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Abstract Small microphone arrays and sound‐source localisation algorithms are increasingly prevalent in the passive acoustic monitoring (PAM) of ecosystems. These technologies enable analysis of natural soundscapes' spatial features, yielding additional insights into biodiversity and ecosystem health. While many of these technologies have been evaluated in the field, there is a lack of controlled, repeatable methods to test them. We developed an ambisonic virtual sound environment (VSE) for simulating real natural soundscapes to evaluate spatial PAM technologies. We validated this novel approach using a PAM recorder with a six‐microphone array, from which we extracted a typical suite of ecoacoustic metrics, including acoustic indices and avian species predictions and localisations from the software BirdNET and HARKBird, respectively. We first verified whether the VSE could replicate natural soundscapes well enough to test PAM technologies by comparing these metrics between field and VSE‐based recordings. To pilot the VSE as an environment for testing PAM hardware, we assessed how orientation impacts the six‐microphone array's performance by using the same suite of metrics to compare VSE recordings made with the array at various pitch angles. Finally, we piloted the VSE as a test platform for PAM software by investigating how BirdNET and HARKBird perform on bird calls added to the VSE‐replicated soundscapes. While the VSE and field recordings had similarities in some metrics, including spectral composition and BirdNET predictions, ambisonics' perceptual bias and susceptibility to spatial aliasing limited the spatial analyses that could be undertaken. Our trials nonetheless revealed that device orientation impacts the performance of HARKBird and certain ecoacoustic indices, and that BirdNET and HARKBird perform best on louder, more directional bird calls. Our results demonstrate the potential for this approach, but highlight limitations to using an ambisonics‐based VSE. We thus provide guidelines for the use and refinement of such systems towards more standardised, controlled benchmarking of PAM technologies, empowering practitioners to make more informed decisions on using these vital tools.

Abstract Multi‐microphone recording adds spatial information to recorded audio with emerging applications in ecosystem monitoring. Specifically placing sounds in space can improve animal count accuracy, locate illegal activity like logging and poaching, track animals to monitor behaviour and habitat use and allow for ‘beamforming’ to amplify sounds from target directions for downstream classification. Studies have shown many advantages of spatial acoustics, but uptake remains limited as the equipment is often expensive, complicated, inaccessible or only suitable for short‐term deployments. With an emphasis on enhanced uptake and usability, we present a low‐cost, open‐source, six‐channel recorder built entirely from commercially available components which can be integrated into a solar‐powered, online system. The MAARU (Multichannel Acoustic Autonomous Recording Unit) works as an independent node in long‐term autonomous, passive and/or short‐term deployments. Here, we introduce MAARU's hardware and software and present the results of lab and field tests investigating the device's durability and usability. MAARU records multichannel audio with similar costs and power demands to equivalent omnidirectional recorders. MAARU devices have been deployed in the United Kingdom and Brazil, where we have shown MAARUs can accurately localise pure tones up to 6 kHz and bird calls as far as 8 m away (±10° range, 100% and >60% of signals, respectively). Louder calls may have even further detection radii. We also show how beamforming can be used with MAARUs to improve species ID confidence scores. MAARU is an accessible, low‐cost option for those looking to explore spatial acoustics accurately and easily with a single device, and without the formidable expenses and processing complications associated with establishing arrays. Ultimately, the added directional element of the multichannel recording provided by MAARU allows for enhanced recording of sonic environments, further enabling a potential step change in the uptake of spatial acoustics in the wider field.

Abstract Targeted gene delivery to the brain is a critical tool for neuroscience research and has significant potential to treat human disease. However, the site-specific delivery of common gene vectors such as adeno-associated viruses (AAVs) is typically performed via invasive injections, which limit its applicable scope of research and clinical applications. Alternatively, focused ultrasound blood-brain-barrier opening (FUS-BBBO), performed noninvasively, enables the site-specific entry of AAVs into the brain from systemic circulation. However, when used in conjunction with natural AAV serotypes, this approach has limited transduction efficiency and results in substantial undesirable transduction of peripheral organs. Here, we use high throughput in vivo selection to engineer new AAV vectors specifically designed for local neuronal transduction at the site of FUS-BBBO. The resulting vectors substantially enhance ultrasound-targeted gene delivery and neuronal tropism while reducing peripheral transduction, providing a more than ten-fold improvement in targeting specificity in two tested mouse strains. In addition to enhancing the only known approach to noninvasively target gene delivery to specific brain regions, these results establish the ability of AAV vectors to be evolved for specific physical delivery mechanisms.

Processing-structure-property relationships of 3D-printed multi-scale porous ceramics were investigated. Direct ink writing (DIW) of oil-templated colloidal pastes produced hierarchically porous beta-tricalcium phosphate (TCP) scaffolds. Print architecture and microporosity within filaments were varied, mimicking bone structure. The scaffolds exhibited 60–70 % porosity with interconnected macropores 300–700 μm and microporosity within the filaments at the 10 micron-scale. Varying surfactant and oil concentrations created two micro-pore morphologies – bubble-like pores (emulsion) and channel-like pores (capillary suspension). Emulsion scaffolds were stronger, stiffer and more reliable than capillary suspension scaffolds under both compression and bending. Reducing nozzle diameter and inter-filament distance improved strength and stiffness, at lower density. Immersed at physiological pH, the hierarchically porous TCP scaffolds' strength and modulus degraded at a moderate rate suitable for bone tissue engineering (BTE). Mechanical behavior can be controlled by manipulating process parameters which influence the material's structure. These properties were comparable with trabecular bone, promising for BTE.

Abstract Background Achondroplasia, caused by a pathogenic variant in the fibroblast growth factor receptor 3 gene, is the most common skeletal dysplasia. The Lifetime Impact of Achondroplasia Study in Europe (LIAISE; NCT03449368) aimed to quantify the burden of achondroplasia among individuals across a broad range of ages, including adults. Methods Demographic, clinical and healthcare resource use data were collected from medical records of achondroplasia patients enrolled in 13 sites across six European countries in this retrospective, observational study. Descriptive statistics or event rates per 100 person-years were calculated and compared across age groups as well as by history of limb lengthening. Patient-reported outcomes (quality of life [QoL], pain, functional independence, work productivity and activity impairments) were evaluated using questionnaires at the time of enrolment. An exploratory analysis investigated correlations between height (z-score or centimetres) and patient-reported outcomes. Results Overall, 186 study patients were included, with a mean age of 21.7 ± 17.3 years (range 5.0–84.4). At least one complication or surgery was reported for 94.6% and 72.0% of patients, respectively, at a rate of 66.6 and 21.5 events per 100 person-years. Diverse medical and surgical complications were reported for all ages in a bimodal distribution, occurring more frequently in the youngest and oldest age groups. A total of 40 patients had previously undergone limb lengthening (capped at 20% per the study protocol). The most frequent surgery types varied by age, in line with complication profiles. Healthcare resource use was high across all age groups, especially among the youngest and oldest individuals, and did not differ substantially according to history of limb lengthening. Compared to general population values, patients reported impaired QoL particularly for physical functioning domains. In addition, patients reported difficulty carrying out daily activities independently and pain starting in childhood. Patient height correlated with multiple patient-reported outcomes. Conclusions The findings of this study suggest that, across an individual’s lifetime, achondroplasia is associated with multisystem complications, reduced QoL and functionality, and increased pain. These results highlight the large amount of healthcare resources that individuals with achondroplasia require throughout their lifespans and provide novel insights into current achondroplasia management practices across Europe. Trial registration ClinicalTrials.gov, NCT03449368, Submitted 14 December 2017 – prospectively registered, https://clinicaltrials.gov/ct2/show/record/NCT03449368

Abstract Background Hypophosphatasia (HPP) is a rare and underdiagnosed condition characterized by deficient bone and teeth mineralization. The aim of this study was first, to evaluate the diagnostic utility of employing alkaline phosphatase (ALP) threshold levels to identify adults with variants in ALPL among individuals with persistently low ALP levels and second, to determine the value of also including its substrates (serum pyridoxal-5′-phosphate—PLP—and urinary phosphoetanolamine-PEA) for this purpose in order to create a biochemical algorithm that could facilitate the diagnostic work-up of HPP. Results The study population comprised 77 subjects with persistent hypophosphatasaemia. They were divided into two groups according to the presence (+GT) or absence (−GT) of pathogenic ALPL variants: 40 +GT and 37 −GT. Diagnostic utility measures were calculated for different ALP thresholds and Receiver Operating Characteristic (ROC) curves were employed to determine PLP and PEA optimal cut-off levels to predict the presence of variants. The optimal threshold for ALP was 25 IU/L; for PLP, 180 nmol/L and for PEA, 30 µmol/g creatinine. Biochemical predictive models were assessed using binary logistic regression analysis and bootstrapping machine learning technique and results were then validated. For ALP 180 nmol/L) that when combined, seem to be very useful to identify individuals with ALPL variants.

While significant progress has been made in understanding global carbon (C) cycling, the mechanisms regulating belowground C fluxes and storage are still uncertain. New molecular technologies have the power to elucidate these processes, yet we have no widespread standardized implementation of molecular techniques. To address this gap, we introduce the Molecular Observation Network (MONet), a decadal vision from the Environmental Molecular Sciences Laboratory (EMSL), to develop a national network for understanding the molecular composition, physical structure, and hydraulic and biological properties of soil and water. These data are essential for advancing the next generation of multiscale Earth systems models. In this paper, we discuss the 1000 Soils Pilot for MONet, including a description of standardized sampling materials and protocols and a use case to highlight the utility of molecular-level and microstructural measurements for assessing the impacts of wildfire on soil. While the 1000 Soils Pilot generated a plethora of data, we focus on assessments of soil organic matter (SOM) chemistry via Fourier-transform ion cyclotron resonance-mass spectrometry and microstructural properties via X-ray computed tomography to highlight the effects of recent fire history in forested ecosystems on belowground C cycling. We observed decreases in soil respiration, microbial biomass, and potential enzyme activity in soils with high frequency burns. Additionally, the nominal oxidation state of carbon in SOM increased with burn frequency in surface soils. This results in a quantifiable shift in the molecular signature of SOM and shows that wildfire may result in oxidation of SOM and structural changes to soil pore networks that persist into deeper soils.

Introduction: FATCO (Fibular Aplasia, Tibial Campomelia and Oligosyndactyly) is a very infrequent skeletal dysplasia classified within the limb hypoplasia-reduction defects group whose genetic cause has not yet been identified. The advent of next-generation sequencing is enabling the diagnosis of diseases with no previously known genetic cause.Methods: We performed a thorough autopsy on a fetus whose pregnancy was legally terminated due to severe malformations detected by ultrasound. A trio exome was run to identify the genetic cause and risk of recurrence. Previous literature of similar cases was systematically searched.Results: Anatomopathological analyses revealed complete fibular aplasia, shortened and campomelic tibia, absent ankle joint, club right foot and a split foot malformation, leading to the diagnosis of FATCO. Exome sequencing showed that the female fetus carried a de novo nonsense variant in DLX5. The literature search permitted the collection of information on 43 patients with FATCO, the majority of whom were males diagnosed postnatally. In most cases, lower limbs were affected exclusively, but in 39.5% of cases the upper limbs were also affected.Conclusion: The pathologies associated with DLX5 variants encompass a wide spectrum of manifestations ranging from abnormalities exclusively in the hands and feet to long bones such as the tibia and fibula.

Introduction: Saethre-Chotzen syndrome, a craniosynostosis syndrome characterized by the premature closure of the coronal sutures, dysmorphic facial features and limb anomalies, is caused by haploinsufficiency of TWIST1. Although the majority of variants localize in the coding region of the gene, two variants in the 5′ UTR have been recently reported to generate novel upstream initiation codons.Methods: Skeletal dysplasia Next-generation sequencing (NGS) panel was used for genetic analysis in a patient with bicoronal synostosis, facial dysmorphisms and limb anomalies. The variant pathogenicity was assessed by a luciferase reporter promoter assay.Results: Here, we describe the identification of a third ATG-creating de novo variant, c.-18C>T, in the 5′ UTR of TWIST1 in the patient with a clinical diagnosis of Saethre-Chotzen syndrome. It was predicted to create an out-of-frame new upstream translation initiation codon resulting in a 40 amino acid larger functionally inactive protein. We performed luciferase reporter promoter assays to demonstrate that the variant does indeed reduce translation from the main open reading frame.Conclusion: This is the third variant identified in this region and confirms the introduction of upstream ATGs in the 5′ UTR of TWIST1 as a pathogenic mechanism in Saethre-Chotzen syndrome. This case report shows the necessity for performing functional characterization of variants of unknown significance within national health services.

Resumen: La acondroplasia requiere un seguimiento multidisciplinario, con el objetivo de prevenir y manejar las complicaciones, mejorar la calidad de vida y favorecer su independencia e inclusión social. Esta revisión se justifica por las múltiples publicaciones generadas en los últimos años que han llevado a cabo un cambio en su gestión. Se han desarrollado diferentes guías y recomendaciones, entre las que destacan la realizada por la Academia Americana de Pediatría en 2005 recientemente actualizada (2020), la guía japonesa (2020), el primer Consenso Europeo (2021) y el Consenso Internacional sobre el diagnóstico, abordaje, enfoque multidisciplinario y manejo de individuos con acondroplasia a lo largo de la vida (2021). Sin embargo, y a pesar de estas recomendaciones, actualmente existe una gran variabilidad a nivel mundial en el manejo de las personas con acondroplasia, con consecuencias médicas, funcionales y psicosociales en los pacientes y sus familias. Por ello, es fundamental integrar estas recomendaciones en la práctica clínica diaria, teniendo en cuenta la situación particular de cada sistema sanitario. Abstract: Achondroplasia requieres a multidisciplinary follow-up, with the aim of preventing and managing complications, improving the quality of life and favoring their independence and social inclusion. This review is justified by the multiple publications generated in recent years that have carried out a change in its management. Different guidelines and recommendations have been developed, among which the one made by the American Academy of Pediatrics in 2005 recently updated (2020), the Japanese guide (2020), the first European Consensus (2021) and the International Consensus on the diagnosis, approach multidisciplinary approach and management of individuals with achondroplasia throughout life (2021). However, and despite these recommendations, there is currently a great worldwide variability in the management of people with achondroplasia, with medical, functional and psychosocial consequences in patients and their families. Therefore, it is essential to integrate these recommendations into daily clinical practice, taking into account the particular situation of each health system.

Students experience challenges with persistence, retention, graduation, and overall academic success in colleges and universities, particularly when courses are taught by adjunct instructors. Using a sample of 21,274 student results in three different general education disciplines from 2010 to 2019, the authors found that there was a disparity between adjunct and full-time faculty members in those key outcomes. The purpose of this study is to analyze data about student persistence, retention, and academic skills and its relationships with type of instructor (adjunct or non-adjunct) to consider the means by which the results may help to respond effectively to negative indicators in those areas. In addition to including adjunct instructors in professional development and student engagement activities on campuses, strategically hiring full-time faculty may result in gains that offset the higher financial outlay for those instructors.

Abstract Acoustic indices derived from environmental soundscape recordings are being used to monitor ecosystem health and vocal animal biodiversity. Soundscape data can quickly become very expensive and difficult to manage, so data compression or temporal down‐sampling are sometimes employed to reduce data storage and transmission costs. These parameters vary widely between experiments, with the consequences of this variation remaining mostly unknown. We analyse field recordings from North‐Eastern Borneo across a gradient of historical land use. We quantify the impact of experimental parameters (MP3 compression, recording length and temporal subsetting) on soundscape descriptors (Analytical Indices and a convolutional neural net derived AudioSet Fingerprint). Both descriptor types were tested for their robustness to parameter alteration and their usability in a soundscape classification task. We find that compression and recording length both drive considerable variation in calculated index values. However, we find that the effects of this variation and temporal subsetting on the performance of classification models is minor: performance is much more strongly determined by acoustic index choice, with Audioset fingerprinting offering substantially greater (12%–16%) levels of classifier accuracy, precision and recall. We advise using the AudioSet Fingerprint in soundscape analysis, finding superior and consistent performance even on small pools of data. If data storage is a bottleneck to a study, we recommend Variable Bit Rate encoded compression (quality = 0) to reduce file size to 23% file size without affecting most Analytical Index values. The AudioSet Fingerprint can be compressed further to a Constant Bit Rate encoding of 64 kb/s (8% file size) without any detectable effect. These recommendations allow the efficient use of restricted data storage whilst permitting comparability of results between different studies.

BackgroundLow serum alkaline phosphatase levels are the hallmark of hypophosphatasia, a disorder due to pathogenic variants of the ALPL gene. However, some patients do not carry ALPL variants and the cause of low alkaline phosphatase remains unknown. We aimed to determine health-related quality of life in adults with low alkaline phosphatase and explore the differences between patients with and without ALPL mutations.MethodsWe studied 35 adult patients with persistently low alkaline phosphatase unrelated to secondary acquired causes who had ALPL sequenced, and 35 controls of similar age. Three questionnaires about body pain (Brief Pain Inventory, BPI), physical disability (Health Assessment Questionnaire Disability Index, HAQ-DI), and health-related quality of life (36-item Short-Form Health Survey, SF-36) were delivered by telephone interviews.ResultsThe mean BPI intensity and interference scores were higher in the patient group (p=0.04 and 0.004, respectively). All domains of the HAQ instrument tended to score better in the control group, with significant differences in the “reach” score (p=0.037) and the overall mean score (0.23 vs 0.09; p=0.029). Patients scored worse than controls in several SF-36 dimensions (Role physical, p=0.039; Bodily pain p=0.046; Role emotional, p=0.025). Patients with and without pathogenic variants scored similarly across all tests, without between-group significant differences.ConclusionsPatients with persistently low levels of alkaline phosphatase have significantly worse scores in body pain and other health-related quality of life dimensions, without differences between patients with and without pathogenic variants identified in ALPL gene. This is consistent with the latter ones carrying mutations in regulatory regions.

Germline mutations in the DNMT3A gene can cause an overgrowth syndrome associated with behavioural and hematopoietic phenotypes. Here the authors describe a mouse model of this syndrome that recapitulates many of these features, including conserved alterations in DNA methylation in the blood cells of both species.

Type 1 diabetes (T1D) is an autoimmune disease culminating in the destruction of insulin-producing pancreatic cells. There is a need for the development of novel antigen-specific strategies to delay cell destruction, including combinatorial strategies that do not elicit systemic immunosuppression. Gamma-aminobutyric acid (GABA) is expressed by immune cells, β-cells, and gut bacteria and is immunomodulatory. Glutamic-acid decarboxylase 65 (GAD65), which catalyzes GABA from glutamate, is a T1D autoantigen. To test the efficacy of combinatorial GABA treatment with or without GAD65-immunization to dampen autoimmune responses, we enrolled recent-onset children with T1D in a one-year clinical trial (ClinicalTrials.gov NCT02002130) and examined T cell responses. We isolated peripheral blood mononuclear cells and evaluated cytokine responses following polyclonal activation and GAD65 rechallenge. Both GABA alone and GABA/GAD65-alum treatment inhibited Th1 cytokine responses over the 12-month study with both polyclonal and GAD65 restimulation. We also investigated whether patients with HLA-DR3-DQ2 and HLA-DR4-DQ8, the two highest-risk human leukocyte antigen (HLA) haplotypes in T1D, exhibited differences in response to GABA alone and GABA/GAD65-alum. HLA-DR4-DQ8 patients possessed a Th1-skewed response compared to HLA-DR3-DQ2 patients. We show that GABA and GABA/GAD65-alum present an attractive immunomodulatory treatment for children with T1D and that HLA haplotypes should be considered.

Abstract Background Hypophosphatasia (HPP) is an inborn error of metabolism characterized by low levels of serum alkaline phosphatase (ALP). Scarce evidence exists about features that should signal the potential association between hypophosphatasaemia and HPP in adults. The aim of this study is to estimate the prevalence of ALPL variants in subjects with persistent hypophosphatasaemia and determine the associated clinical and laboratory features. For this cross-sectional study, laboratory records of 386,353 subjects were screened by measurement of ALP activity. A total of 85 (0.18%) subjects with persistent hypophosphatasaemia (≥2 serum alkaline phosphatase–ALP–measurements ≤35 IU/L and none > 45 IU/L) were included (secondary causes previously discarded). ALPL genetic testing and a systematized questionnaire to retrieve demographic, clinical and laboratory data were performed. Descriptive analysis and logistic regression models were employed to identify the clinical and laboratory characteristics associated with ALPL variants. Results Forty subjects (47%) had a variant(s) in ALPL. With regard to clinical characteristics, the presence of an ALPL variant was significantly associated only with musculoskeletal pain (OR: 7.6; 95% IC: 1.9–30.9). Nevertheless, a trend to present more dental abnormalities (OR: 3.6; 95% IC: 0.9–13.4) was observed. Metatarsal stress fractures were also more frequent (4 vs 0; p

Abstract Two‐phase fluid flow properties underlie quantitative prediction of water and gas movement, but constraining these properties typically requires multiple time‐consuming laboratory methods. The estimation of two‐phase flow properties (van Genuchten parameters, porosity, and intrinsic permeability) is illustrated in cores of vitric nonwelded volcanic tuff using Bayesian parameter estimation that fits numerical models to observations from spontaneous imbibition experiments. The uniqueness and correlation of the estimated parameters is explored using different modeling assumptions and subsets of the observed data. The resulting estimation process is sensitive to both moisture retention and relative permeability functions, thereby offering a comprehensive method for constraining both functions. The data collected during this relatively simple laboratory experiment, used in conjunction with a numerical model and a global optimizer, result in a viable approach for augmenting more traditional capillary pressure data obtained from hanging water column, membrane plate extractor, or mercury intrusion methods. This method may be useful when imbibition rather than drainage parameters are sought, when larger samples (e.g., including heterogeneity or fractures) need to be tested that cannot be accommodated in more traditional methods, or when in educational laboratory settings.

Decellularized extracellular matrix (dECM) deposited by mesenchymal stromal cells (MSCs) has emerged as a promising substrate for improved expansion of MSCs. To date, essentially all studies that have produced dECM for MSC expansion have done so on tissue culture plastic or glass. However, substrate surface chemistry has a profound impact on the adsorption of proteins that mediate cell-material interactions, and different surface chemistries can cause changes in cell behavior, ECM deposition, and the in vivo response to a material. This study tested the hypothesis that substrate surface chemistry impacts the deposition of ECM and its subsequent bioactivity. This hypothesis was tested by producing glass surfaces with various surface chemistries (amine, carboxylic acid, propyl, and octyl groups) using silane chemistry. ECM was deposited by an immortalized MSC line, decellularized, and characterized through SDS-PAGE and immunofluorescence microscopy. No significant difference was observed in dECM composition or microarchitecture on the different surfaces. The decellularized surfaces were seeded with primary MSCs and their proliferation and differentiation were assessed. The presence of dECM improved the proliferation of primary MSCs by ~100% in comparison to surface chemistry controls. Additionally, the adipogenesis increased by 50–90% on all dECM surfaces in comparison to surface chemistry controls, and the osteogenesis increased by ~50% on the octyl-modified surfaces when dECM was present. However, no statistically significant differences were observed within the set of dECM surfaces or control surfaces. These results support the null hypothesis, meaning surface chemistry (over the range tested in this work) is not a key regulator of the composition or bioactivity of MSC-derived dECM. These results are significant because they provide an important insight into regenerative engineering technologies. Specifically, the utilization of dECM in stem cell manufacturing and tissue engineering applications would require the dECM to be produced on a wide variety of substrates. This work indicates that it can be produced on materials with a range of surface chemistries without undesired changes in the bioactivity of the dECM.

Excessive emotional arousal has been shown to impact physiological health in both veterinary species and human animals. The focus of work in many models of veterinary behavioural medicine has predominantly been associated with reducing activation of the protective emotional systems; in particular, fear-anxiety. The management of the engaging emotional systems of desire-seeking, social play, care and lust has not traditionally been considered in the treatment of physiological health of veterinary species. This article reviews the literature in both veterinary and human fields on the relationship between emotional arousal of both protective and engaging emotional systems and physical health conditions. The current literature describing the regulatory control of sleep on emotional arousal is also discussed. An exemplary case report of a seven month old male entire Cocker Spaniel showing fly-snapping behaviour which had been non-responsive to leviteracetam (Keppra) is presented. The emotional health assessment and treatment of this case is described along with the short and long term (fourteen month follow up) outcomes to demonstrate that some patients presenting in this way can be effectively managed with an appropriate behavioural medicine treatment plan. The authors put forward the argument that an emotional health assessment should be considered an essential component of the work up of all such cases.

Abstract Of interest to the Underground Nuclear Explosion Signatures Experiment are patterns and timing of explosion‐generated noble gases that reach the land surface. The impact of potentially simultaneous flow of water and gas on noble gas transport in heterogeneous fractured rock is a current scientific knowledge gap. This article presents field and laboratory data to constrain and justify a triple continua conceptual model with multimodal multiphase fluid flow constitutive equations that represents host rock matrix, natural fractures, and induced fractures from past underground nuclear explosions (UNEs) at Aqueduct and Pahute Mesas, Nevada National Security Site, Nevada, USA. Capillary pressure from mercury intrusion and direct air–water measurements on volcanic tuff core samples exhibit extreme spatial heterogeneity (i.e., variation over multiple orders of magnitude). Petrographic observations indicate that heterogeneity derives from multimodal pore structures in ash‐flow tuff components and post‐depositional alteration processes. Comparisons of pre‐ and post‐UNE samples reveal different pore size distributions that are due in part to microfractures. Capillary pressure relationships require a multimodal van Genuchten (VG) constitutive model to best fit the data. Relative permeability estimations based on unimodal VG fits to capillary pressure can be different from those based on bimodal VG fits, implying the choice of unimodal vs. bimodal fits may greatly affect flow and transport predictions of noble gas signatures. The range in measured capillary pressure and predicted relative permeability curves for a given lithology and between lithologies highlights the need for future modeling to consider spatially distributed properties.

Optimal sleep duration and quality is difficult to define. There are strong arguments for a relationship between sleep, in particular REM sleep, and emotional health and behaviour in a variety of species. This study aims to broaden the level of knowledge regarding canine sleep durations and characteristics and begin research into the relationship between behavioural responses and the duration and quality of sleep. A caregiver questionnaire was used to capture information regarding the duration and characteristics of canine sleep, how easily this cohort of dogs were disturbed from sleep, and caregiver perceptions of the severity of problem behaviours shown by this cohort (n = 1330). A quadratic relationship between canine sleep duration whilst a caregiver is in bed and severity of problem behaviour is shown, with less than 8 h sleep and more than 10 h sleep correlating with increased severity of problem behaviours in this cohort. Dogs which were more easily disturbed from sleep at times their caregiver was out of bed, showed increased reported severity of problem behaviours. Whilst it is not possible to determine an optimal canine sleep duration, sufficient evidence is presented to argue that problem behaviour should not be remedied by sleep deprivation.

There are demands to involve patients in medical education research (MER). This study surveyed researchers to examine the extent and nature of patient involvement in MER. It obtained 283 completed surveys (response rate of 5%). Of the respondents, 153 (54.1%) indicated that they involve patients in MER. Of these respondents, 102 (66.7%) stated that patients are data sources in MER, 41 (26.8%) noted that patients are involved as advisors and/or reviewers, and/or 22 (14.4%) indicated that patients are involved as team members. These respondents reported that they involve patients to improve the relevance of their MER to patients (n = 99; 64.7%), connect MER to patient outcomes (n = 98; 64.1%), and improve the appropriateness of MER (n = 92; 60.1%). The 130 respondents who do not involve patients in MER do not involve them because they believe that their research topic(s) are irrelevant to patients (n = 68; 52.3%), they have limited resources for patient involvement (n = 40; 30.8%), and/or they do not know how to involve patients (n = 28; 21.5%). Researchers need to consider how they can conduct their MER with patients.

While self-regulated learning is a standard model for online coursework, this approach emphasizes the applicability of Learning Management System (LMS) usage in face-to-face and hybrid course formats. Self-regulated learning has become an important component of education, both as a primary tool in online coursework and as a supplemental resource in face-to-face courses. (Boekaerts, 1999). Yet despite its importance, research suggests that rather than utilizing the full potential of learning management and course management systems, instructors primarily use LMS and CMS as a delivery mode for course content (Boekarts, 1997; Vovides et al., 2007). Such underutilization not only minimizes the capacities of such systems, but limits the opportunities for students to engage in multimodal self-regulated learning. This paper offers three specific techniques to improve self-regulated learning via LMS: flipped learning, chunking, and micro-learning. Research findings have led to support for each of the above-mentioned techniques (Nwosisi et al., 2016; Miller, 1956; Major & Calandrino, 2018). The authors provide examples of techniques used in their own courses, how each facilitates self-regulated learning, and how utilizing the full capabilities of learning management systems engages students in multimodal self-regulated learning. Common findings and recommendations will also be noted, with the goal of providing a framework for instructors to apply each technique via learning management systems in their own courses.

Anal squamous cell carcinoma (ASCC) is a rare neoplasm. Chemoradiotherapy is the standard of care, with no therapeutic advances achieved over the past three decades. Thus, a deeper molecular characterization of this disease is still necessary. We analyzed 46 paraffin-embedded tumor samples from patients diagnosed with primary ASCC by exome sequencing. A bioinformatics approach focused in the identification of high-impact genetic variants, which may act as drivers of oncogenesis, was performed. The relation between genetics variants and prognosis was also studied. The list of high-impact genetic variants was unique for each patient. However, the pathways in which these genes are involved are well-known hallmarks of cancer, such as angiogenesis or immune pathways. Additionally, we determined that genetic variants in BRCA2, ZNF750, FAM208B, ZNF599, and ZC3H13 genes are related with poor disease-free survival in ASCC. This may help to stratify the patient's prognosis and open new avenues for potential therapeutic intervention. In conclusion, sequencing of ASCC clinical samples appears an encouraging tool for the molecular portrait of this disease.

Objective: The recovery of patients with partial thickness isolated hand burns managed with an epidermal skin substitute appears to be rapid and the necessity for routine hand therapy interventions in this setting is unknown. This study investigated the need for hand therapy for these patients. Methods: A randomized controlled trial was undertaken. The Treatment Group received routine hand therapy provided by a physiotherapist, including assessment, daily range of motion exercises, education and, if required, edema management and outpatient physiotherapy follow-up. Control Group participants received no hand therapy input. Outcomes included the Michigan Hand Questionnaire (baseline, 1, 2, 4 weeks and 3 months post-injury), finger total active motion, wrist range, grip strength (1, 2 and 4 weeks) and participant satisfaction (4 weeks). Results: Twenty-nine participants were recruited over a 2.3 year period. All outcomes significantly improved over time (p ≤ 0.008). No significant between-group differences were observed for any outcome except the pain subscale of the Michigan Hand Questionnaire. Participants with deeper burns had significantly poorer outcomes for some Michigan Hand Questionnaire data. Study limitations included a small sample size, heterogeneity and some loss to follow-up. Conclusions: While the provision of routine hand therapy interventions for patients with partial thickness isolated hand/forearm burns that were managed with an epidermal skin substitute did not appear to be of benefit, study limitations means these results cannot be extrapolated and reinforces the need for further research. Routine hand therapy input may be of benefit for those with deeper burns. Keywords: Burns, Skin, Artificial, Physical therapy modalities, Hand, Injuries

Cellular stressors can impact clonal hematopoiesis. Here, the authors explore the impact of cytotoxic therapy and hematopoietic transplantation on clonal expansion, suggesting different stressors can promote expansion of distinct long-lived clones.

Leakage pathways through caprock lithologies for underground storage of CO2 and/or enhanced oil recovery (EOR) include intrusion into nano-pore mudstones, flow within fractures and faults, and larger-scale sedimentary heterogeneity (e.g., stacked channel deposits). To assess multiscale sealing integrity of the caprock system that overlies the Morrow B sandstone reservoir, Farnsworth Unit (FWU), Texas, USA, we combine pore-to-core observations, laboratory testing, well logging results, and noble gas analysis. A cluster analysis combining gamma ray, compressional slowness, and other logs was combined with caliper responses and triaxial rock mechanics testing to define eleven lithologic classes across the upper Morrow shale and Thirteen Finger limestone caprock units, with estimations of dynamic elastic moduli and fracture breakdown pressures (minimum horizontal stress gradients) for each class. Mercury porosimetry determinations of CO2 column heights in sealing formations yield values exceeding reservoir height. Noble gas profiles provide a “geologic time-integrated” assessment of fluid flow across the reservoir-caprock system, with Morrow B reservoir measurements consistent with decades-long EOR water-flooding, and upper Morrow shale and lower Thirteen Finger limestone values being consistent with long-term geohydrologic isolation. Together, these data suggest an excellent sealing capacity for the FWU and provide limits for injection pressure increases accompanying carbon storage activities.

It is known that zearalenone (ZON) interacts directly with estrogen receptors, and its in vivo effects on reproduction have been well-documented in several species. In contrast, reports of ZON's impact on horse reproduction are conflicting and inconclusive, some studies confounded by the presence of mycotoxins such as deoxynivalenol in the feed. This study assesses the effect of chronic consumption of zearalenone on reproduction in cycling mares fed >95% pure ZON (0, 2, or 8 mg/da; n = 7 mares/treatment) for three estrous cycles, followed by artificial insemination, through 16 days of pregnancy. Animals were on ZON treatment for between 70 and 121 days (average 84) depending on individual cycle patterns. ZON-induced changes in serum concentration of estradiol (E2) and progesterone (P4), and total estrogenicity were measured using RIAs and the E-screen assay, respectively. Effects on reproductive physiology and pregnancy were monitored by ultrasound and clinical parameters. No significant changes were found in reproductive hormone levels of E2, or P4 for mares on ZON treatments compared to controls, although there was a significant (P < 0.01) increase in P4 levels across Cycle number in High ZON (8 mg/da) treated mares. There was also an increasing trend in the interovulatory interval in the High ZON treatment group. The overall estrogenicity was similar across treatments and over time, not differing from controls or between ZON treatment groups. Adverse uterine and ovarian effects were also not observed, but pregnancy rates were mixed with only 4 of 7 mares on Low ZON becoming pregnant, and only 3 maintaining pregnancy and fetal heartbeat by Day 30, compared to 5 of 6 control mares and all 7 mares on High ZON. Because reproductive efficiency and hormone concentrations are highly variable across individuals, this study did not demonstrate that ZON at 2 or 8 mg/da was detrimental to mares' reproduction. Yet, inferring that ZON treatments were completely without effect is also not appropriate, as the absence of measurable significant differences could be attributed to the limited sample size. Most importantly, there were no extreme signs of toxicology, in contrast to previous reports when ZON was fed at these “doses.”

Summary: Neoantigen-specific T cells are increasingly viewed as important immunotherapy effectors, but physically isolating these rare cell populations is challenging. Here, we describe a sensitive method for the enumeration and isolation of neoantigen-specific CD8+ T cells from small samples of patient tumor or blood. The method relies on magnetic nanoparticles that present neoantigen-loaded major histocompatibility complex (MHC) tetramers at high avidity by barcoded DNA linkers. The magnetic particles provide a convenient handle to isolate the desired cell populations, and the barcoded DNA enables multiplexed analysis. The method exhibits superior recovery of antigen-specific T cell populations relative to literature approaches. We applied the method to profile neoantigen-specific T cell populations in the tumor and blood of patients with metastatic melanoma over the course of anti-PD1 checkpoint inhibitor therapy. We show that the method has value for monitoring clinical responses to cancer immunotherapy and might help guide the development of personalized mutational neoantigen-specific T cell therapies and cancer vaccines. : Peng et al. report a sensitive method to detect tumor-associated neoantigen-specific T cells. Neoantigens and fluorescent DNA barcodes, presented on nanoparticle scaffolds, permit multiplex capture and analysis of specific T cell populations from blood or tumor. Neoantigen-specific T cell numbers track tumor volume in a melanoma patient responding to immunotherapy. Keywords: neoantigens, cancer immunotherapy, nanotechnology, microfluidics, T cell receptor