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Resting-state alpha brain rhythms provide a foundation for basic as well as higher-order brain processes. Research suggests atypical maturation of the peak frequency of resting-state alpha activity (= PAF) in autism spectrum disorder (ASD). The present study examined resting-state alpha activity in young school-aged children, obtaining magnetoencephalographic (MEG) eyes-closed resting-state data from 47 typically developing (TD) males and 45 ASD males 6.0 to 9.3 years old. Results confirmed a higher PAF in ASD versus TD, and demonstrated that alpha power differences between groups were linked to the shift of PAF in ASD. Additionally, a higher PAF was associated with better cognitive performance in TD but not ASD. Finding thus suggested functional consequences of group differences in resting-state alpha activity.

Prolonged ischemic priapism presents a treatment challenge given the difficulty in achieving detumescence and effects on sexual function. To evaluate current practice patterns, an open, web-based multi-institutional survey querying surgeons' experience with and perceived efficacy of tunneling maneuvers (corporoglanular tunneling and penoscrotal decompression), as well as impressions of erectile recovery, was administered to members of societies specializing in male genital surgery. Following distribution, 141 responses were received. Tunneling procedures were the favored first-line surgical intervention in the prolonged setting (99/139, 71.2% tunneling vs. 14/139, 10.1% implant, p

Abstract Evasion of cell death is a hallmark of cancer, and consequently the induction of cell death is a common strategy in cancer treatment. However, the molecular mechanisms regulating different types of cell death are poorly understood. We have formerly shown that in the epidermis of hypomorphic zebrafish hai1a mutant embryos, pre-neoplastic transformations of keratinocytes caused by unrestrained activity of the type II transmembrane serine protease Matriptase-1 heal spontaneously. This healing is driven by Matriptase-dependent increased sphingosine kinase (SphK) activity and sphingosine-1-phosphate (S1P)-mediated keratinocyte loss via apical cell extrusion. In contrast, amorphic hai1a fr26 mutants with even higher Matriptase-1 and SphK activity die within a few days. Here we show that this lethality is not due to epidermal carcinogenesis, but to aberrant tp53-independent apoptosis of keratinocytes caused by increased levels of pro-apoptotic C16 ceramides, sphingolipid counterparts to S1P within the sphingolipid rheostat, which severely compromises the epidermal barrier. Mathematical modelling of sphingolipid rheostat homeostasis, combined with in vivo manipulations of components of the rheostat or the ceramide de novo synthesis pathway, indicate that this unexpected overproduction of ceramides is caused by a negative feedback loop sensing ceramide levels and controlling ceramide replenishment via de novo synthesis. Therefore, despite their initial decrease due to increased conversion to S1P, ceramides eventually reach cell death-inducing levels, making transformed pre-neoplastic keratinocytes die even before they are extruded, thereby abrogating the normally barrier-preserving mode of apical live cell extrusion. Our results offer an in vivo perspective of the dynamics of sphingolipid homeostasis and its relevance for epithelial cell survival versus cell death, linking apical cell extrusion and apoptosis. Implications for human carcinomas and their treatments are discussed.

Abstract Background Experimental studies indicate that phytocannabinoids have immune-modulatory properties. However, the effects of chronic cannabis use (CCU) in adolescents on their immune cells have been scarcely investigated to date, although CCU is increasingly observed in this age group. Methods In this study, we analyzed DNA methylation and gene expression of immune cell markers in whole-blood samples of adolescent CCU-outpatients and non-cannabis-using (NCU) controls (n = 14 vs. n = 15, mean age = 16.1 ± 1.3 years). Site-specific DNA methylation values were used to calculate A) proportion estimates of circulating white blood cell (WBC) types and B) mean DNA methylation values of common immune cell markers (CD4, CD8A, CD19, FCGR3A, CD14, FUT4, MPO), whose gene expression levels were additionally determined. Results CCU adolescents had a lower estimated proportion of B cells compared to NCU subjects. An originally observed higher proportion of granulocytes in CCU subjects, however, was attenuated when controlling for past-year tobacco use. The observed differences in mean DNA methylation and gene expression of immune cell markers were not statistically significant. Conclusion The results of our explorative study indicate that CCU in adolescents is associated with altered levels of circulating WBCs. Further studies with larger cohorts are warranted to confirm our findings and to provide insights regarding their functional consequences.

Abstract Personalized treatment for patients with advanced solid tumors critically depends on the deep characterization of tumor cells from patient biopsies. Here, we comprehensively characterize a pan-cancer cohort of 150 malignant serous effusion (MSE) samples at the cellular, molecular, and functional level. We find that MSE-derived cancer cells retain the genomic and transcriptomic profiles of their corresponding primary tumors, validating their use as a patient-relevant model system for solid tumor biology. Integrative analyses reveal that baseline gene expression patterns relate to global ex vivo drug sensitivity, while high-throughput drug-induced transcriptional changes in MSE samples are indicative of drug mode of action and acquired treatment resistance. A case study exemplifies the added value of multi-modal MSE profiling for patients who lack genetically stratified treatment options. In summary, our study provides a functional multi-omics view on a pan-cancer solid tumor cohort and underlines the feasibility and utility of MSE-based precision oncology.

This paper employs a qualitative case study to suggest how the research journey of doctoral students can be improved in educational institutions by encouraging the formation of small and informal Communities of Practice (CoP). It examines themes emerging from the feelings and opinions of four part-time professional doctorate students about their study experience and participation in their emergent CoP. A peer group developed where the students share their experience, expertise, insight, and knowledge in a caring and supportive, but informal, forum. CoP could become an effective tool to aid retention, identity development and wellbeing of postgraduate level students, factors which have been previously identified as key areas of risk. An autoethnographic approach was used to review the feelings, perceptions, and opinions of the four case study group members about their experiences of the informal CoP to date. Thematic analysis of transcripts and WhatsApp communications was used to reveal the perceived common benefits and gains from participation in the informal CoP such as joy, safe spaces, and identity development, aligning members experiences to a CoP lifecycle. The study found small group formation at doctoral programme induction, and encouragement for students to organise their own regular study days using of social channels, may impact overall success. Application and adaptation of this doctoral CoP model could form the basis for future research and a model for academic institutions to suggest to new and existing students

Abstract Background Trigeminal‐mediated headshaking is a neuropathic facial pain condition in horses. No treatment has been entirely successful. Repetitive transcranial magnetic stimulation (rTMS) is used in human medicine as a treatment for various neuropathic pain conditions, and good results have been achieved in cases of trigeminal neuralgia. Objectives Apply rTMS to horses with trigeminal‐mediated headshaking (TMHS) and to evaluate tolerability, application of the setting, and success rate. Animals Seventeen horses with nonseasonal signs of TMHS. Methods Other underlying causes of headshaking were ruled out. The rTMS was performed under standing sedation on 5 consecutive days applying 3 sets of 500 stimulations each, with a stimulation strength of 5 Hz. Horses were evaluated on Day 1 (t0) and Day 5 (t1) of the treatment and 2 (t2) and 4 weeks (t3) afterwards using a special scoring system. Results The rTMS was well tolerated. Headshaking signs during exercise were decreased by 70% (Day 5; t1). Four weeks after rTMS, signs were still decreased (mean reduction of 50%) during exercise. Improvement of mean resting and exercise scores was significant (P ±0.8). Conclusions and Clinical Importance Repetitive transcranial magnetic stimulation may be a promising treatment for neuropathic pain and headshaking in affected horses. Pain‐free periods after treatment differ individually, and repeated treatment may be necessary. More studies should be performed to determine ideal settings for horses.

Instructional quality is a central element in the context of teaching and learning. However, there is still a lack of clarity on what is meant by good inclusive education. In the present study, N = 24 primary school teachers from Germany were interviewed about their understanding of good inclusive teaching. The results of the qualitative study reveal that there are several factors, which are seen as essential for the quality of inclusive education. The features of good inclusive teaching mentioned by the primary school teachers especially refer to differentiation and individualisation. Furthermore, the interviewed teachers emphasise the support of community and a positive learning climate as important characteristics of good inclusive teaching. The findings of this study also reveal that for some of the teachers, there seems to be no difference between good inclusive teaching and good regular teaching. Other mentioned features for the quality of inclusive education refer to team teaching and the availability of specific framework conditions such as personnel or spatial resources.

This study was launched after re-analyzing teacher narratives from an earlier study; the narratives were reflections on environmental education practices. The analysis involved using a framework that relates Habits of Mind to educational theories. An unsurprising outcome was finding Habits of Mind associated with mindfulness and constructivism. An unanticipated finding was to learn how incremental learning theory explains why teachers strive to include environmental education in their lessons. Although there has been environmental research related to growth and fixed mindsets, more studies in environmental education are needed to explore how incremental learning theory plays a role in the decisions and actions of exemplary environmental educators. Therefore, to begin this exploration, a new study was conducted using the framework to analyze interviews with ten currently practicing teachers. The findings give insights into the following Habits of Mind associated with incremental beliefs: wonderment and awe, continuous learning, striving for accuracy, risk-taking, and persistence.

Study objectivesAdolescence is characterized by significant brain development, accompanied by changes in sleep timing and architecture. It also is a period of profound psychosocial changes, including the initiation of alcohol use; however, it is unknown how alcohol use affects sleep architecture in the context of adolescent development. We tracked developmental changes in polysomnographic (PSG) and electroencephalographic (EEG) sleep measures and their relationship with emergent alcohol use in adolescents considering confounding effects (e.g. cannabis use).MethodsAdolescents (n = 94, 43% female, age: 12-21 years) in the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study had annual laboratory PSG recordings across 4-years. Participants were no/low drinkers at baseline.ResultsLinear mixed effect models showed developmental changes in sleep macrostructure and EEG, including a decrease in slow wave sleep and slow wave (delta) EEG activity with advancing age. Emergent moderate/heavy alcohol use across three follow-up years was associated with a decline in percentage rapid eye movement (REM) sleep over time, a longer sleep onset latency (SOL) and shorter total sleep time (TST) in older adolescents, and lower non-REM delta and theta power in males.ConclusionsThese longitudinal data show substantial developmental changes in sleep architecture. Emergent alcohol use during this period was associated with altered sleep continuity, architecture, and EEG measures, with some effects dependent on age and sex. These effects, in part, could be attributed to the effects of alcohol on underlying brain maturation processes involved in sleep-wake regulation.

Baited traps are a basic component of both specific and generic surveillance programs targeting wood-boring beetles at risk of introduction to new habitats because of global trade. Among the numerous protocols developed over the years for generic surveillance of longhorn beetles, jewel beetles, and bark and ambrosia beetles is the simultaneous use of black multi-funnel traps set up in the understory and green multi-funnel traps set up in the canopy of forested areas surrounding ports and other entry points. These traps are commonly baited with multi-lure blends of pheromones and host volatiles. In this study, we tested this trapping protocol in areas surrounding eight entry points located in Europe and North America to determine: i) the relative performance of black-understory traps and green-canopy traps among the targeted taxa; and ii) whether the dissimilarity among communities of beetles collected by the understory vs. canopy traps was affected by taxon and amount of forest cover in the traps’ surroundings. A total of 96,963 individuals belonging to 358 species of wood-boring beetles were collected, including 21 non-native species. Black-understory multi-funnel traps were generally more efficient than green-canopy multi-funnel traps for detecting longhorn beetles and bark and ambrosia beetles, whereas the opposite trend was observed for jewel beetles. Differences between beetle communities caught in black-understory and green-canopy traps were mainly attributed to differences in species richness in jewel beetles, while both differences in species richness and species turnover contributed to the dissimilarity between communities of longhorn beetles and bark and ambrosia beetle. The difference in the number of jewel beetle species caught by the two trapping methodologies decreased with increasing forest cover, whereas species turnover increased when moving from an urban-dominated to a forest-dominated landscape. Overall, these results suggest that the simultaneous use of both black-understory and green-canopy multi-funnel traps can be considered a very efficient approach for generic surveillance of longhorn beetles, jewel beetles and bark and ambrosia beetles in both urban-dominated and forest-dominated areas surrounding entry points.

Kristine Jensen,1 Thomas Egenod,2 Daniel P Franzen,3,4 Michael Perch1,5 1Department of Cardiology, Section for Lung Transplantation and Respiratory Medicine, Rigshospitalet Heart Center, Copenhagen, Denmark; 2Department of Interventional Pulmonology, Dupuytren University Hospital, Limoges, France; 3Department of Internal Medicine, Uster Hospital, Uster, Switzerland; 4Department of Pulmonology, University of Zurich, Zurich, Switzerland; 5Department of Clinical Medicine, University of Copenhagen, Copenhagen, DenmarkCorrespondence: Michael Perch, Department of Cardiology, Section for Lung Transplantation and Respiratory Medicine, Rigshospitalet, Heart Center, Inge Lehmanns Vej 7, Copenhagen, 2100, Denmark, Email Michael.perch@regionH.dkAbstract: Endoscopic lung volume reduction (ELVR) is an established treatment option for patients with severe emphysema. Not all patients are candidates for this type of intervention, and in the context of significant airway secretions, they may be excluded from treatment. Bronchial Rheoplasty (BR) was developed to treat mucus hypersecretion by delivering nonthermal pulsed electric fields to the airway epithelium and submucosa. The literature to date demonstrates that patients treated with BR in clinical studies have a reduction in airway goblet cell hyperplasia as well as substantive clinical improvement in the setting of chronic bronchitis (CB). In this case series, we present four patients treated at three different institutions who had previously undergone ELVR with beneficial outcome. However, over time, these patients subsequently developed worsening clinical issues, including complaints of increased and thickened mucus, along with exacerbations in the setting of a loss of some ELVR-associated benefits. These patients then underwent exploratory treatment with BR with the intent of reducing their secretion burden and potentially restoring the efficacy associated with the initial placement of the airway valves. All BR procedures were well tolerated, and three of the four patients showed substantial improvement in their symptom burden. Airway examinations during the second of the two BR procedures also revealed what appeared to be less airway mucosal inflammation and a decrease in the quantity of airway secretions. Therefore, treatment with BR may have the potential to improve and restore the initial benefits associated with ELVR, thus enhancing long-term outcomes. Further clinical studies with sufficient follow-up are warranted to assess this in a larger cohort of patients, and to determine whether treatment with BR prior to ELVR may make more patients eligible for this treatment through reduction in their secretions and/or symptoms.Keywords: bronchial rheoplasty, endobronchial valves, emphysema

Abstract Overly restrictive clinical trial eligibility criteria can reduce generalizability, slow enrollment, and disproportionately exclude historically underrepresented populations. The eligibility criteria for 196 Alzheimer’s Disease and Related Dementias (AD/ADRD) trials funded by the National Institute on Aging were analyzed to identify common criteria and their potential to disproportionately exclude participants by race/ethnicity. The trials were categorized by type (48 Phase I/II pharmacological, 7 Phase III/IV pharmacological, 128 non-pharmacological, 7 diagnostic, and 6 neuropsychiatric) and target population (51 AD/ADRD, 58 Mild Cognitive Impairment, 25 at-risk, and 62 cognitively normal). Eligibility criteria were coded into the following categories: Medical, Neurologic, Psychiatric, and Procedural. A literature search was conducted to describe the prevalence of disparities for eligibility criteria for African Americans/Black (AA/B), Hispanic/Latino (H/L), American Indian/Alaska Native (AI/AN) and Native Hawaiian/Pacific Islander (NH/PI) populations. The trials had a median of 15 criteria. The most frequent criterion were age cutoffs (87% of trials), specified neurologic (65%), and psychiatric disorders (61%). Underrepresented groups could be disproportionately excluded by 16 eligibility categories; 42% of trials specified English-speakers only in their criteria. Most trials (82%) contain poorly operationalized criteria (i.e., criteria not well defined that can have multiple interpretations/means of implementation) and criteria that may reduce racial/ethnic enrollment diversity.

Abstract There are two known mechanisms by which natural killer (NK) cells recognize and kill diseased targets: (i) direct killing and (ii) antibody-dependent cell-mediated cytotoxicity (ADCC). We investigated an indirect NK cell activation strategy for the enhancement of human NK cell killing function. We did this by leveraging the fact that toll-like receptor 9 (TLR9) agonism within pools of human peripheral blood mononuclear cells (PBMCs) results in a robust interferon signaling cascade that leads to NK cell activation. After TLR9 agonist stimulation, NK cells were enriched and incorporated into assays to assess their ability to kill tumor cell line targets. Notably, differential impacts of TLR9 agonism were observed—direct killing was enhanced while ADCC was not increased. To ensure that the observed differential effects were not attributable to differences between human donors, we recapitulated the observation using our Natural Killer—Simultaneous ADCC and Direct Killing Assay (NK-SADKA) that controls for human-to-human differences. Next, we observed a treatment-induced decrease in NK cell surface CD16—known to be shed by NK cells post-activation. Given the essential role of CD16 in ADCC, such shedding could account for the observed differential impact of TLR9 agonism on NK cell-mediated killing capacity.

Maturation of auditory cortex neural encoding processes was assessed in children with typical development (TD) and autism. Children 6-9 years old were enrolled at Time 1 (T1), with follow-up data obtained ~ 18 months later at Time 2 (T2), and ~ 36 months later at Time 3 (T3). Findings suggested an initial period of rapid auditory cortex maturation in autism, earlier than TD (prior to and surrounding the T1 exam), followed by a period of faster maturation in TD than autism (T1-T3). As a result of group maturation differences, post-stimulus group differences were observed at T1 but not T3. In contrast, stronger pre-stimulus activity in autism than TD was found at all time points, indicating this brain measure is stable across time.

Matrix stiffening is ubiquitous in solid tumors and can direct epithelial-mesenchymal transition (EMT) and cancer cell migration. Stiffened niche can even cause poorly invasive oral squamous cell carcinoma (OSCC) cell lines to acquire a less adherent, more migratory phenotype, but mechanisms and durability of this acquired "mechanical memory" are unclear. Here, we observed that contractility and its downstream signals could underlie memory acquisition; invasive SSC25 cells overexpress myosin II (vs. noninvasive Cal27 cells) consistent with OSCC. However, prolonged exposure of Cal27 cells to a stiff niche or contractile agonists up-regulated myosin and EMT markers and enabled them to migrate as fast as SCC25 cells, which persisted even when the niche softened and indicated "memory" of their prior niche. Stiffness-mediated mesenchymal phenotype acquisition required AKT signaling and was also observed in patient samples, whereas phenotype recall on soft substrates required focal adhesion kinase (FAK) activity. Phenotype durability was further observed in transcriptomic differences between preconditioned Cal27 cells cultured without or with FAK or AKT antagonists, and such transcriptional differences corresponded to discrepant patient outcomes. These data suggest that mechanical memory, mediated by contractility via distinct kinase signaling, may be necessary for OSCC to disseminate.