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Objectives Informing research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.Design In the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.Setting UK stroke services.Participants 3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.Results Of those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.Conclusion It is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration number ISRCTN83290762; Post-results.

Abstract Background Mucopolysaccharidosis (MPS) type IVA is a rare lysosomal storage disorder caused by aberrations of the N-acetyl-galactosamine-6-sulfatase (GALNS) enzyme. MPS IVA is associated with a wide gamut of respiratory and airway disorders that manifest in a continuum of severity. In individuals exhibiting severe phenotypic expression, terminal stages of the disease frequently culminate in life-threatening, critical airway obstruction. These manifestations of end-stage disease are engendered by an insidious progression of multi-level airway pathologies, comprising of tracheomalacia, stenosis, tortuosity and 'buckling'. Historically, the management of end-stage airway disease has predominantly leaned towards palliative modalities. However, contemporary literature has posited that the potential benefits of tracheal resection with aortopexy, performed under cardiopulmonary bypass (CPB), may offer a promising therapeutic option. In this context, we report on outcomes from patients undergoing a novel approach to tracheal resection that is combined with manubrial resection, leading to improved airway calibre, obviating the requisition for CPB. Results In this study, seven patients with severe MPS IVA exhibited clinical symptoms and radiological evidence indicative of advanced airway obstruction. All patients had a tracheal resection with a partial upper manubriectomy via transcervical approach, which did not require CPB. The surgical cohort consisted of 5 females and 2 males, the median age was 16 years (range 11-19) and the median height was 105.6cm (range 96.4-113.4). Postoperatively, significant improvements were seen in forced expiratory volume in 1 second (FEV1), with a mean increase of 0.68 litres (95% CI: 0.45-0.91; SD: 0.20). Notably, other spirometry variables also showed meaningful improvements, providing evidence of positive treatment effects. Furthermore, there were no major long-term complications, and the procedure resulted in a significant enhancement in patient-reported domains using PedsQL (version 4.0). Conclusions This study represents the largest case series to date, on tracheal resection in patients with severe MPS IVA. Our findings demonstrate the effectiveness of the transcervical approach with partial manubriectomy for improving respiratory function and quality of life for individuals with advanced airway obstruction. Tracheal resection presents a promising treatment modality for severe cases of MPS IVA. Successful outcomes rely on meticulous multidisciplinary assessment, judicious decision-making, and appropriate timing of tracheal surgery. Further research and long-term follow-up studies are warranted to validate the long-term efficacy and safety of this approach.

Abstract Background Current clustering of multimorbidity based on the frequency of common disease combinations is inadequate. We estimated the causal relationships among prevalent diseases and mapped out the clusters of multimorbidity progression among them. Methods In this cohort study, we examined the progression of multimorbidity among 190 diseases among over 500,000 UK Biobank participants over 12.7 years of follow-up. Using a machine learning method for causal inference, we analyzed patterns of how diseases influenced and were influenced by others in females and males. We used clustering analysis and visualization algorithms to identify multimorbidity progress constellations. Results We show the top influential and influenced diseases largely overlap between sexes in chronic diseases, with sex-specific ones tending to be acute diseases. Patterns of diseases that influence and are influenced by other diseases also emerged (clustering significance P au > 0.87), with the top influential diseases affecting many clusters and the top influenced diseases concentrating on a few, suggesting that complex mechanisms are at play for the diseases that increase the development of other diseases while share underlying causes exist among the diseases whose development are increased by others. Bi-directional multimorbidity progress presents substantial clustering tendencies both within and across International Classification Disease chapters, compared to uni-directional ones, which can inform future studies for developing cross-specialty strategies for multimorbidity. Finally, we identify 10 multimorbidity progress constellations for females and 9 for males (clustering stability, adjusted Rand index >0.75), showing interesting differences between sexes. Conclusion Our findings could inform the future development of targeted interventions and provide an essential foundation for future studies seeking to improve the prevention and management of multimorbidity.

Background: Postoperative gastrointestinal dysfunction (POGD) remains a common morbidity after gastrointestinal surgery. POGD is associated with delayed hospital recovery, increased length of stay, poor patient satisfaction and experience, and increased economic hardship. The I-FEED scoring system was created by a group of experts to address the lack of a consistent objective definition of POGD. However, the I-FEED tool needs clinical validation before it can be adopted into clinical practice. The scope of this phase 1 Quality Improvement initiative involves the feasibility of implementing percussion into the nursing workflow without additional burden. Methods: All gastrointestinal/colorectal surgical unit registered nurses underwent comprehensive training in abdominal percussion. This involved understanding the technique, its application in postoperative gastrointestinal dysfunction assessment, and its integration into the existing nursing documentation in the Electronic Health Record (EHR). After six months of education and practice, a six-question survey was sent to all inpatient GI surgical unit nurses about incorporating the percussion assessment into their routine workflow and documentation. Results: Responses were received from 91% of day-shift nurses and 76% of night-shift registered nurses. Overall, 95% of the nurses were confident in completing the abdominal percussion during their daily assessment. Conclusion: Nurses’ effective use of the I-FEED tool may help improve patient outcomes after surgery. The tool could also be an effective instrument for the early identification of postoperative gastrointestinal dysfunction (POGD) in surgical patients.

BackgroundThere is a need for improved methodologies on how to longitudinally analyze, interpret and learn from the Surveys on Patient Safety Culture™ (SOPS), developed by the Agency for Healthcare Research and Quality (AHRQ). Typically, SOPS quantify results by the percentage of positive responses, but this approach may miss insights from neutral or negative feedback.Study designThe SOPS were distributed every two years from 2011 to 2022 to all hospital staff at one academic institution from perioperative services. Differences between rates of “positive” and “negative” scores (“Delta”), and “neutral” responses over time were calculated. The coefficient of determination (R2) was used to assess the correlation strength of the positive scores as the primary outcomes provided by the SOPS and Delta values over time. Finally, we evaluated patterns (crossing and converging [indicating “worrisome” patterns] vs. diverging [suggesting “desirable” pattern] vs. stable [suggesting “neutral” pattern]) of the longitudinal scores.ResultsA total of 1,035 responses were analyzed [51 and 40 survey items for SOPS v1 and v2 (2022 only), respectively]. Comparing the R2 values of the positive only scores to the Delta scores demonstrated a change in effect size for “Nonpunitive Response to Error” (R2 = 0.290 vs. 0.420). Of the 13 specific categories measured through SOPS, plotting negative vs. positive values elucidated 2 crossing, 2 converging and 2 diverging patterns indicating both a decrease in positive responses and an increase in negative responses rather than neutral.ConclusionLongitudinal analysis of the SOPS using the directional measures, Delta and pattern trends can provide organizations with additional key insights regarding culture of patient safety.

Abstract Generalized linear models (GLMs) are an integral tool in ecology. Like general linear models, GLMs assume linearity, which entails a linear relationship between independent and dependent variables. However, because this assumption acts on the link rather than the natural scale in GLMs, it is more easily overlooked. We reviewed recent ecological literature to quantify the use of linearity. We then used two case studies to confront the linearity assumption via two GLMs fit to empirical data. In the first case study we compared GLMs to generalized additive models (GAMs) fit to mammal relative abundance data. In the second case study we tested for linearity in occupancy models using passerine point‐count data. We reviewed 162 studies published in the last 5 years in five leading ecology journals and found less than 15% reported testing for linearity. These studies used transformations and GAMs more often than they reported a linearity test. In the first case study, GAMs strongly out‐performed GLMs as measured by AIC in modeling relative abundance, and GAMs helped uncover nonlinear responses of carnivore species to landscape development. In the second case study, 14% of species‐specific models failed a formal statistical test for linearity. We also found that differences between linear and nonlinear (i.e., those with a transformed independent variable) model predictions were similar for some species but not for others, with implications for inference and conservation decision‐making. Our review suggests that reporting tests for linearity are rare in recent studies employing GLMs. Our case studies show how formally comparing models that allow for nonlinear relationships between the dependent and independent variables has the potential to impact inference, generate new hypotheses, and alter conservation implications. We conclude by suggesting that ecological studies report tests for linearity and use formal methods to address linearity assumption violations in GLMs.

Dust is a sink for many semi-volatile compounds including flame retardants of the organophosphate ester (OPE) and brominated flame-retardant (BFR) classes. Given the large amount of time that we spend indoors, our exposure to these compounds via dust is of significant interest. Here, we present a novel microextraction approach to determine quantitative levels of selected OPEs and BFRs sampled from residential air filters from HVAC systems using a small volume of solvent. Dust samples (25 mg) is extracted with 1 mL of hexane/acetone (50/50, v/v). Upon solvent extraction of these HVAC dust samples, the analytes (TCPP, TDCPP, TPHP, T24DtBPP, TBBPA, and TriBBPA) were quantified via gas chromatography-mass spectrometry (GC/MS) or liquid chromatography-mass spectrometry (LC/MS). The methods for extracting these compounds from HVAC dust samples are detailed here with extensive method validation data to demonstrate accuracy and precision of these methods. • Dust is a sink for many semi-volatile compounds, including novel or emerging indoor pollutants like the organophosphate ester flame retardant T24DtBPP. • Here, a small amount of dust (25 mg) is extracted with a small volume of solvent (1 mL hexane and acetone) prior to analysis via chromatographic separation and mass spectrometric detection.

Abstract Background The Genetic Frontotemporal Initiative Staging Group has proposed clinical criteria for the diagnosis of prodromal frontotemporal dementia (FTD), termed mild cognitive and/or behavioral and/or motor impairment (MCBMI). The objective of the study was to validate the proposed research criteria for MCBMI-FTD in a cohort of genetically confirmed FTD cases against healthy controls. Methods A total of 398 participants were enrolled, 117 of whom were carriers of an FTD pathogenic variant with mild clinical symptoms, while 281 were non-carrier family members (healthy controls (HC)). A subgroup of patients underwent blood neurofilament light (NfL) levels and anterior cingulate atrophy assessment. Results The core clinical criteria correctly classified MCBMI vs HC with an AUC of 0.79 (p < 0.001), while the addition of either blood NfL or anterior cingulate atrophy significantly increased the AUC to 0.84 and 0.82, respectively (p < 0.001). The addition of both markers further increased the AUC to 0.90 (p < 0.001). Conclusions The proposed MCBMI criteria showed very good classification accuracy for identifying the prodromal stage of FTD.

Abstract INTRODUCTION Alzheimer's disease (AD) is the predominant dementia globally, with heterogeneous presentation and penetrance of clinical symptoms, variable presence of mixed pathologies, potential disease subtypes, and numerous associated endophenotypes. Beyond the difficulty of designing treatments that address the core pathological characteristics of the disease, therapeutic development is challenged by the uncertainty of which endophenotypic areas and specific targets implicated by those endophenotypes to prioritize for further translational research. However, publicly funded consortia driving large‐scale open science efforts have produced multiple omic analyses that address both disease risk relevance and biological process involvement of genes across the genome. METHODS Here we report the development of an informatic pipeline that draws from genetic association studies, predicted variant impact, and linkage with dementia associated phenotypes to create a genetic risk score. This is paired with a multi‐omic risk score utilizing extensive sets of both transcriptomic and proteomic studies to identify system‐level changes in expression associated with AD. These two elements combined constitute our target risk score that ranks AD risk genome‐wide. The ranked genes are organized into endophenotypic space through the development of 19 biological domains associated with AD in the described genetics and genomics studies and accompanying literature. The biological domains are constructed from exhaustive Gene Ontology (GO) term compilations, allowing automated assignment of genes into objectively defined disease‐associated biology. This rank‐and‐organize approach, performed genome‐wide, allows the characterization of aggregations of AD risk across biological domains. RESULTS The top AD‐risk‐associated biological domains are Synapse, Immune Response, Lipid Metabolism, Mitochondrial Metabolism, Structural Stabilization, and Proteostasis, with slightly lower levels of risk enrichment present within the other 13 biological domains. DISCUSSION This provides an objective methodology to localize risk within specific biological endophenotypes and drill down into the most significantly associated sets of GO terms and annotated genes for potential therapeutic targets.

Abstract INTRODUCTION We aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD). METHODS Neuropsychiatric and motor domains were added to the standard CDR plus NACC FTLD generating a new CDR plus NACC FTLD‐NM scale. This was assessed in 522 mutation carriers and 310 mutation‐negative controls from the Genetic Frontotemporal dementia Initiative (GENFI). RESULTS The new scale led to higher global severity scores than the CDR plus NACC FTLD: 1.4% of participants were now considered prodromal rather than asymptomatic, while 1.3% were now considered symptomatic rather than asymptomatic or prodromal. No participants with a clinical diagnosis of an FTD spectrum disorder were classified as asymptomatic using the new scales. DISCUSSION Adding new domains to the CDR plus NACC FTLD leads to a scale that encompasses the wider phenotypic spectrum of FTD with further work needed to validate its use more widely. Highlights The new Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains neuropsychiatric and motor (CDR plus NACC FTLD‐NM) rating scale was significantly positively correlated with the original CDR plus NACC FTLD and negatively correlated with the FTD Rating Scale (FRS). No participants with a clinical diagnosis in the frontotemporal dementia spectrum were classified as asymptomatic with the new CDR plus NACC FTLD‐NM rating scale. Individuals had higher global severity scores with the addition of the neuropsychiatric and motor domains. A receiver operating characteristic analysis of symptomatic diagnosis showed nominally higher areas under the curve for the new scales.

ABSTRACTPseudomonas aeruginosa is a ubiquitous bacterium and a notorious opportunistic pathogen that forms biofilm structures in response to many environmental cues. Biofilm formation includes attachment to surfaces and the production of the exopolysaccharide Pel, which is present in both the PAO1 and PA14 laboratory strains of P. aeruginosa. Biofilms help protect bacterial cells from host defenses and antibiotics and abet infection. The carbon source used by the cells also influences biofilm, but these effects have not been deeply studied. We show here that glycerol, which can be liberated from host surfactants during infection, encourages surface attachment and magnifies colony morphology differences. We find that glycerol kinase is important but not essential for glycerol utilization and relatively unimportant for biofilm behaviors. Among downstream enzymes predicted to take part in glycerol utilization, Edd stood out as being important for glycerol utilization and for enhanced biofilm phenotypes in the presence of glycerol. Thus, gluconeogenesis and catabolism of anabolically produced glucose appear to impact not only the utilization of glycerol but also glycerol-stimulated biofilm phenotypes. Finally, waxworm moth larvae and nematode infection models reveal that interruption of the Entner-Doudoroff pathway, but not abrogation of glycerol phosphorylation, unexpectedly increases P. aeruginosa lethality in both acute and chronic infections, even while stimulating a stronger immune response by Caenorhabditis elegans.IMPORTANCEPseudomonas aeruginosa, the ubiquitous environmental bacterium and human pathogen, forms multicellular communities known as biofilms in response to various stimuli. We find that glycerol, a common carbon source that bacteria can use for energy and biosynthesis, encourages biofilm behaviors such as surface attachment and colony wrinkling by P. aeruginosa. Glycerol can be derived from surfactants that are present in the human lungs, a common infection site. Glycerol-stimulated biofilm phenotypes do not depend on phosphorylation of glycerol but are surprisingly impacted by a glucose breakdown pathway, suggesting that it is glycerol utilization, and not its mere presence or cellular import, that stimulates biofilm phenotypes. Moreover, the same mutations that block glycerol-stimulated biofilm phenotypes also impact P. aeruginosa virulence in both acute and chronic animal models. Notably, a glucose-breakdown mutant (Δedd) counteracts biofilm phenotypes but shows enhanced virulence and stimulates a stronger immune response in Caenorhabditis elegans.

IntroductionPosterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by progressive impairment in visuospatial and perceptual function linked to atrophy of the occipito-parietal cortex. Besides the salient visual impairment, several studies have documented subtle changes in language may also be present. Sentence repetition is a highly constrained linguistic task involving multiple linguistic and cognitive processes and have been shown to be impaired in other AD spectrum disorders, with little consensus on its relevance in PCA. This aim of this study was to further delineate the linguistic and cognitive features of impaired language in PCA using a sentence repetition task.MethodSeven PCA patients and 16 healthy controls verbally repeated 16 sentences from the Boston Diagnostic Aphasia Examination. Responses were transcribed orthographically and coded for accuracy (percentage accuracy; percentage Correct Information Units; Levenshtein Distance) and for temporal characteristics (preparation duration (ms); utterance duration (ms); silent pause duration (ms); speech duration (ms); dysfluency duration (ms)). The potential modulating effects of attentional control and working memory capacity were explored.ResultsPCA patients showed lower overall accuracy with retained semantic content of the sentences, and lower phonological accuracy. Temporal measures revealed longer preparation and utterance duration for PCA patients compared to controls, alongside longer speech duration but comparable dysfluency duration. PCA patients also showed comparable silent pause duration to controls. Attentional control, measured using the Hayling sentence completion task, predicted accuracy of sentence repetition.DiscussionThe findings suggest that sentence repetition is impaired in PCA and is characterized by phonological, response planning and execution difficulties, underpinned in part by attentional control mechanisms. The emerging profile of language impairment in PCA suggests vulnerability of similar cognitive systems to other Alzheimer’s syndromes, with subtle differences in clinical presentation.

Background Sudden cardiac death (SCD) is a significant global public health problem accounting for 15% to 20% of all deaths. A great majority of SCD is associated with coronary heart disease, which may first be detected at autopsy. The ankle–brachial index (ABI) is a simple, noninvasive measure of subclinical atherosclerosis. The purpose of this study was to examine the relationship between ABI and SCD in a middle‐aged biracial general population. Methods and Results Participants of the ARIC (Atherosclerosis Risk in Communities) study with an ABI measurement between 1987 and 1989 were included. ABI was categorized as low (≤0.90), borderline (0.90–1.00), normal (1.00–1.40), and noncompressible (>1.40). SCD was defined as a sudden pulseless condition presumed to be caused by a ventricular tachyarrhythmia in a previously stable individual and was adjudicated by a committee of cardiac electrophysiologists, cardiologists, and internists. Cox proportional hazards models were used to evaluate the associations between baseline ABI and incident SCD. Of the 15 081 participants followed for a median of 23.5 years, 556 (3.7%) developed SCD (1.96 cases per 1000 person‐years). Low and borderline ABIs were associated with an increased risk of SCD (demographically adjusted hazard ratios [HRs], 2.27 [95% CI, 1.64–3.14] and 1.52 [95% CI, 1.17–1.96], respectively) compared with normal ABI. The association between low ABI and SCD remained significant after adjustment for traditional cardiovascular risk factors (HR, 1.63 [95% CI, 1.15–2.32]). Conclusions Low ABI is independently associated with an increased risk of SCD in a middle‐aged biracial general population. ABI could be incorporated into future SCD risk prediction models.

Background Pulse wave velocity (PWV) is a noninvasive measure of arterial stiffness and predictor of cardiovascular disease. However, the association between PWV and vascular calcification across different vascular beds has not been fully investigated. This study aimed to quantify the association between PWV and multiterritory calcification and to explore whether PWV can identify individuals with vascular calcification beyond traditional risk factors. Methods and Results Among 1351 older adults (mean age, 79.2 years [SD, 4.1]) from the ARIC (Atherosclerosis Risk in Communities) study, we measured segment‐specific PWVs: heart–carotid, heart–femoral, carotid–femoral, heart–ankle, brachial–ankle, and femoral–ankle. Dependent variables were high calcium score (≥75th percentile of Agatston score) across different vascular beds: coronary arteries, aortic valve ring, aortic valve, mitral valve, ascending aorta, and descending aorta. Quartiles of carotid–femoral, heart–femoral, heart–ankle, and brachial–ankle PWV were significantly associated with coronary artery calcium (eg, adjusted odds ratio [OR] for the highest versus lowest quartile of carotid–femoral PWV, 1.84 [95% CI, 1.24–2.74]). Overall, PWVs were most strongly associated with descending aorta calcification, with significant results for carotid–femoral, heart–femoral, heart–ankle, and brachial–ankle PWV (eg, adjusted OR for the highest versus lowest quartile of carotid–femoral PWV, 3.99 [95% CI, 2.61–6.17]). In contrast, femoral–ankle PWV was inversely associated with descending aorta calcification. Some PWVs improved the discrimination of coronary artery calcium and descending aorta calcification beyond traditional risk factors. Conclusions The associations of PWV with vascular calcification varied substantially across segments, with descending aorta calcification most closely linked to PWVs. Our study suggests that some PWVs, especially carotid–femoral PWV, are helpful to identify individuals with coronary artery calcium and descending aorta calcification.

Background Right ventricular ejection fraction (RVEF) and end‐diastolic volume (RVEDV) are not readily assessed through traditional modalities. Deep learning–enabled ECG analysis for estimation of right ventricular (RV) size or function is unexplored. Methods and Results We trained a deep learning–ECG model to predict RV dilation (RVEDV >120 mL/m2), RV dysfunction (RVEF ≤40%), and numerical RVEDV and RVEF from a 12‐lead ECG paired with reference‐standard cardiac magnetic resonance imaging volumetric measurements in UK Biobank (UKBB; n=42 938). We fine‐tuned in a multicenter health system (MSHoriginal [Mount Sinai Hospital]; n=3019) with prospective validation over 4 months (MSHvalidation; n=115). We evaluated performance with area under the receiver operating characteristic curve for categorical and mean absolute error for continuous measures overall and in key subgroups. We assessed the association of RVEF prediction with transplant‐free survival with Cox proportional hazards models. The prevalence of RV dysfunction for UKBB/MSHoriginal/MSHvalidation cohorts was 1.0%/18.0%/15.7%, respectively. RV dysfunction model area under the receiver operating characteristic curve for UKBB/MSHoriginal/MSHvalidation cohorts was 0.86/0.81/0.77, respectively. The prevalence of RV dilation for UKBB/MSHoriginal/MSHvalidation cohorts was 1.6%/10.6%/4.3%. RV dilation model area under the receiver operating characteristic curve for UKBB/MSHoriginal/MSHvalidation cohorts was 0.91/0.81/0.92, respectively. MSHoriginal mean absolute error was RVEF=7.8% and RVEDV=17.6 mL/m2. The performance of the RVEF model was similar in key subgroups including with and without left ventricular dysfunction. Over a median follow‐up of 2.3 years, predicted RVEF was associated with adjusted transplant‐free survival (hazard ratio, 1.40 for each 10% decrease; P=0.031). Conclusions Deep learning–ECG analysis can identify significant cardiac magnetic resonance imaging RV dysfunction and dilation with good performance. Predicted RVEF is associated with clinical outcome.

A 43-year-old man presented with severe heart failure secondary to high-risk light chain cardiac amyloidosis. He underwent chemotherapy and autologous stem cell transplantation with complete hematologic response. Serial cardiac magnetic resonance imaging post-transplant demonstrated gradual normalization of biventricular function and myocardial T1, a surrogate measure of disease burden.

Virtual field trips in physical geography transcend our human limitations regarding distance and accessibility, allowing students to experience exemplars of physical environments. These experiences can be critical for students to connect to the physical world beyond traditional classroom formats of communicating themes and features in physical geography. To maximize the learning potential of these experiences, designers must engage in a translational process to take resources and content from the physical world and migrate it to an online, virtual format. However, these virtual learning experiences need to account for how learners learn; and should draw heavily on the foundations of educational research and field sciences, while highlighting the awe and beauty of the natural landscape itself. Crafting these spatial stories of the natural world with learning elements requires careful and intentional design to maximize the perception of physical features, patterns, and processes at the landscape scale. To help field-trip developers comprehend the workflows used to create perceptible, rich environments that spur students’ learning, we propose a development process (TECCUPD) as a guide to navigate the intersection of education and science, using an example of geodiversity and alpine glacial landscapes found in Glacier National Park, Montana.

Background: Transcranial ultrasound stimulation (TUS) holds promise as a novel technology for non-invasive neuromodulation, with greater spatial precision than other available methods and the ability to target deep brain structures. However, its safety and efficacy for behavioural and electrophysiological modulation remains controversial and it is not yet clear whether it can be used to manipulate the neural mechanisms supporting higher cognitive function in humans. Moreover, concerns have been raised about a potential TUS-induced auditory confound. Objectives: We aimed to investigate whether TUS can be used to modulate higher-order visual function in humans in an anatomically-specific way whilst controlling for auditory confounds. Methods: We used participant-specific skull maps, functional localisation of brain targets, acoustic modelling and neuronavigation to guide TUS delivery to human visual motion processing cortex (hMT+) whilst participants performed a visual motion detection task. We compared the effects of hMT+ stimulation with sham and control site stimulation and examined EEG data for modulation of task-specific event-related potentials. An auditory mask was applied which prevented participants from distinguishing between stimulation and sham trials. Results: Compared with sham and control site stimulation, TUS to hMT+ improved accuracy and reduced response times of visual motion detection. TUS also led to modulation of the task-specific event-related EEG potential. The amplitude of this modulation correlated with the performance benefit induced by TUS. No pathological changes were observed comparing structural MRI obtained before and after stimulation. Conclusions: The results demonstrate for the first time the precision, efficacy and safety of TUS for stimulation of higher-order cortex and cognitive function in humans whilst controlling for auditory confounds.

Abstract Background Approximately a third of frontotemporal dementia (FTD) is genetic with mutations in three genes accounting for most of the inheritance: C9orf72, GRN, and MAPT. Impaired synaptic health is a common mechanism in all three genetic variants, so developing fluid biomarkers of this process could be useful as a readout of cellular dysfunction within therapeutic trials. Methods A total of 193 cerebrospinal fluid (CSF) samples from the GENetic FTD Initiative including 77 presymptomatic (31 C9orf72, 23 GRN, 23 MAPT) and 55 symptomatic (26 C9orf72, 17 GRN, 12 MAPT) mutation carriers as well as 61 mutation-negative controls were measured using a microflow LC PRM-MS set-up targeting 15 synaptic proteins: AP-2 complex subunit beta, complexin-2, beta-synuclein, gamma-synuclein, 14–3-3 proteins (eta, epsilon, zeta/delta), neurogranin, Rab GDP dissociation inhibitor alpha (Rab GDI alpha), syntaxin-1B, syntaxin-7, phosphatidylethanolamine-binding protein 1 (PEBP-1), neuronal pentraxin receptor (NPTXR), neuronal pentraxin 1 (NPTX1), and neuronal pentraxin 2 (NPTX2). Mutation carrier groups were compared to each other and to controls using a bootstrapped linear regression model, adjusting for age and sex. Results CSF levels of eight proteins were increased only in symptomatic MAPT mutation carriers (compared with controls) and not in symptomatic C9orf72 or GRN mutation carriers: beta-synuclein, gamma-synuclein, 14–3-3-eta, neurogranin, Rab GDI alpha, syntaxin-1B, syntaxin-7, and PEBP-1, with three other proteins increased in MAPT mutation carriers compared with the other genetic groups (AP-2 complex subunit beta, complexin-2, and 14–3-3 zeta/delta). In contrast, CSF NPTX1 and NPTX2 levels were affected in all three genetic groups (decreased compared with controls), with NPTXR concentrations being affected in C9orf72 and GRN mutation carriers only (decreased compared with controls). No changes were seen in the CSF levels of these proteins in presymptomatic mutation carriers. Concentrations of the neuronal pentraxins were correlated with brain volumes in the presymptomatic period for the C9orf72 and GRN groups, suggesting that they become abnormal in proximity to symptom onset. Conclusions Differential synaptic impairment is seen in the genetic forms of FTD, with abnormalities in multiple measures in those with MAPT mutations, but only changes in neuronal pentraxins within the GRN and C9orf72 mutation groups. Such markers may be useful in future trials as measures of synaptic dysfunction, but further work is needed to understand how these markers change throughout the course of the disease.

Abstract Background Monoacylglycerol lipase (MAGL) is a key serine hydrolase which terminates endocannabinoid signaling and regulates arachidonic acid driven inflammatory responses within the central nervous system. To develop [11C]PF-06809247 into a clinically usable MAGL positron emission tomography (PET) radioligand, we assessed the occupancy of MAGL by an inhibitor in the non-human primate (NHP) brain. Additionally, we measured the whole-body distribution of [11C]PF-06809247 in NHP and estimated human effective radiation doses. Methods Seven cynomolgus monkeys were enrolled for brain PET measurements. Two PET measurements along with arterial blood sampling were performed in each NHP: one baseline and one pretreatment condition with intravenous administration of PF-06818883, a pro-drug of a selective MAGL inhibitor (total of seven doses between 0.01 and 1.27 mg/kg). Kinetic parameters K 1, k 2 and k 3 were estimated by a two tissue compartment (2TC) model using metabolite corrected plasma radioactivity as the input function. k 4 was set as 0 according to the irreversible binding of [11C]PF-06809247. K i by 2TC and Patlak analysis were calculated as the influx constant. The target occupancy was calculated using K i at baseline and pretreatment conditions. Two cynomolgus monkeys were enrolled for whole-body PET measurements. Estimates of the absorbed radiation dose in humans were calculated with OLINDA/EXM 1.1 using the adult male reference model. Results Radioactivity retention was decreased in all brain regions following pretreatment with PF-06818883. Occupancy was measured as 25.4–100.5% in a dose dependent manner. Whole-body PET showed high radioactivity uptake values in the liver, small intestine, kidney, and brain. The effective dose of [11C]PF-06809247 was calculated as 4.3 μSv/MBq. Conclusions [11C]PF-06809247 is a promising PET ligand for further studies of MAGL in the human brain.

Abstract Background A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD.

Summary: Decellularization of esophagi from several species for tissue engineering is well described, but successful implantation in animal models of esophageal replacement has been challenging. The purpose of this study was to assess feasibility and applicability of esophageal replacement using decellularized porcine esophageal scaffolds in a new pre-clinical model. Following surgical replacement in rabbits with a vascularizing muscle flap, we observed successful anastomoses of decellularized scaffolds, cues of early neovascularization, and prevention of luminal collapse by the use of biodegradable stents. However, despite the success of the surgical procedure, the long-term survival was limited by the fragility of the animal model. Our results indicate that transplantation of a decellularized porcine scaffold is possible and vascular flaps may be useful to provide a vascular supply, but long-term outcomes require further pre-clinical testing in a different large animal model.

Abstract Proteogenomics is an increasingly common method for species identification as it allows for rapid and inexpensive interrogation of an unknown organism’s proteome—even when the proteome is partially degraded. The proteomic method typically uses tandem mass spectrometry to survey all peptides detectable in a sample that frequently contains hundreds or thousands of proteins. Species identification is based on detection of a small numbers of species-specific peptides. Genetic analysis of proteins by mass spectrometry, however, is a developing field, and the bone proteome, typically consisting of only two proteins, pushes the limits of this technology. Nearly 20% of highly confident spectra from modern human bone samples identify non-human species when searched against a vertebrate database—as would be necessary with a fragment of unknown bone. These non-human peptides are often the result of current limitations in mass spectrometry or algorithm interpretation errors. Consequently, it is difficult to know if a “species-specific” peptide used to identify a sample is actually present in that sample. Here we evaluate the causes of peptide sequence errors and propose an unbiased, probabilistic approach to determine the likelihood that a species is correctly identified from bone without relying on species-specific peptides.

Upper cross syndrome (UCS) is a condition caused from prolonged poor posture manifesting as thoracic hyperkyphosis with forward head and shoulder postures. It has been associated with several other secondary conditions, causing pain and discomfort to those with the condition. This is a case report of a 35-year-old female presenting to clinic with a sharp pain in the neck, upper back, and sternum area for 4 weeks and gastroesophageal reflux disease (GERD). She had been working at home for several months after the shelter at home order was issued. Following evaluation and corrective treatment with cervical adjustment and soft tissue massage, the patient’s posture improved and reported full pain resolution. Her symptoms of GERD concurrently resolved as well. She continued to receive chiropractic adjustment two times per month for correcting spinal misalignment. Full restoration of posture was attained on the full spine radiographs at 9 months follow-up. The patient remained symptom-free at 12 months follow-up. Manipulative and preventive therapies aimed at treating and preventing UCS should be more widely adopted to prevent secondary conditions.

Low socioeconomic status (SES) and living in a disadvantaged neighborhood are associated with poor cardiovascular health. Multiple lines of evidence have linked DNA methylation to both cardiovascular risk factors and social disadvantage indicators. However, limited research has investigated the role of DNA methylation in mediating the associations of individual- and neighborhood-level disadvantage with multiple cardiovascular risk factors in large, multi-ethnic, population-based cohorts. We examined whether disadvantage at the individual level (childhood and adult SES) and neighborhood level (summary neighborhood SES as assessed by Census data and social environment as assessed by perceptions of aesthetic quality, safety, and social cohesion) were associated with 11 cardiovascular risk factors including measures of obesity, diabetes, lipids, and hypertension in 1,154 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). For significant associations, we conducted epigenome-wide mediation analysis to identify methylation sites mediating the relationship between individual/neighborhood disadvantage and cardiovascular risk factors using the JT-Comp method that assesses sparse mediation effects under a composite null hypothesis. In models adjusting for age, sex, race/ethnicity, smoking, medication use, and genetic principal components of ancestry, epigenetic mediation was detected for the associations of adult SES with body mass index (BMI), insulin, and high-density lipoprotein cholesterol (HDL-C), as well as for the association between neighborhood socioeconomic disadvantage and HDL-C at FDR q < 0.05. The 410 CpG mediators identified for the SES-BMI association were enriched for CpGs associated with gene expression (expression quantitative trait methylation loci, or eQTMs), and corresponding genes were enriched in antigen processing and presentation pathways. For cardiovascular risk factors other than BMI, most of the epigenetic mediators lost significance after controlling for BMI. However, 43 methylation sites showed evidence of mediating the neighborhood socioeconomic disadvantage and HDL-C association after BMI adjustment. The identified mediators were enriched for eQTMs, and corresponding genes were enriched in inflammatory and apoptotic pathways. Our findings support the hypothesis that DNA methylation acts as a mediator between individual- and neighborhood-level disadvantage and cardiovascular risk factors, and shed light on the potential underlying epigenetic pathways. Future studies are needed to fully elucidate the biological mechanisms that link social disadvantage to poor cardiovascular health.

Type A GABA receptors (GABAARs) are pentameric combinations of protein subunits that give rise to tonic (ITonicGABA) and phasic (i.e., synaptic; ISynapticGABA) forms of inhibitory GABAAR signaling in the central nervous system. Remodeling and regulation of GABAAR protein subunits are implicated in a wide variety of healthy and injury-dependent states, including epilepsy. The present study undertook a detailed analysis of GABAAR signaling using whole-cell patch clamp recordings from mouse dentate granule cells (DGCs) in coronal slices containing dorsal hippocampus at 1–2 or 8–13 weeks after a focal, controlled cortical impact (CCI) or sham brain injury. Zolpidem, a benzodiazepine-like positive modulator of GABAARs, was used to test for changes in GABAAR signaling of DGCs due to its selectivity for α1 subunit-containing GABAARs. Electric charge transfer and statistical percent change were analyzed in order to directly compare tonic and phasic GABAAR signaling and to account for zolpidem’s ability to modify multiple parameters of GABAAR kinetics. We observed that baseline ITonicGABA is preserved at both time-points tested in DGCs ipsilateral to injury (Ipsi-DGCs) compared to DGCs contralateral to injury (Contra-DGCs) or after sham injury (Sham-DGCs). Interestingly, application of zolpidem resulted in modulation of ITonicGABA across groups, with Ipsi-DGCs exhibiting the greatest responsiveness to zolpidem. We also report that the combination of CCI and acute application of zolpidem profoundly augments the proportion of GABAAR charge transfer mediated by tonic vs. synaptic currents at both time-points tested, whereas gene expression of GABAAR α1, α2, α3, and γ2 subunits is unchanged at 8–13 weeks post-injury. Overall, this work highlights the shift toward elevated influence of tonic inhibition in Ipsi-DGCs, the impact of zolpidem on all components of inhibitory control of DGCs, and the sustained nature of these changes in inhibitory tone after CCI injury.