Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours.

Each tumour contains diverse cellular states that underlie intratumour heterogeneity (ITH), a central challenge of cancer therapeutics1. Dozens of recent studies have begun to describe ITH by single-cell RNA sequencing, but each study typically profiled only a small number of tumours and provided a narrow view of transcriptional ITH2. Here we curate, annotate and integrate the data from 77 different studies to reveal the patterns of transcriptional ITH across 1,163 tumour samples covering 24 tumour types. Among the malignant cells, we identify 41 consensus meta-programs, each consisting of dozens of genes that are coordinately upregulated in subpopulations of cells within many tumours. The meta-programs cover diverse cellular processes including both generic (for example, cell cycle and stress) and lineage-specific patterns that we map into 11 hallmarks of transcriptional ITH. Most meta-programs of carcinoma cells are similar to those identified in non-malignant epithelial cells, suggesting that a large fraction of malignant ITH programs are variable even before oncogenesis, reflecting the biology of their cell of origin. We further extended the meta-program analysis to six common non-malignant cell types and utilize these to map cell-cell interactions within the tumour microenvironment. In summary, we have assembled a comprehensive pan-cancer single-cell RNA-sequencing dataset, which is available through the Curated Cancer Cell Atlas website, and leveraged this dataset to carry out a systematic characterization of transcriptional ITH.

Pet collars containing tetrachlorvinphos (TCVP): evaluation of the results of torsion and on-animal release studies and implications for post-application consumer exposure and risk analysis.

Tetrachlorvinphos (TCVP) is the pesticidal active ingredient found in some flea and tick collars for dogs and cats. Recent studies sponsored by The Hartz Mountain Corporation, confirm the safety of TCVP as an active ingredient in pet collars. Based upon data from these new studies and results previously relied upon by the U.S. Environmental Protection Agency, the following conclusions have been made: Torsion study data clearly indicate that approximately 93% of released formulation from TCVP containing pet collars is in a liquid phase immediately following activation.Further, even more relevant to human health risk analysis associated with post-application exposures, in vivo data from dogs wearing TCVP pet collars definitively document that TCVP dust released from the collar is rapidly absorbed into the sebum. The maximum ratio of dust to liquid was 0.023% dust to 99.977% liquid.In vivo fur data provide scientific evidence confirming that the mechanism of dissemination of TCVP from pet collars is as a liquid suspended or dissolved in the animal's sebum, even though it may be released from the collar as a solid. Thus, potential post-application exposure to TCVP, including immediately following collar placement, is almost entirely to a liquid phase.Based upon EPA's refined and conservative "untrimmed" collar risk assessment, post-application incidental oral hand-to-mouth activity by children aged 1 to <2 years of age results in margins of exposure significantly greater than the level of concern of 1000, and therefore do not present unreasonable health risk.

Internet gaming disorder behaviours: a preliminary exploration of individualism and collectivism profiles.

BACKGROUND: Internet Gaming Disorder (IGD) behaviours involve excessive use of Internet games to the extent that one's everyday life is compromised. It has been suggested that IGD symptoms are dependent on whether one is more individualistic or collectivistic. However, the range of potential individualism-collectivismeffects on IGD presentations remains largely unknown. The current study aims to further understanding of the role of individualistic and collectivistic tendencies in IGD, allowing us to develop more gamer centredIGD prevention and intervention strategies. METHODS: One thousand and thirty-twocommunity participants withinternet gaming experience were measured online for IGD symptom's severity using the Internet Gaming Disorder Scale - Short Form (IGDS9-SF) andindividualism-collectivism behavioursvia the Individualism & Collectivism Scale (ICS). Latent Class Analysis (LCA) and T-Tests were performed in relation to their responses. RESULTS: Upon inspection of the LCA output, two profiles of internet gamers were identified. These includedthe Collectivism Aversivegamers (CA; 11%) and the Collectivism Neutral gamers (CN; 89%). The CA gamers displayed significantly higher IGD behaviours overall, and, were higher inpreoccupation, withdrawal symptoms, tolerance, relapse, deception, escapism/mood modification, and functional impairment compared to CN gamers. There were no differences between CA and CN gamers in loss of interest and conflicts with others. CONCLUSIONS: The findings suggest that one's individualism-collectivism orientation can influence the presentation of IGD. Specifically, those who are less collectivistic or are less influenced by social groups willdisplay greater IGD symptoms and present a profile that requires a different intervention from gamers who are more collectivistic. Researchers and clinicians should emphasize the value of belonging in a collective and experiencing equality with others in relation to mental health and gaming patterns.

Evaluation of Depilatory Agents in the Treatment of Hair-Thread Tourniquet Syndrome.

Background Hair-thread tourniquet syndrome (HTTS) is the constriction of an appendage or tissue by a hair thread, which can cause ischemia and necrosis of distal tissues. Depilatory agents have the potential to release the hair tourniquet without exposing the patient to the risks of surgery. OBJECTIVES: This review aims to evaluate the effectiveness, benefits, complications, and contraindications of depilatory agents in HTTS. METHODS: Relevant terms to HTTS and depilatory agents were used to search for articles on MEDLINE and EMBASE databases using the NHS Healthcare Databases Advanced Search engine. RESULTS: In total, 19 of the 295 articles identified in the primary search were included in the final review. Articles described the benefits of depilatory agents as painless, well tolerated, and non-invasive. Contraindications described include use on mucosal membranes, non-hair tourniquet, and allergy. Sixty-four percent (n = 55) of patients had resolution of their HTTS after one or two cycles of depilatory agent treatment. CONCLUSIONS: The use of depilatory agents has multiple potential benefits. The authors propose a treatment algorithm for the use of depilatory agents in HTTS and recommend that all acute centers should store and train staff in their use.

Effects of vowel coproduction on the timecourse of tone recognition.

Vowel contrasts tend to be perceived independently of pitch modulation, but it is not known whether pitch can be perceived independently of vowel quality. This issue was investigated in the context of a lexical tone language, Mandarin Chinese, using a printed word version of the visual world paradigm. Eye movements to four printed words were tracked while listeners heard target words that differed from competitors only in tone (test condition) or also in onset consonant and vowel (control condition). Results showed that the timecourse of tone recognition is influenced by vowel quality for high, low, and rising tones. For these tones, the time for the eyes to converge on the target word in the test condition (relative to control) depended on the vowel with which the tone was coarticulated with /a/ and /i/ supporting faster recognition of high, low, and rising tones than /u/. These patterns are consistent with the hypothesis that tone-conditioned variation in the articulation of /a/ and /i/ facilitates rapid recognition of tones. The one exception to this general pattern-no effect of vowel quality on falling tone perception-may be due to fortuitous amplification of the harmonics relevant for pitch perception in this context.

Crowdfunding pharmacy- and medication-related products: How successful is it?

OBJECTIVE: To determine whether crowdfunding of pharmacy-related products through popular online platforms is a viable means to attain funding and what factors influence success. METHODS: Kickstarter and Indiegogo were searched for projects related to pharmacy using select key words. Projects were included for analysis if they were a device or system relevant to pharmacy care and excluded if found to be nonrelevant to medication management purposes or were of an artistic nature. Projects were assessed for their success in reaching their primary funding goals and also whether they were still in business following completion of their crowdfunding phase. RESULTS: Subsequent to the application of the inclusion and exclusion criteria to the dataset, 40 projects were identified, of which 13 reached their desired crowdfunding funding amounts. The most commonly created crowdfunded projects were those involving medication adherence or storage tools. Anecdotal evidence points to media attention leading to continued success beyond the initial crowdfunding phase of the business. The presence of a medical professional on the project team or the inclusion of a product demonstration did not lead to a different rate of success. CONCLUSION: The crowdfunding of pharmacy care-related products appear to have a low success rate, although Indiegogo might offer a higher success rate compared with Kickstarter in this niche product area. The products' ability to garner media attention seems to be a primary driver in the business surviving past the crowdfunding stage and becoming a lasting success.

Assessment of Community Awareness and Practices Concerning Indoor Air Pollutants - Madison County, Alabama, June 2017.

The Alabama Department of Public Health (ADPH) conducts an annual community assessment to evaluate household preparedness and local public health concerns. In June 2017, ADPH conducted a Community Assessment for Public Health Emergency Response (CASPER), focusing on indoor air pollutants in seven neighborhoods in Madison County, Alabama, where a large percentage of homes were built before 1980. Local health partners had concerns about indoor air quality and environmental risks such as radon; however, limited information was available regarding community awareness, prevention, and mitigation measures related to potential exposures. Weighted response frequencies were calculated from assessment responses. Among 192 household interview respondents, 78.4% were aware of potential indoor lead exposures, but only 12.6% of respondents living in houses built before 1978 reported that the house had been tested for lead. Similarly, respondents in 70.2% of households had heard of radon; however, only 7.3% of houses had been tested for radon. Smoking was reported by residents of 45.7% of households; among those, 48.4% reported that smoking occurred inside the house. Identified gaps in exposure prevention and mitigation, including low lead and radon testing rates and a high prevalence of indoor smoking, were shared with the local health department, and recommendations for timely interventions and policy guidance (e.g., targeted education campaigns and smoking cessation programs) were presented. Results of this CASPER demonstrated its usefulness and efficiency in gathering community-level data to help guide public health policies and timely interventions.

Surgical treatment of detrusor underactivity: a short term proof of concept study.

OBJECTIVES: To compare the surgical outcomes of men with bladder outlet obstruction (BOO) due to benign prostatic obstruction (BPO) to those with detrusor underactivity (DU) or acontractile detrusor (DA). MATERIALS AND METHODS: This retrospective, IRB approved study included men who underwent BPO surgery for refractory LUTS or urinary retention. Patients were grouped based on videourodynamic (VUDS) findings: 1) men with BOO, 2) men with DU and 3) men with DA. The primary outcome measure was the Patient Global Impression of Improvement (PGII). Secondary outcome measures included uroflow (Qmax), post-void residual volume (PVR) and the need for clean intermittent catheterization (CIC). RESULTS: One hundred and nineteen patients were evaluated: 1) 34 with BOO, 2) 62 with DU and 3) 23 with DA. Subjective success rate (PGII) was highest in the BOO group (97%) and those with DU (98%), while DA patients had a PGII success of 26%, (p<0.0001). After surgery, patients with BOO had the lowest PVR (68.5mL). Fifty-six patients (47%) performed CIC pre-operatively (47% of BOO, 32% of DU and 87% of DA patients). None of the patients in the BOO and DU groups required CIC post operatively compared to16/23 (69%) of patients in the DA group (p<0.0001). CONCLUSIONS: BPO surgery is a viable treatment option in men with presumed BOO and DU while DA is a poor prognostic sign in men who do not void spontaneously pre-operatively.

An examination of the different ways that non-native phones may be perceptually assimilated as uncategorized.

This study examined three ways that perception of non-native phones may be uncategorized relative to native (L1) categories: focalized (predominantly similar to a single L1 category), clustered (similar to > 2 L1 categories), and dispersed (not similar to any L1 categories). In an online study, Egyptian Arabic speakers residing in Egypt categorized and rated all Australian English vowels. Evidence was found to support focalized, clustered, and dispersed uncategorized assimilations. Second-language (L2) category formation for uncategorized assimilations is predicted to depend upon the degree of perceptual overlap between the sets of L1 categories listeners use in assimilating each phone within an L2 contrast.

Investigating the role of articulatory organs and perceptual assimilation of native and non-native fricative place contrasts.

The perceptual assimilation model (PAM; Best, C. T. [1995]. A direct realist view of cross-language speech perception. In W. Strange (Ed.), Speech perception and linguistic experience: Issues in cross-language research (pp. 171-204). Baltimore, MD: York Press.) accounts for developmental patterns of speech contrast discrimination by proposing that infants shift from untuned phonetic perception at 6 months to natively tuned perceptual assimilation at 11-12 months, but the model does not predict initial discrimination differences among contrasts. To address that issue, we evaluated the Articulatory Organ Hypothesis, which posits that consonants produced using different articulatory organs are initially easier to discriminate than those produced with the same articulatory organ. We tested English-learning 6- and 11-month-olds' discrimination of voiceless fricative place contrasts from Nuu-Chah-Nulth (non-native) and English (native), with one within-organ and one between-organ contrast from each language. Both native and non-native contrasts were discriminated across age, suggesting that articulatory-organ differences do not influence perception of speech contrasts by young infants. The results highlight the fact that a decline in discrimination for non-native contrasts does not always occur over age.

Perceptual assimilation and discrimination of non-native vowel contrasts.

Research on language-specific tuning in speech perception has focused mainly on consonants, while that on non-native vowel perception has failed to address whether the same principles apply. Therefore, non-native vowel perception was investigated here in light of relevant theoretical models: the Perceptual Assimilation Model (PAM) and the Natural Referent Vowel (NRV) framework. American-English speakers completed discrimination and native language assimilation (categorization and goodness rating) tests on six nonnative vowel contrasts. Discrimination was consistent with PAM assimilation types, but asymmetries predicted by NRV were only observed for single-category assimilations, suggesting that perceptual assimilation might modulate the effects of vowel peripherality on non-native vowel perception.

Development of phonological constancy: 19-month-olds, but not 15-month-olds, identify words in a non-native regional accent.

By 12 months, children grasp that a phonetic change to a word can change its identity (phonological distinctiveness). However, they must also grasp that some phonetic changes do not (phonological constancy). To test development of phonological constancy, sixteen 15-month-olds and sixteen 19-month-olds completed an eye-tracking task that tracked their gaze to named versus unnamed images for familiar words spoken in their native (Australian) and an unfamiliar non-native (Jamaican) regional accent of English. Both groups looked longer at named than unnamed images for Australian pronunciations, but only 19-month-olds did so for Jamaican pronunciations, indicating that phonological constancy emerges by 19 months. Vocabulary size predicted 15-month-olds' identifications for the Jamaican pronunciations, suggesting vocabulary growth is a viable predictor for phonological constancy development.

Focusing the lens of language experience: perception of Ma'di stops by Greek and English bilinguals and monolinguals.

Monolingual listeners are constrained by native language experience when categorizing and discriminating unfamiliar non-native contrasts. Are early bilinguals constrained in the same way by their two languages, or do they possess an advantage? Greek-English bilinguals in either Greek or English language mode were compared to monolinguals on categorization and discrimination of Ma'di stop-voicing distinctions that are non-native to both languages. As predicted, English monolinguals categorized Ma'di prevoiced plosive and implosive stops and the coronal voiceless stop as English voiced stops. The Greek monolinguals categorized the Ma'di short-lag voiceless stops as Greek voiceless stops, and the prevoiced implosive stops and the coronal prevoiced stop as Greek voiced stops. Ma'di prenasalized stops were uncategorized. Greek monolinguals discriminated the non-native voiced-voiceless contrasts very well, whereas the English monolinguals did poorly. Bilinguals were given all oral and written instructions either in English or in Greek (language mode manipulation). Each language mode subgroup categorized Ma'di stop-voicing comparably to the corresponding monolingual group. However, the bilinguals' discrimination was unaffected by language mode: both subgroups performed intermediate to the monolinguals for the prevoiced-voiceless contrast. Thus, bilinguals do not possess an advantage for unfamiliar non-native contrasts, but are nonetheless uniquely configured language users, differing from either monolingual group.

Calamities causing loss of museum collections: a historical and global perspective on museum disasters.

With alarming frequency, significant collections in natural history museums have been destroyed or damaged through insurrections, cyclones, wars, fires, floods, or earthquakes particularly in the nineteenth century but continuing into the twentieth century with World War II bombings, fires, and earthquakes being the primary causes of loss in fifty-seven institutions across thirty countries. We review the loss or damage of museum collections globally, and their varied causes. We emphasize the benefits of dispersal of a sample of paratypes across institutions as an essential feature of taxonomic practice. We argue that museums do not own type material but are acting as perpetual custodians of type material on behalf of science and society in general, and that museums, therefore, have an obligation to minimize the risk to their collections. The significance of the loss of type material would be ameliorated if, when there are numerous paratypes or syntypes, members of a type series were distributed among several institutions. This is currently common practice but historically this was not always the case and might not be possible if only a single holotype is available. We also reaffirm the need for scientists around the globe to develop specific protocols to protect collections of biological and cultural materials from loss or damage from natural and human-created disasters now and into the future. We comment on recent moves to modify the Zoological Code of Nomenclature to allow the use of images as "type" material when describing new species with the image serving as a substitute for "physical" specimens deposited in museum collections. Although our focus is on herpetological collections, our particular interest and area of expertise, our observations apply broadly to all collections, including those of animals, plants, and anthropological or ethnographic material.

Understanding the neural mechanisms for infants' perception of native and non-native speech.

Though perceptual narrowing has been widely recognized as a process guiding cognitive development and category learning in infancy and early childhood, its neural mechanisms and traits at a cortical level remain unclear. Using an electroencephalography (EEG) abstract mismatch negativity (MMN) paradigm, Australian infants' neural sensitivity to (native) English and (non-native) Nuu-Chah-Nulth speech contrasts was examined in a cross-sectional design at the onset (5-6 months) and offset (11-12 months) of perceptual narrowing. Immature mismatch responses (MMR) were observed among younger infants for both contrasts, while older infants showed MMR response to the non-native contrast, and both MMR and MMN to the native contrast. Sensitivity to the Nuu-Chah-Nulth contrast at perceptual narrowing offset was retained yet stayed immature. Findings conform to perceptual assimilation theories, reflecting plasticity in early speech perception and development. Compared to behavioural paradigms, neural examination effectively reveals experience-induced processing differences to subtle contrasts at the offset of perceptual narrowing.

How Tone, Intonation and Emotion Shape the Development of Infants' Fundamental Frequency Perception.

Fundamental frequency (ƒ 0), perceived as pitch, is the first and arguably most salient auditory component humans are exposed to since the beginning of life. It carries multiple linguistic (e.g., word meaning) and paralinguistic (e.g., speakers' emotion) functions in speech and communication. The mappings between these functions and ƒ 0 features vary within a language and differ cross-linguistically. For instance, a rising pitch can be perceived as a question in English but a lexical tone in Mandarin. Such variations mean that infants must learn the specific mappings based on their respective linguistic and social environments. To date, canonical theoretical frameworks and most empirical studies do not view or consider the multi-functionality of ƒ 0, but typically focus on individual functions. More importantly, despite the eventual mastery of ƒ 0 in communication, it is unclear how infants learn to decompose and recognize these overlapping functions carried by ƒ 0. In this paper, we review the symbioses and synergies of the lexical, intonational, and emotional functions that can be carried by ƒ 0 and are being acquired throughout infancy. On the basis of our review, we put forward the Learnability Hypothesis that infants decompose and acquire multiple ƒ 0 functions through native/environmental experiences. Under this hypothesis, we propose representative cases such as the synergy scenario, where infants use visual cues to disambiguate and decompose the different ƒ 0 functions. Further, viable ways to test the scenarios derived from this hypothesis are suggested across auditory and visual modalities. Discovering how infants learn to master the diverse functions carried by ƒ 0 can increase our understanding of linguistic systems, auditory processing and communication functions.

The contribution of visual articulatory gestures and orthography to speech processing: Evidence from novel word learning.

Auditory speech appears to be linked to visual articulatory gestures and orthography through different mechanisms. Yet, both types of visual information have a strong influence on speech processing. The present study directly compared their contributions to speech processing using a novel word learning paradigm. Native speakers of French, who were familiar with English, learned minimal pairs of novel English words containing the English /θ/-/f/ phonemic contrast under one of three exposure conditions: (a) the auditory forms of novel words alone, (b) the auditory forms associated with articulatory gestures, or (c) the auditory forms associated with orthography. The benefits of the three methods were compared during training and at two posttraining time points where the visual cues were no longer available. We also assessed participants' auditory-only discrimination of the /θ/-/f/ contrast pretraining and posttraining. During training, the visual cues facilitated novel word learning beyond the benefit of the auditory input alone. However, these additional benefits did not persist when participants' discrimination and novel word learning performance were assessed immediately after training. Most interestingly, after a night's sleep, participants who were exposed to orthography during training showed significant improvement in both discrimination and novel word learning compared to the previous day. The findings are discussed in terms of online versus residual impacts of articulatory gestures and orthography on speech processing. While both visual cues are beneficial when they are simultaneously presented with speech, only orthography shows residual impacts leading to a sleep-dependent enhancement of lexical knowledge through memory consolidation and retuning of the second language /θ/-/f/ contrast. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Prevalence of Visible Subdural Spaces in Benign Enlargement of Subarachnoid Spaces in Infancy: A Retrospective Analysis Utilizing Magnetic Resonance Imaging.

OBJECTIVE: Benign Enlargement of the Subarachnoid Spaces in Infancy (BESSI) is a common finding during workup for progressive macrocephaly. BESSI has been associated with slightly higher prevalence of subdural (SD) spaces and a risk for developing subdural hematoma. This study utilizes fast brain magnetic resonance imaging (MRI) to investigate the prevalence of visible SD spaces in BESSI. METHODS: A retrospective review was performed for all pediatric patients who underwent brain MRI for macrocephaly. Patients with a diagnosis of BESSI were included in the study. A total of 109 patients met the inclusion criteria. Patient demographics were collected, and images were reviewed for size of subarachnoid, visible SD spaces, and ventricle size. Descriptive and inferential statistics were performed. RESULTS: The average age was 8 ± 4.6 months, 64 (59%) were male, and 55 patients had no previous medical history (50%). Sixty-seven percent of all patients were identified to have visible SD spaces. Eleven patients had confirmed SD hematomas; 1 patient was deemed to have abusive head trauma. Visible SD spaces were associated with younger age (6.9 months). Thirty-one patients with visible SD spaces had follow-up MRI, with complete resolution by 33 months. CONCLUSIONS: BESSI is a self-limiting pathology that has been associated with visible SD spaces and potential risk for SD hemorrhages. We report a high prevalence of visible SD spaces within BESSI through utilization of fast brain MRI. These spaces may contribute to the higher rate of incidental subdural hematoma in this population.

Genome-wide CRISPR screen identifies PRC2 and KMT2D-COMPASS as regulators of distinct EMT trajectories that contribute differentially to metastasis.

Epithelial-mesenchymal transition (EMT) programs operate within carcinoma cells, where they generate phenotypes associated with malignant progression. In their various manifestations, EMT programs enable epithelial cells to enter into a series of intermediate states arrayed along the E-M phenotypic spectrum. At present, we lack a coherent understanding of how carcinoma cells control their entrance into and continued residence in these various states, and which of these states favour the process of metastasis. Here we characterize a layer of EMT-regulating machinery that governs E-M plasticity (EMP). This machinery consists of two chromatin-modifying complexes, PRC2 and KMT2D-COMPASS, which operate as critical regulators to maintain a stable epithelial state. Interestingly, loss of these two complexes unlocks two distinct EMT trajectories. Dysfunction of PRC2, but not KMT2D-COMPASS, yields a quasi-mesenchymal state that is associated with highly metastatic capabilities and poor survival of patients with breast cancer, suggesting that great caution should be applied when PRC2 inhibitors are evaluated clinically in certain patient cohorts. These observations identify epigenetic factors that regulate EMP, determine specific intermediate EMT states and, as a direct consequence, govern the metastatic ability of carcinoma cells.