered to proto-Earth's solid lower mantle. We find that TMM is intrinsically 2.0-3.5% denser than proto-Earth's mantle based on models of Theia's mantle and the observed higher FeO content of the Moon. Our mantle convection models show that dense TMM blobs with a size of tens of kilometres after the impact can later sink and accumulate into LLVP-like thermochemical piles atop Earth's core and survive to the present day. The LLVPs may, thus, be a natural consequence of the Moon-forming giant impact. Because giant impacts are common at the end stages of planet accretion, similar mantle heterogeneities caused by impacts may also exist in the interiors of other planetary bodies.