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A fluorine-18 labelled probe was developed to target bromodomain and extraterminal (BET) proteins for molecular imaging of cancer with positron emission tomography.

Human interactions across settings shape young people’s learning and development, and building adult expertise in facilitating productive interactions takes deliberate practice and reflective experience. However, relational practices are not consistently part of adult learning for those who work with youth. We describe a 2-year design study to develop the Simple Interactions Leadership Program, a professional learning workshop focused on relational practices. We refined the program across 3 iterations with library and after-school staff (with a total of 41 participants). Iterative changes included adding participant-driven “try-it-out” projects, adding external accountability features, and combining staff from the library and after-school sectors. Using artifacts and memos from workshops and participants’ reflections, we found that these features incrementally improved participants’ engagement, depth of learning, and sense of professional community—which we suggest are three central goals for related professional development efforts. As a collective youth-serving field, we need effective and scalable ways to help adults recognize and strengthen their relational practices with young people. The Simple Interactions Leadership Program offers a flexible structure for professional learning focused on building expertise in relational practice while sustaining change and improvement through continuous reflection within communities of practice.

Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), is known to cause more than 50 diseases1,2. However, repeat expansions are often not explored beyond neurological and neurodegenerative disorders. In some cancers, mutations accumulate in short tracts of TRs, a phenomenon termed microsatellite instability; however, larger repeat expansions have not been systematically analysed in cancer3–8. Here we identified TR expansions in 2,622 cancer genomes spanning 29 cancer types. In seven cancer types, we found 160 recurrent repeat expansions (rREs), most of which (155/160) were subtype specific. We found that rREs were non-uniformly distributed in the genome with enrichment near candidate cis-regulatory elements, suggesting a potential role in gene regulation. One rRE, a GAAA-repeat expansion, located near a regulatory element in the first intron of UGT2B7 was detected in 34% of renal cell carcinoma samples and was validated by long-read DNA sequencing. Moreover, in preliminary experiments, treating cells that harbour this rRE with a GAAA-targeting molecule led to a dose-dependent decrease in cell proliferation. Overall, our results suggest that rREs may be an important but unexplored source of genetic variation in human cancer, and we provide a comprehensive catalogue for further study.

We employ several galaxy formation models, in particular, L-GALAXIES, IllustrisTNG, and EAGLE, as well as observational samples from SDSS and DESI, to investigate galactic conformity, the observed large-scale correlation between the star-formation properties of central (primary) galaxies and those of their neighbours. To analyse the models and observations uniformly, we introduce CENSAT, a new algorithm to define whether a galaxy is a central or a satellite system based on an isolation criterion. We find that the conformity signal is present, up to at least 5 Mpc from the centres of low- and intermediate-mass centrals in the latest version of L-GALAXIES (Ayromlou et al. 2021), IllustrisTNG, and EAGLE, as well as in SDSS and DESI observational samples. In comparison, the conformity signal is substantially weaker in an older version of L-GALAXIES (Henriques et al. 2020). One of the main differences between this older model and the other models is its neglect of ram-pressure stripping of the gas reservoirs of galaxies except within the boundaries of massive cluster haloes. Our observational comparisons demonstrate that this difference significantly affects the observed large-scale conformity signal. Furthermore, by examining the contribution of backsplash, fly-by, central, and satellite galaxies to the conformity signal, we show that much, but not all, of it arises from primary galaxies near massive systems. Remaining tensions between the models and observations may be solved by modifying the physical prescriptions for how feedback processes affect the distribution and kinematics of gas and the environment around galaxies out to scales of several Megaparsecs., Comment: Submitted to MNRAS

Open-system electronic nicotine delivery systems (ENDS) permit modifications to device characteristics such as power, potentially increasing nicotine and toxicant delivery. Limiting liquid nicotine concentration may carry unintended consequences by prompting users to increase device power to increase nicotine delivery. This study examined the abuse liability of ENDS across nicotine concentration and power settings. In a clinical laboratory study, n = 19 exclusive ENDS users and n = 13 dual ENDS/cigarette users, aged 21-55 completed four Latin-square ordered conditions that varied by liquid nicotine concentration (10 mg/ml [low], 30 mg/ml [high]) and device power (15 watts [low], 30 watts [high]), that were followed by a fifth own brand (OB) condition. A progressive ratio task (PRT) using bar presses to earn ENDS puffs was used to assess abuse liability and compare between conditions using mixed effects linear regressions. The low nicotine/high watt condition was associated with a significantly higher number of bar presses and puffs earned relative to the OB ENDS, high nicotine/high watt, and high nicotine/low watt conditions (p < .05). Findings appeared to be driven largely by exclusive ENDS users; most comparisons were not significant among dual users. Participants worked significantly harder for puffs of low nicotine/high watt ENDS, highlighting previous findings that suggest limiting liquid nicotine concentration without addressing power settings may be insufficient to reduce the abuse liability of ENDS. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Many effective strategies exist to keep students safe, supported, and engaged in school. Restorative practice (RP) is a powerful approach for achieving these goals as it elevates student voice and can strengthen school climate. Annie M. White and John Kenneth Weiss share findings from an initiative through which high school student-faculty teams learned strategies to use RP practices and incorporate student voice to improve school climate. After two years, students gained the confidence to work for school change. They offer implementation recommendations, including prioritizing relationship-building, reaching a critical mass, and providing structure for engagement. Ultimately, they found that student voice and engagement may be key to improving school climate.

Malignant mesothelioma (MM) is an incurable cancer of the serosal lining that is often caused by exposure to asbestos. Therefore, novel agents for the prevention and treatment of this disease are urgently needed. Asbestos induces the release of pro-inflammatory cytokines such as IL-1β and IL-6, which play a role in MM development. IL-6 is a component of the JAK-STAT3 pathway that contributes to inflammation-associated tumorigenesis. Glycoprotein 130 (gp130), the signal transducer of this signaling axis, is an attractive drug target because of its role in promoting neoplasia via the activation of downstream STAT3 signaling. The anticancer drug, SC144, inhibits the interaction of gp130 with the IL-6 receptor (IL6R), effectively blunting signaling from this inflammatory axis. To test whether the inflammation-related release of IL-6 plays a role in the formation of MM, we evaluated the ability of SC144 to inhibit asbestos-induced carcinogenesis in a mouse model. The ability of sulindac and anakinra, an IL6R antagonist/positive control, to inhibit MM formation in this model was tested in parallel. Asbestos-exposed Nf2+/−;Cdkn2a+/− mice treated with SC144, sulindac or anakinra showed significantly prolonged survival compared to asbestos-exposed vehicle-treated mice. STAT3 activity was markedly decreased in MM specimens from SC144-treated mice. Furthermore, SC144 inhibited STAT3 activation by IL-6 in cultured normal mesothelial cells, and in vitro treatment of MM cells with SC144 markedly decreased the expression of STAT3 target genes. The emerging availability of newer, more potent SC144 analogs showing improved pharmacokinetic properties holds promise for future trials, benefitting individuals at high risk of this disease.

During the late 19th and early 20th centuries, intensive land use nearly eliminated red spruce (Picea rubens Sarg.) throughout portions of West Virginia (WV). Red spruce has been slow to regenerate on mountaintop heathland barrens surrounding Canaan Valley, West Virginia (WV), and little is known about the nature of encroachment. Using field surveys, geospatial data, and statistical modelling, the objectives were to 1) characterize and compare red spruce encroachment at two upland heath study areas in West Virginia (Bear Rocks and Cabin Mountain), 2) characterize percent cover of major ground cover types associated with red spruce regeneration sites in order to elucidate biotic interactions, and 3) model the biophysical correlates of red spruce encroachment using geospatial data and statistical modelling. Red spruce count was similar at both study areas, but there were substantially more seedlings and saplings at Cabin Mountain. Modelling revealed a positive relationship between red spruce count and rock cover and a negative relationship between red spruce and stand distance. Published version

An infection-resistant, immediately available conduit for trauma and urgent vascular reconstruction remains a critical need for successful limb salvage. While autologous vein remains the gold standard, vein-limited patients and size mismatch are common issues. The Human Acellular Vessel (HAV) (Humacyte, Inc., Durham, NC) is a bioengineered conduit with off-the-shelf availability and resistance to infection, ideal characteristics for patients with challenging revascularization scenarios. This report describes HAV implantation in patients with complex limb-threatening ischemia and limited conduit options who may have otherwise faced limb loss.The Food and Drug Administration (FDA) expanded-access program was used to allow urgent implantation of the HAV for arterial reconstruction. Electronic medical records were reviewed with extraction of relevant data including patient demographics, surgical implantation, patency, infectious complications, and mortality.The HAV was implanted in 8 patients requiring vascular reconstruction. Graft or soft tissue infection was present in 2 patients. One patient with severe penetrating pelvic injury had 4 HAV placed to repair bilateral external iliac artery and vein injuries. There was 1 technical failure due to poor outflow, 2 patients died unrelated to HAV use, and 5 lower extremity bypasses maintained patency at an average of 11.4 months (range: 4-20 months). No HAV infectious complications were identified.This report is the first United States series describing early outcomes using the HAV under the FDA expanded-access program for urgent vascular reconstruction. The HAV demonstrates resistance to infection, reliable patency, and offers surgeons an immediate option when confronted with complex revascularization scenarios. Assessment of long-term outcomes will be important for future studies.

Insertion of cerebrospinal fluid (CSF) shunts in patients with idiopathic intracranial hypertension (IIH) is challenging mainly due to the small ventricles and phenotypical body habitus. In this report the authors present their surgical protocol for insertion of a ventriculoperitoneal shunt (VPS) in patients with IIH and the associated revision rates.The protocol comprises the following: shunt surgery by neurosurgeons with expertise in CSF disorders; a frontal VPS usually right sided but left sided if the left ventricle is bigger; use of the proGAV 2.0 valve with gravitational unit, set at 10 and the M.scio telemetric sensor; cannulation of the ventricle with StealthStation EM navigation system; and laparoscopic insertion of the peritoneal catheter. The authors describe the protocol and rationale and evidence behind each component and present the results of a prospective analysis on revision rates.The protocol has been implemented since 1 July, 2019, and by 28 February, 2022, sixty-two patients with IIH had undergone primary VPS insertion. The 30-day revision rate was 6.5%, and overall 11.3% of patients underwent revision during the study period, which compares favorably with the literature. The etiology for early failures was related to the surgical technique.The components of the Birmingham standardized IIH shunt protocol are evidence based and address the technical challenges of CSF diversion in patients with IIH. This protocol is associated with a low revision rate, and the authors recommend standardization for CSF shunting in IIH.

In melanoma, predicting which tumors will ultimately metastasize guides treatment decisions. Transcriptional signatures of primary tumors have been utilized to predict metastasis, but which among these are driver or passenger events remains unclear. We used data from the adjuvant AVAST-M trial to identify a predictive gene signature in localized tumors that ultimately metastasized. Using a zebrafish model of primary melanoma, we interrogated the top genes from the AVAST-M signature in vivo. This identified GRAMD1B, a cholesterol transfer protein, as a bona fide metastasis suppressor, with a majority of knockout animals rapidly developing metastasis. Mechanistically, excess free cholesterol or its metabolite 27-hydroxycholesterol promotes invasiveness via activation of an AP-1 program, which is associated with increased metastasis in humans. Our data demonstrate that the transcriptional seeds of metastasis are embedded within localized tumors, suggesting that early targeting of these programs can be used to prevent metastatic relapse. Significance: We analyzed human melanoma transcriptomics data to identify a gene signature predictive of metastasis. To rapidly test clinical signatures, we built a genetic metastasis platform in adult zebrafish and identified GRAMD1B as a suppressor of melanoma metastasis. GRAMD1B-associated cholesterol overload activates an AP-1 program to promote melanoma invasion. This article is highlighted in the In This Issue feature, p. 1

Objectives: To develop outcomes of care quality measures derived from the dental electronic health record (EHR) to assess the occurrence and timely treatment of tooth decay. Methods: Quality measures were developed to assess whether decay was treated within 6 months and if new decay occurred in patients seen. Using EHR-derived data of the state of each tooth surface, algorithms compared the patient's teeth at different dates to determine if decay was treated or new decay had occurred. Manual chart reviews were conducted at three sites to validate the measures. The measures were implemented and scores were calculated for three sites over four calendar years, 2016 through 2019. Results: About 954 charts were manually reviewed for the timely treatment of tooth decay measure, with measure performance of sensitivity 97%, specificity 85%, positive predictive value (PPV) 91%, negative predictive value (NPV) 95%. About 739 charts were reviewed for new decay measure, with sensitivity 94%, specificity 99%, PPV 99%, and NPV 94%. Across all sites and years, 52.8% of patients with decay were fully treated within 6 months of diagnosis (n = 247,959). A total of 23.8% of patients experienced new decay, measured at an annual exam (n = 640,004). Conclusion: Methods were developed and validated for assessing timely treatment of decay and occurrence of new decay derived from EHR data, creating effective outcome measures. These EHR-based quality measures produce accurate and reliable results that support efforts and advancement in quality assessment, quality improvement, patient care and research.

PurposeResearch shows that the majority of investors, consumers and even younger consumers who are interested in social responsibility are unaware of B Corps. Companies spend significant time and money to obtain B Corp status that B Lab, the non-profit that certifies companies, wants to use as a force for good. Using signaling theory and corporate communication theory, the study examines whether B Corps market their B Corp status effectively on B Corps' social media sites to determine whether brand equity is being built there for the B Corp label by the B Corp companies themselves.Design/methodology/approachThe authors content analyzed social media activity of 100 randomly selected US B Corps ranging in size and industry type over a two-month period on Facebook, LinkedIn, Twitter, and Instagram. The sample was selected from the listing of the B Corporations on the B Lab website using a skip interval method. The authors searched for preselected keywords within two main categories, one directly mentioning B Corps (such as B Corp logo and B Corp name), and another discussing company social responsibility activities that directly relate to what B Corps do but did not mention the B Corp name.FindingsThe study finds that half of the B Corps had no social media presence. Of those who were active on social media, most B Corps did not mention B Corp status while many of the B Corps discussed social responsibility activities that directly talked about workers, environment, community, and governance, the areas that B Corp certification covers.Research limitations/implicationsThe study indicates that reverse decoupling might better explain communication of B Corp certification on social media than signaling theory. The finding is consistent with more recent research on certifications that shows that obtaining certifications by companies does not have to be followed by marketing certificates even when that could be beneficial. On the other hand, communication of general pro-social claims is consistent with the assumptions of the signaling theory and often used by B Corps. The study suggests why companies market general claims but not a B Corp label. Findings also suggest that when promoting the B Corp label is not done, a firm's internal values are not being expressed externally but when social responsible activities are promoted, a firm's internal values are being expressed externally. The research points to a missed opportunity for B Corps that spend significant resources to get certified. Future studies should employ larger samples with and international companies and venture into other forms of marketing through which B Corp status may be conveyed.Practical implicationsB Corps can easily connect information on the socially responsible activities of B Corps with B Corp status on social media and reap the benefits of B Corps by creating equity for B Corp label on multiple levels. This would also help B-Lab that strives to develop a stronger brand for the B Corps' certification. When consumers know what B Corp stands for, consumers are willing to pay premium prices. Investors are also increasingly interested in companies that care for stakeholders and the environment and are governed in transparent and socially responsible ways.Social implicationsB Corps are described by the B-Lab as a “force for good” that benefits communities, environment and society. Understanding how certifications such as B Corps are communicated to the public and improving how they are communicated can help businesses reap more benefits from B Corps' socially responsible activity and help consumers and investors become educated about such companies so that B Corps can support them. This is important as B-Corps certification is still not well known. Marketing B Corp certification more effectively can help develop a wider and stronger network of businesses that want to do good, investors that want to found socially responsible companies and consumers who want to buy from B Corps. To create such a marketplace B Corps need to be better marketed online.Originality/valueThe study shows that the authors cannot assume that the certifications that companies obtain, often using significant resources and potentially offering many benefits for building brand equity, will be communicated to the stakeholders to reap these benefits. The study provides possible reasons for why companies may not market such endeavors. The study questions assumptions implicit in signaling theory and by using reverse decoupling the study explains why companies may pursue certifications but not market that the companies obtain them even when pro-social certifications have a great potential to differentiate a company among stakeholders that look for socially responsible firms. The study questions what this means for creating a change in business to become a “force for good.”

The structure of the title compound, 2C18H19ClN4O·HCl or (CNO)2·HCl (C36H39Cl3N8O2), at 100 K has tetragonal (I4/m) symmetry. The dihedral angle between the benzene rings of the fused ring system of the CNO molecule is 40.08 (6)° and the equivalent angle between the seven-membered ring and its pendant N-oxide ring is 31.14 (7)°. The structure contains a very strong, symmetrical O—H...O hydrogen bond [O...O = 2.434 (2) Å] between two equivalent R 3N+—O− moieties, which share a proton lying on a crystallographic twofold rotation axis. These units then form a (CNO)4·(HCl)2 ring by way of two equivalent N—H...Cl hydrogen bonds (Cl− site symmetry m). These rings are catenated into infinite chains propagating along the c-axis direction by way of shape complementarity and directional C—H...N and C—H...π interactions.

Residual feed intake (RFI) is commonly used to measure feed efficiency but individual intake recording systems are needed. Feeding behavior may be used as an indicator trait for feed efficiency using less expensive precision livestock farming technologies. Our goal was to estimate genetic parameters for feeding behavior and the genetic correlations with feed efficiency in Holstein cows. Data consisted of 75,877 daily feeding behavior records of 1,328 mid-lactation Holstein cows in 31 experiments conducted from 2009 to 2020 with an automated intake recording system. Feeding behavior traits included number of feeder visits per day, number of meals per day, duration of each feeder visit, duration of each meal, total duration of feeder visits, intake per visit, intake per meal [kg of dry matter (DM)], feeding rate per visit, and feeding rate per meal (kg of DM per min). The meal criterion was estimated as 26.4 min, which means that any pair of feeder visits separated by less than 26.4 min were considered part of the same meal. The statistical model included lactation and days in milk as fixed effects, and experiment-treatment, animal, and permanent environment as random effects. Genetic parameters for feeding behavior traits were estimated using daily records and weekly averages. Estimates of heritability for daily feeding behavior traits ranged from 0.09 ± 0.02 (number of meals; mean ± standard error) to 0.23 ± 0.03 (feeding rate per meal), with repeatability estimates ranging from 0.23 ± 0.01 (number of meals) to 0.52 ± 0.02 (number of feeder visits). Estimates of heritability for weekly averages of feeding behavior traits ranged from 0.19 ± 0.04 (number of meals) to 0.32 ± 0.04 (feeding rate per visit), with repeatability estimates ranging from 0.46 ± 0.02 (duration of each meal) to 0.62 ± 0.02 (feeding rate per visit and per meal). Most of the feeding behavior measures were strongly genetically correlated, showing that with more visits or meals per day, cows spend less time in each feeder visit or meal with lower intake per visit or meal. Weekly averages for feeding behavior traits were analyzed jointly with RFI and its components. Number of meals was genetically correlated with milk energy (0.48), metabolic body weight (-0.27), and RFI (0.19). Duration of each feeder visit and meal were genetically correlated with milk energy (0.43 and 0.44, respectively). Total duration of feeder visits per day was genetically correlated with DM intake (0.29), milk energy (0.62), metabolic body weight (-0.37), and RFI (0.20). Intake per visit and meal were genetically correlated with DM intake (0.63 and 0.87), milk energy (0.47 and 0.69), metabolic body weight (0.47 and 0.68), and RFI (0.31 and 0.65). Feeding rate was genetically correlated with DM intake (0.69), metabolic body weight (0.67), RFI (0.47), and milk energy (0.21). We conclude that measures of feeding behavior could be useful indicators of dairy cow feed efficiency, and individual cows that eat at a slower rate may be more feed efficient.

Trichomycetes are a group of fungi and protists living in the guts of immature aquatic insects and other arthropods. The nature of this relationship is poorly understood but it is mostly described as obligately commensalistic, with the microbes exploiting a unique microhabitat. Collections of trichomycetes were made from freshwater insects in aquatic habitats near Castlegar in the Columbia Mountains, part of the Rocky Mountain Range in southeastern British Columbia. The collection sites were at altitudes ranging from 435 to 935 m and were made in July 2006. A total of 32 species were recorded including four new species, Harpella filispora sp. nov., Orphella columbiensis sp. nov., Smittium nodiradicatum sp. nov., and Smitium basiangustatum sp. nov. described here. These are the first records from Western Canada and two, Austrosmittium patagonicum and Glotzia distorta are new continental records. These findings are compared to reports from the western edge of the Rocky Mountain range near the Boise Mountains in Idaho and the Southern Rockies in Colorado.

Laboratory studies used to assess the environmental fate of organic chemicals such as pesticides fail to replicate environmental conditions, resulting in large errors in predicted transformation rates. We combine laboratory and field data to identify the dominant loss processes of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) in lakes for the first time. Microbial and photochemical degradation are individually assessed using laboratory-based microcosms and irradiation studies, respectively. Field campaigns are conducted in six lakes to quantify 2,4-D loss following large-scale herbicide treatments. Irradiation studies show that 2,4-D undergoes direct photodegradation, but modeling efforts demonstrated that this process is negligible under environmental conditions. Microcosms constructed using field inocula show that sediment microbial communities are responsible for degradation of 2,4-D in lakes. Attempts to quantify transformation products are unsuccessful in both laboratory and field studies, suggesting that their persistence is not a major concern. The synthesis of laboratory and field experiments is used to demonstrate best practices in designing laboratory persistence studies and in using those results to mechanistically predict contaminant fate in complex aquatic environments.

To analyze radiomic features obtained from pre-treatment T2-weighted MRI acquisitions in patients with histologically proven intramedullary high-grade osteosarcomas and assess the accuracy of radiomic modelling as predictive biomarker of tumor necrosis following neoadjuvant chemotherapy (NAC), overall survival (OS), and disease-free survival (DFS).Pre-treatment MRI exams in 105 consecutive patients who underwent NAC and resection of high-grade intramedullary osteosarcoma were evaluated. Histologic necrosis following NAC, and clinical outcome-survival data was collected for each case. Radiomic features were extracted from segmentations performed by two readers, with poorly reproducible features excluded from further analysis. Cox proportional hazard model and Spearman correlation with multivariable modelling were used for assessing relationships of radiomics features with OS, DFS, and histologic tumor necrosis.Study included 74 males, 31 females (mean 32.5yrs, range 15-77 years). Histologic assessment of tumor necrosis following NAC was available in 104 cases, with good response (≥ 90% necrosis) in 41, and poor response in 63. Fifty-three of 105 patients were alive at follow-up (median 40 months, range: 2-213 months). Median OS was 89 months. Excluding 14 patients with metastases at presentation, median DFS was 19 months. Eleven radiomics features were employed in final radiomics model predicting histologic tumor necrosis (mean AUC 0.708 ± 0.046). Thirteen radiomic features were used in model predicting OS (mean concordance index 0.741 ± 0.011), and 12 features retained in predicting DFS (mean concordance index 0.745 ± 0.010).T2-weighted MRI radiomic models demonstrate promising results as potential prognostic biomarkers of prospective tumor response to neoadjuvant chemotherapy and prediction of clinical outcomes in conventional osteosarcoma.

While adverse events (AEs) are all too prevalent, their underlying causes are difficult to assess because they are often multifactorial. Standardizing the language of dental AEs is an important first step toward increasing patient safety for the dental patient.We followed a multimodal approach building a dental AE inventory, which included a literature review; review of the MAUDE database; a cross-sectional, self-administered patient survey; focus groups; interviews with providers and domain experts; and chart reviews.One hundred eight unique allergy/toxicity/foreign body response, 70 aspiration/ingestion of foreign body, 70 infection, 52 wrong site/wrong patient/wrong procedure, 23 bleeding, 48 pain, 149 hard tissue injury, 127 soft tissue injury, 91 nerve injury, 171 other systemic complication, and 177 other orofacial complication were identified. Subtype AEs within the categories revealed that allergic reaction, aspiration, pain, and wrong procedure were the most common AEs identified among known (i.e., chart reviews) and hypothetical (i.e., interviews) sources.Using a multimodal approach, a broad list of dental AEs was developed, in which the AEs were classed into 12 categories. Hard tissue injury was noted frequently during interviews and in actuality. Pain was the unexpected AE that was consistently identified with every modality used.Most AEs result in temporary harm with hard tissue injury being a common AE identified through interviews and in actuality through chart reviews. Acknowledging that AEs happen is an important step toward mitigating them and assuring quality of care for our patients.

— Erythroxylum macrophyllum is a morphologically variable and widely distributed species complex in Central and South America with several sub-specific taxa and numerous species included in its synonymy. A single variety grows in the Colombo-Venezuelan savanna region which can be distinguished from the rest of the E. macrophyllum complex by the size of leaves, cataphyll and stipule characteristics, and shape of calyx lobes. A molecular phylogeny reconstructed from 519 nuclear genes also reveals that the savanna variety is more closely related to E. acuminatum and E. pauciflorum than E. macrophyllum. This phylogenomic evidence also suggests Erythroxylum sect. Macrocalyx, to which E. macrophyllum belongs, is a polyphyletic taxonomic section. We thus propose elevating this variety to specific status, as Erythroxylum savannarum. We provide an updated taxonomic description, information about its habitat and distribution, and justify its informal IUCN categorization of Near Threatened (NT).

To assess the clinical utility of exome sequencing for patients with developmental and epileptic encephalopathies (DEEs).Over 2 years, patients with DEEs were recruited for singleton exome sequencing. Parental segregation was performed where indicated.Of the 103 patients recruited (54 males, 49 females; aged 2 weeks-17 years), the genetic aetiology was identified in 36 out of 103 (35%) with management implications in 13 out of 36. Exome sequencing revealed pathogenic or likely pathogenic variants in 30 out of 103 (29%) patients, variants of unknown significance in 39 out of 103 (38%), and 34 out of 103 (33%) were negative on exome analysis. After the description of new genetic diseases, a molecular diagnosis was subsequently made for six patients or through newly available high-density chromosomal microarray testing.We demonstrate the utility of exome sequencing in routine clinical care of children with DEEs. We highlight that molecular diagnosis often leads to changes in management and informs accurate prognostic and reproductive counselling. Our findings reinforce the need for ongoing analysis of genomic data to identify the aetiology in patients in whom the cause is unknown. The implementation of genomic testing in the care of children with DEEs should become routine in clinical practice.The cause was identified in 35% of patients with developmental and epileptic encephalopathies. KCNQ2, CDKL5, SCN1A, and STXBP1 were the most frequently identified genes. Reanalysis of genomic data found the cause in an additional six patients. Genetic aetiology was identified in 41% of children with seizure onset under 2 years, compared to 18% with older onset. Finding the molecular cause led to management changes in 36% of patients with DEEs.

Given the recent push for universal screening, it is important to take into account how well a screener identifies children at risk for reading problems as well as how screener and sample information contribute to this classification. Picking the best cut-point for a particular sample and screening goal can be challenging given that test manuals often report classification information for a specific cut-point and sample base rate which may not generalize to other samples. By assuming a bivariate normal distribution, it is possible to calculate all of the classification information for a screener based on the correlation between the screener and outcome, the cut-point on the outcome (i.e., the base rate in the sample), and the cut-point on the screener. We provide an example with empirical data to validate these estimation procedures. This information is the basis for a free online tool that provides classification information for a given correlation between screener and outcome and cut-points on each. Results show that the correlation between screener and outcome needs to be greater than .9 (higher than observed in practice) to obtain good classification. These findings are important for researchers, administrators, and practitioners because current screeners do not meet these requirements. Since a correlation is dependent on the reliability of the measures involved, we need screeners with better reliability and/or multiple measures to increase reliability. Additionally, we demonstrate the impact of base rate on positive predictive power and discuss how gated screening can be useful in samples with low base rates.

Rubber band ligation is a commonly used method for the removal of tissue abnormalities. Most commonly, rubber band ligation is performed to remove internal hemorrhoids unresponsive to first line treatments to avoid surgery. While the procedure is considered safe, patients experience mild to significant pain and discomfort until the tissue sloughs off. As patients commonly require multiple bandings and sessions, reducing these side effects can have a considerable effect on patient adherence and quality of life. To reduce pain and discomfort, we developed drug-eluting rubber bands for ligation procedures. We investigated the potential for a band to elute anesthetics and drug combinations to durably manage pain for a period of up to five days, while exhibiting similar mechanical properties to conventional rubber bands. We show that the rubber bands retain their mechanical properties despite significant drug loading. Lidocaine, released from the bands, successfully altered the calcium dynamics of cardiomyocytes in-vitro and modulated heart rate in zebrafish embryos, while the bands exhibited lower cytotoxicity than conventional bands. Ex-vivo studies demonstrated substantial local drug release in enteric tissues. These latex-free bands exhibited sufficient mechanical and drug-eluting properties to serve both ligation and local analgesic functions, potentially enabling pain reduction for multiple indications.

Enteral nutrition is a critical intervention that supports the growth of children with pulmonary hypoplasia (PH). We explored the experiences of caregivers and providers caring for children with PH to better understand gaps in knowledge transfer and identify barriers and facilitators to caregiving to inform interventions that may improve support.This qualitative study included 10 interviews with caregivers and 10 clinical team members at a single integrated care program for children with PH. An inductive and iterative coding strategy was employed to produce a codebook. After cluster analysis, themes were generated to capture participant sentiments.Themes were defined along a care continuum (1) initiation, (2) adaptation, and (3) maintenance that represented distinct phases of adjustment to enteral nutrition support (1) in the perinatal period and initial neonatal intensive care unit (NICU) admission, (2) from discharge planning through the family's first days at home and establishment of a stable feeding regime, and (3) through long-term follow-up and weaning. Notable subthemes included uncertainty, partnerships in training, and obstacles to adaptation.Among children with PH, the caregiver-provider relationship during the perinatal and NICU course is critical to promoting caregiver adaptation to the needs of the child. Ongoing considerations to support resource alignment and transition to a stable feeding regimen may facilitate caregiver adjustment to a "new normal," culminating in successful growth and/or weaning. These findings will inform interventions focused on training curricula, discharge planning, and the provision of follow-up in the context of an integrated care program for PH.