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Short bowel syndrome is a devastating gastrointestinal disorder in which decreased bowel length results in inadequate absorption causing nutritional deficiencies. Current treatment options are accompanied by significant morbidity. We have proposed spring-mediated distraction enterogenesis as a method to lengthen bowel with success seen in porcine jejunum. We hypothesize that spring-mediated distraction enterogenesis can be demonstrated in porcine ileum with preservation of ileal structure and function.Laparotomy was performed on juvenile female mini-Yucatan pigs and a gelatin-encapsulated compressed nitinol spring was inserted into the ileal lumen and affixed proximally and distally. A control segment distal to the spring segment was marked with sutures. Postoperatively, pigs were placed on a liquid diet and euthanized on postoperative day 7. Spring and control segments were measured and processed for immunohistochemistry to evaluate for the presence of vitamin B12-intrinsic factor cotransporter, chromogranin A-producing cells, and 5-HT producing cells.All seven pigs survived to postoperative day 7 with no adverse effects. On average, pigs gained 84.3 ± 66.4 g/d. Spring segments lengthened 1.5 ± 0.7 cm with a relative lengthening by 128% ± 56%, which was statistically significant when compared to control (P 0.01). The average density of chromogranin-A cells in control compared to spring segments was not significantly changed (2.9 ± 1.1 cells/mm versus 3.2 ± 1.2 cells/mm, P = 0.17). Both vitamin B12-intrinsic factor cotransporter and 5-HT producing cells were present in both control and lengthened ileum.Intraluminal nitinol springs significantly lengthened porcine ileum. The increase in density of enteroendocrine cells may indicate enhanced endocrine function of the lengthened ileum.

Currently, there is no accurate noninvasive measurement system to diagnose gastrointestinal (GI) motility disorders. Wireless skin patches have been introduced to provide an accurate noninvasive measurement of GI myoelectric activity which is essential for developing neuro-stimulation devices to treat GI motility disorders. The aim of this study is to compare the external and internal electrical signal measurements in ambulatory pigs.Yucatan pigs underwent placement of internal electrodes on the stomach, small intestine, and colon. Wires were brought through the abdominal wall. Signals were collected by a wireless receptor. Four external patches were placed on the abdominal skin to record the signals simultaneously. Pigs were kept for 6 d while the sensors were continuously recording the data from both systems.Internal sensors detected rich signals from each organ. The stomach had a dominant frequency that ranged from 4 to 4.5 cpm, with occasional higher frequencies at 2, 3 and 4 times that. Small intestine signals had their primary energy in the 12-15 cpm range. Colon signals primarily displayed a dominant broad peak in the 4-6 cpm region. External skin patches detected a substantial fraction of the activities measured by the internal electrodes. A clear congruence in the frequency spectrum was observed between the internal and external readings.Internally measured myoelectrical signals confirmed different patterns of rhythmic activity of the stomach, small intestine, and colon. Skin patches provided GI myoelectric measurement with a range of frequencies that could be useful in the diagnosis and treatment of motility disorders.

Historically, self-regulation has provided some professions with power and market control. Currently, however, governments have scrutinized this approach, and priorities have shifted toward other mandates. This study examines the case of paramedics in Ontario, Canada, where self-regulation is still the dominant regulatory model for the healthcare professions but not for paramedics. Instead, paramedics in Ontario are co-regulated by government and physician-directed groups, with paramedics subordinate to both. This paper, which draws on interviews with paramedic industry leaders analyzed through the lens of institutional work, examines perspectives on the relevance of self-regulation to the paramedic professionalization project. Participants had varying views on the importance of self-regulation in obtaining professional status, with some rejecting its role in professionalization and others embracing regulatory reform. Because paramedics disagree on what being a profession means, the collective professionalization project has stalled. This research has implications for understanding the impact of intraprofessional relationships and conflict on professionalization projects.

Cytomegalovirus (CMV) is the most common virus associated with congenital infection worldwide and is a major cause of sensorineural hearing loss (SNHL) and developmental delay. Up to 90% of infants with congenital CMV (cCMV) infection are asymptomatic at birth, making the diagnosis challenging.

To evaluate the outcomes of gonioscopy-assisted transluminal trabeculotomy (GATT) in adult eyes with uncontrolled uveitic glaucoma.We reviewed 16 eyes from 13 patients. Surgical success was defined as intraocular pressure (IOP) reduction20% from baseline or IOP between 5 and 21 mmHg by the 3-month visit while on a stable number or fewer IOP-lowering agents and no need for additional glaucoma surgery.At 12 months, the cumulative success rate was 81%. Mean IOP was 37.8 ± 13.0 mmHg at baseline and 12.2 ± 3.0 mmHg at 12 months (68% reduction;This small retrospective study suggests that GATT is effective and safe as an initial surgical treatment for medically refractory glaucoma in uveitic adult eyes.

Aim: This study evaluated the real-world performance of six test systems for detection of SARS-CoV-2 in 138 pediatric and 110 adult maternal patients. Materials & methods: Nasopharyngeal swabs were tested directly using the Aptima™ SARS-CoV-2 (Aptima) and Simplexa™ COVID-19 Direct (Simplexa), and with Altona RealStar® RT-PCR and CDC RT-PCR with nucleic acid extracted on the Roche® MagNA Pure 96 (Altona-MP96) or bioMérieux EMAG® (Altona-EMAG). Results & Conclusion: Overall percent-positive and percent-negative agreements among the six test systems were, respectively: Aptima: 94.8 and 100%; Altona-MP96: 96.5 and 99.3%; CDC-MP96: 100 and 99.3%; Altona-EMAG: 86.1 and 100%; CDC-EMAG: 98.2 and 100%; Simplexa: 87 and 99.2%. The six test systems showed agreement ranging from 92.7 (κ = 0.85) to 98.8% (κ = 0.98).

The objective of the paper is to present foreign trade of milk and dairy products in the EU. Particular attention is paid to exports and imports of milk and dairy products in the EU and globally. Graphs and tabular and descriptive methods are used to analyze the changes in trade. The analysis of foreign trade focuses mainly on 2020; however, global export of selected dairy products was analyzed for the years 2000–2020. The survey shows the development of trade for milk and dairy products in the EU countries and the world.

Hospital-acquired infections pose significant costly global challenges to patient care. Rapid and sensitive methods to identify potential outbreaks are integral to infection control measures. Whole-genome sequencing (WGS)-based bacterial strain typing provides higher discriminatory power over standard nucleotide banding pattern-based methods such as repetitive sequence-based PCR (rep-PCR). However, integration of WGS into clinical epidemiology is limited by the lack of consensus in methodology and data analysis/interpretation. In this study, WGS was performed on genomic DNA extracted from 22 multidrug-resistant Pseudomonas aeruginosa (MDR-PA) isolates using next-generation sequencing. Resulting high-quality reads were analyzed for phylogenetic relatedness using a whole-genome multilocus sequence typing (wgMLST)-based software program and single-nucleotide variant phylogenomics (SNVPhyl). WGS-based results were compared with conventional MLST and archived rep-PCR results. Rep-PCR identified three independent clonal clusters of MDR-PA. Only one clonal cluster identified by rep-PCR, an endemic strain within the pediatric cystic fibrosis population at Texas Children's Hospital, was concordantly identified using wgMLST and SNVPhyl. Results were highly consistent between the three sequence-based analyses (conventional MLST, wgMLST, and SNVPhyl), and these results remained consistent with the addition of 74 MDR-PA genomes. These WGS-based methods provided greater resolution for strain discrimination than rep-PCR or standard MLST classification, and the ease of use of wgMLST software renders it clinically viable for analysis, interpretation, and reporting of WGS-based strain typing.

Neuroblastoma is a deadly pediatric solid tumor with infrequent recurrent somatic mutations. Particularly, the pathophysiology of tumors without MYCN amplification remains poorly defined. Utilizing an unbiased approach, we performed gene set enrichment analysis of RNA-sequencing data from 498 patients with neuroblastoma and revealed a differentially overexpressed gene signature in MYCN nonamplified neuroblastomas with telomerase reverse transcriptase (TERT) gene overexpression and coordinated activation of oncogenic signaling pathways, including E2Fs, Wnt, Myc, and the DNA repair pathway. Promoter rearrangement of the TERT gene juxtaposes the coding sequence to strong enhancer elements, leading to TERT overexpression and poor prognosis in neuroblastoma, but TERT-associated oncogenic signaling remains unclear. ChIP-seq analysis of the human CLB-GA neuroblastoma cells harboring TERT rearrangement uncovered genome-wide chromatin co-occupancy of Brd4 and H3K27Ac and robust enrichment of H3K36me3 in TERT and multiple TERT-associated genes. Brd4 and cyclin-dependent kinases (CDK) had critical regulatory roles in the expression and chromatin activation of TERT and multiple TERT-associated genes. Epigenetically targeting Brd4 or CDKs with their respective inhibitors suppressed the expression of TERT and multiple TERT-associated genes in neuroblastoma with TERT overexpression or MYCN amplification. ChIP-seq and ChIP-qPCR provided evidence that the CDK inhibitor directly inhibited Brd4 recruitment to activate chromatin globally. Therefore, inhibiting Brd4 and CDK concurrently with AZD5153 and dinaciclib would be most effective in tumor growth suppression, which we demonstrated in neuroblastoma cell lines, primary human cells, and xenografts. In summary, we describe a unique mechanism in neuroblastoma with TERT overexpression and an epigenetically targeted novel therapeutic strategy.Significance:Epigenetically cotargeting Brd4 and Cdks suppresses human neuroblastoma with TERT overexpression by inhibiting the TERT-associated gene expression networks.

Supplementary Fig. S1. Elevated mRNA expression of TERT and TERT-associated genes in NB with TERT gene rearrangement. Supplementary Fig. S2. Effects of dinaciclib on genome-wide chromatin occupancy of epigenetic modulators in CLB-GA cells. Supplementary Fig. S3: C-Myc and MYCN protein expression in four NB cell lines. Supplementary Fig. S4: Effects of dinaciclib on the chromatin occupancy of epigenetic modulators at Dvl2, AURKA, and AURKB and in CLB-GA cells. Supplementary Fig. S5. Association of overexpression of FEN1, BIRC5, and UHRF1 with poor prognosis and effects of dinaciclib on chromatin occupancy of epigenetic modulators in CLB-GA cells. Supplementary Fig. S6. JQ1 sensitive Brd4 binding profiles in OCI-AML3 cells. Supplementary Fig. S7. JQ1 and dinaciclib are synergistic or additive in inducing cytotoxicity in NB cell lines. Supplementary Fig. S8. Combination index (CI) values for synergy experiment combining Dinaciclib with Brd4 inhibitor JQ1. Supplementary Fig. S9. Effects of dinaciclib on phosphorylation of Rb in CLB-GA and Kelly cells. Supplementary table S1. Primer sequences used in ChIP-qPCR and real-time RT-PCR analysis. Supplementary table 2. Gene sets enriched in NB patients with TERT gene rearrangement (n=32) versus without TERT gene rearrangement (n=278) within MYCN non-amplified NB of Tumor Neuroblastoma (TERT)-Fischer-394-custom. Supplementary table 3. Gene sets enriched in NB patients with high versus low TERT within Tumor Neuroblastoma Gene-TARGET-161. Supplementary table 4: Information on patient samples used in this study.

Short Abstract: This paper provides a survey of evidence from computational cognitive psychology, perceptual psychology, developmental psychology, comparative psychology, and social psychology, in favor of the language of thought hypothesis (LoTH). We outline six core properties of LoTs and argue that these properties cluster together throughout cognitive science. Instead of regarding LoT as a relic of the previous century, researchers in cognitive science and philosophy of mind should take seriously the explanatory breadth of LoT-based architectures as computational/representational approaches to the mind continue to advance. Long Abstract: Mental representations remain the central posits of psychology after many decades of scrutiny. However, there is no consensus about the representational format(s) of biological cognition. This paper provides a survey of evidence from computational cognitive psychology, perceptual psychology, developmental psychology, comparative psychology, and social psychology, and concludes that one type of format that routinely crops up is the language of thought (LoT). We outline six core properties of LoTs: (i) discrete constituents; (ii) role-filler independence; (iii) predicate-argument structure; (iv) logical operators; (v) inferential promiscuity; and (vi) abstract content. These properties cluster together throughout cognitive science. Bayesian computational modeling, compositional features of object perception, complex infant and animal reasoning, and automatic, intuitive cognition in adults all implicate LoT-like structures. Instead of regarding LoT as a relic of the previous century, researchers in cognitive science and philosophy of mind must take seriously the explanatory breadth of LoT-based architectures. We grant that the mind may harbor many formats and architectures, including iconic and associative structures as well as deep-neural-network-like architectures. However, as computational/representational approaches to the mind continue to advance, classical compositional symbolic structures—i.e., LoTs—only prove more flexible and well-supported over time.

There is more than 30 years of research on relationships between income inequality and population health. In this article, we propose a research agenda with five recommendations for future research to refine existing knowledge and examine new questions. First, we recommend that future research prioritise analyses with broader time horizons, exploring multiple temporal aspects of the relationship. Second, we recommend expanding research on the effect of public expenditures on the inequality–health relationship. Third, we introduce a new area of inquiry focused on interactions between social mobility, income inequality and population health. Fourth, we argue the need to examine new perspectives on 21st century capitalism, specifically the population health impacts of inequality in income from capital (especially housing), in contrast to inequality in income from labour. Finally, we propose that this research broaden beyond all-cause mortality, to cause-specific mortality, avoidable mortality and subcategories thereof. We believe that such a research agenda is important for policy to respond to the changes following the COVID-19 pandemic.

SARS-CoV-2 has profoundly affected the way healthcare is delivered and has created significant strain on medical facilities globally. As a result, hospitals have had to continuously adapt in order to provide optimal patient care while minimizing the risk of SARS-CoV-2 transmission, particularly in the surgical setting. Texas Children's Hospital developed a set of protocols for surgical screening and clearance of patients in the context of the COVID-19 pandemic. These screening protocols were designed to mitigate the risk of exposing patients and healthcare providers to SARS-CoV-2 and have evolved significantly as a result of the emerging changes in medicine, technology, and governmental regulations. In this article, we share the reasoning behind the development, implementation, and successive modification of our institutional screening protocols.

This article presents changes in the prices of milk and other dairy products in the European Union (EU). First, the descriptive statistics of the prices of milk and dairy products are presented, and then correlation and regression analyses were conducted to measure the relationships between the prices. We used the augmented Dickey-Fuller (ADF) test and generalised autoregressive conditional heteroscedasticity (GARCH) model to measure the stationarity and changes in dairy product prices in the EU. At the EU level, we checked the changes in prices of butter, skim milk powder, whole milk powder, Cheddar, Edam, Gouda, Emmental and whey powder. Our analysis confirmed that the butter, skim milk powder, whole milk powder, Cheddar, Edam and Gouda processes depend on previous values. The biggest price changes were observed in whey powder (34.12%), butter (24.46%) and skim milk powder (21.78%).

Purpose To determine classification criteria for Vogt-Koyanagi-Harada (VKH) disease Design Machine learning of cases with VKH disease and 5 other panuveitides. Methods Cases of panuveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the panuveitides. The resulting criteria were evaluated on the validation set. Results One thousand twelve cases of panuveitides, including 156 cases of early-stage VKH and 103 cases of late-stage VKH, were evaluated. Overall accuracy for panuveitides was 96.3% in the training set and 94.0% in the validation set (95% confidence interval 89.0, 96.8). Key criteria for early-stage VKH included: 1) exudative retinal detachment with characteristic appearance on fluorescein angiogram or optical coherence tomography or 2) panuveitis with ≥2 of 5 neurologic symptoms/signs. Key criteria for late-stage VKH included history of early-stage VKH and either: 1) sunset glow fundus or 2) uveitis and ≥1 of 3 cutaneous signs. The misclassification rates in the learning and validation sets for early-stage VKH were 8.0% and 7.7%, respectively, and for late-stage VKH 1.0% and 12%, respectively. Conclusions The criteria for VKH had a reasonably low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

Purpose To determine classification criteria for Behcet disease uveitis. Design Machine learning of cases with Behcet disease and 5 other panuveitides. Methods Cases of panuveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the intermediate uveitides. The resulting criteria were evaluated on the validation set. Results One thousand twelve of cases panuveitides, including 194 cases of Behcet disease with uveitis, were evaluated by machine learning. The overall accuracy for panuveitides was 96.3% in the training set and 94.0% in the validation set (95% confidence interval 89.0, 96.8). Key criteria for Behcet disease uveitis were a diagnosis of Behcet disease using the International Study Group for Behcet Disease criteria and a compatible uveitis, including: 1) anterior uveitis; 2) anterior chamber and vitreous inflammation; 3) posterior uveitis with retinal vasculitis and/or focal infiltrates; or 4) panuveitis with retinal vasculitis and/or focal infiltrates. The misclassification rates for Behcet disease uveitis were 0.6 % in the training set and 0% in the validation set, respectively. Conclusions The criteria for Behcet disease uveitis had a low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

The purpose of the study is to examine the long-term safety of an endoluminal bowel lengthening device prior to its use in the first human trial. In addition, device performance and natural passage will be evaluated.Endoluminal lengthening springs were surgically placed into the jejunum of Yucatan minipigs using the Eclipse XL1 device. A matching internal control segment of jejunum was marked at the time of operation. Weekly weights and fluoroscopic studies were obtained to evaluate spring deployment and position until devices passed. Animals were euthanized at 28, 60, 90, and 180 days. At necropsy, length measurements were recorded, and histopathologic analysis was performed.There were no bowel obstructions or overt perforations attributable to the device. All surviving animals gained weight and were clinically thriving. All devices passed out of the rectum by 180 days. Bowel lengthening was seen in all experimental segments, and minimal fibrosis was observed by 180 days.Jejunal lengthening persisted after device had passed through the intestinal tract after 180 days. Early histopathologic changes of the jejunum during distraction enterogenesis normalized over time.

short bowel syndrome is marked by inadequate intestinal surface area to absorb nutrients. Current treatments are focused on medical management and surgical reconfiguration of the dilated intestine. We propose the use of spring-mediated distraction enterogenesis as a novel intervention to increase intestinal length. Given our previous success lengthening intestinal segments using springs with spring constant ~7 N/m that exerts 0.46 N or higher, we sought to determine the minimal force needed to lengthen porcine small intestinal segments, and to explore effects on intestine over time.Juvenile Yucatan pigs underwent laparotomy with enterotomy to introduce nitinol springs intraluminally (n = 21 springs). Bowel segments (control, spring-distracted) were retrieved on post-operative day (POD) 7 and 14, and lengths measured. Thickness of cross-sectional intestinal layers were measured using HE, and submucosal collagen fiber orientation measured using trichrome stained sections.all pigs survived to POD7 and 14. Spring constants of at least 2 N/m exerting a minimum force of 0.10 N significantly lengthened intestinal segments (p 0.0001). The stronger the spring force, the greater the induced thickness of various intestinal layers at POD7 and 14. Collagen fiber orientation was also more disordered because of stronger springs.a spring constant of approximately 2 N/m exerting 0.10 N and greater significantly lengthens intestinal segments and stimulates intestinal structural changes at POD7 and 14. This suggests a decreased force is capable of inducing spring-mediated distraction enterogenesis.

In this article we focus upon low-income older adults’ lived experiences of aging, precariousness and housing instability/homelessness in Hamilton, Canada. Precariousness includes involuntary or in...

Although vaccination has reduced the incidence of Haemophilus influenzae type b, nontypeable H. influenzae and other encapsulated types remain a health threat. Little is known regarding the contemporary molecular epidemiology of these organisms. We conducted multilocus sequence typing on invasive H. influenzae during a period of increasing incidence.

BackgroundIt has been shown that the high cost of housing can be detrimental to individual health. However, it is unknown (1) whether high housing costs pose a threat to population health and (2) whether and how social policies moderate the link between housing cost burden and mortality. This study aims to reduce these knowledge gaps.MethodsCountry-level panel data from Organisation for Economic Co-operation and Development (OECD) countries are used. Housing cost to income ratio and age-standardised mortality were obtained from the OECD database. Fixed effects models were conducted to estimate the extent to which the housing cost to income ratio was associated with preventable mortality, treatable mortality, and suicides. In order to assess the moderating effects of social and housing policies, different types of social spending per capita as well as housing policies were taken into account.ResultsHousing cost to income ratio was significantly associated with preventable mortality, treatable mortality, and suicide during the post-global financial crisis (2009–2017) but not during the pre-global financial crisis (2000–2008). Social spending on pensions and unemployment benefits decreased the levels of mortality rate associated with housing cost burden. In countries with higher levels of social housing stock, the link between housing cost burden and mortality was attenuated. Similar patterns were examined for countries with rent control.ConclusionOur findings suggest that housing cost burden can be related to population health. Future studies should examine the role of protective measures that alleviate health problems caused by housing cost burden.

The low prevalence effect is a phenomenon whereby target prevalence affects performance in visual search (e.g., baggage screening) and comparison (e.g., fingerprint examination) tasks, such that people more often fail to detect infrequent target stimuli. For example, when exposed to higher base-rates of ‘matching’ (i.e., from the same person) than ‘non-matching’ (i.e., from different people) fingerprint pairs, people more often misjudge ‘non-matching’ pairs as ‘matches’–an error that can falsely implicate an innocent person for a crime they did not commit. In this paper, we investigated whether forensic science training may mitigate the low prevalence effect in fingerprint comparison. Forensic science trainees (n = 111) and untrained novices (n = 114) judged 100 fingerprint pairs as ‘matches’ or ‘non-matches’ where the matching pair occurrence was either high (90%) or equal (50%). Some participants were also asked to use a novel feature-comparison strategy as a potential attenuation technique for the low prevalence effect. Regardless of strategy, both trainees and novices were susceptible to the effect, such that they more often misjudged non-matching pairs as matches when non-matches were rare. These results support the robust nature of the low prevalence effect in visual comparison and have important applied implications for forensic decision-making in the criminal justice system.

To compare 2 mg intravitreal triamcinolone (IVT) versus 40 mg posterior sub-Tenon triamcinolone acetonide (STT) for the treatment of eyes with pseudophakic cystoid macular edema.A retrospective, single-center review of eyes receiving 2 mg IVT between 3/1/2012-3/1/2017 and 40 mg STT between 1/1/2015-3/1/2017. Visual acuity (VA) and central macular thickness (CMT) were recorded at baseline, 1-, 3-, and 6-month follow-up visits.Forty-five eyes were included in the IVT group and 50 eyes in the STT group. Change in VA from baseline to 1, 3, and 6 months was not significantly different between IVT and STT (6 months: 2.3 lines vs. 2.4 lines,2 mg IVT and 40 mg STT both achieved significant improvement in vision and CMT with no significant difference between interventions at 3- and 6-month follow-up.

Infants and young children are uniquely susceptible to primary viral and bacterial infections, predisposing them to responses of greater frequency and severity than in adults. Etiologies and manifestations of infections in pediatric patients are often different than those in adults. It can be challenging for clinical laboratories to implement appropriate microbiologic methods for rapid and accurate diagnoses in this population. Laboratorians should be cognizant of the distinctive features of children to provide comprehensive pediatric clinical microbiology services. This article discusses laboratory aspects of several clinically significant pediatric pathogens that cause severe harm to patients and impact public health responses.

Purpose One in 5000 newborns is diagnosed with Hirschsprung disease each year in the United States. The potential of employing neural crest stem cells to restore the enteric nervous system has been investigated. Skin-derived precursor cells (SKPs) are multipotent progenitor cells that can differentiate into neurons and gliocytes in vitro and generate enteric ganglion-like structures in rodents. Here we examined the behavior of human SKPs (hSKPs) after their transplantation into a large animal model of colonic aganglionosis. Methods Juvenile minipigs underwent a chemical denervation of the colon to establish an aganglionosis model. The hSKPs were generated from human foreskin and were cultured in neuroglial-selective medium. Cells were labeled with a fluorescent dye and were injected into the porcine aganglionic colon. After one week, transplanted hSKPs were assessed by immunofluorescence for markers of multipotency and neuroglial differentiation. Results In culture, hSKPs expressed nestin and S100b indicative of neuroglial precursors. After xenografting in pigs, hSKPs were identified in the myenteric and submucosal plexuses of the colons. The hSKPs expressed nestin and early neuroglial differentiation markers. Conclusions Human SKPs transplanted into aganglionic colon demonstrated immunophenotypes of neuroglial progenitors, suggesting their potential use for Hirschsprung disease. Level of evidence

Renewable energy sources (RES) can play a significant role in economic growth. This article examines the development of the wind energy market in the EU. The applicable regulations, directives, and legal acts are reviewed, and the State’s role in the development of the renewable energy market is discussed. The analyses were carried out based on the available literature and Eurostat data. The authors of the paper used basic statistics to summarize the changes in wind energy and make a prognosis. The data analysis uses the Autoregressive Integrated Moving Average Method (ARIMA). The survey found that the highest average wind cumulative installed capacities were in Germany (31026 MW), Spain (18602 MW), United Kingdom (7894 MW) and France (6108 MW). Our analysis indicates that the biggest average annual installed wind capacity was in Germany (2952.6 MW), Spain (1224.5 MW) and the United Kingdom (1363.8 MW). These same countries achieved the highest average wind gross electricity production in the years 2004–17: Germany (50.9 TWh), Spain (39.3 TWh) and United Kingdom (18.9 TWh). The study finds that wind cumulative installed capacity will increase in most countries of the EU.

Background Nonthermal irreversible electroporation (NTIRE) has been shown to ablate the small intestinal epithelium while maintaining submucosal and muscularis propriae integrity. NTIRE is used here in a first-in-mouse study to eliminate the native intestinal stem cell population to understand optimal parameters and timeline of mucosal regeneration. Methods Adult C57 background mice underwent laparotomy and electroporation of 1.5 cm of jejunum using a BTX 830 ECM electroporator and electrode calipers. Parameters were varied by voltage, pulse number, interval, and duration to determine optimal de-epithelialization. Electroporated segments were extracted 1 to 3 d after intervention with same-animal control segment. Cross sections were preserved, and measurements were taken to compare effects of parameters on villi height, crypt depth, crypt obliteration, and serosal thickness. Results Morbidity was limited at a standard set of electroporation parameters (14%), and increased with higher voltage, longer interval, and shorter or longer pulses. Serosa/muscularis thickness was unaffected by varying interventions. Crypt depth and obliterated crypts were most affected by modulating pulse number, intervals, and duration. Villi height was most significantly shortened by altering pulse duration, with limited recovery by day 3, otherwise mucosal regeneration was observed in most cases by this point. Conclusions NTIRE is an effective method of denuding small intestinal epithelium in mice and temporarily ablating crypts while sparing the support scaffold for native regeneration. This first-in-mouse study of electroporation suggests it is a practical tool that can be utilized in a small mammalian system.

Purpose: Cryptococcus neoformans is a budding yeast that has a tropism for the central nervous system where it may cause meningitis, which has a high mortality rate. Endophthalmitis is rare and typically occurs in the setting of meningitis and disseminated disease. This report describes an atypical presentation of cryptococcal endophthalmitis and outlines the appropriate workup and management for this disease. Methods: A case report is presented. Results: A 66-year-old man on chemotherapy who presented with blurry vision without any extraocular symptoms was diagnosed with cryptococcal endophthalmitis and found to have underlying bloodstream and central nervous system infection on subsequent workup. He was treated with intravenous and intravitreal antifungals and remained systemically well, although a large subretinal mass lesion remained stable at 2-month follow-up. Conclusions: Cryptococcal endophthalmitis may be the initial presentation of disseminated cryptococcal disease. If vitreous cultures grow Cryptococcus, clinicians should presume that meningitis is present, regardless of symptoms, until proven otherwise.

PURPOSE: To evaluate long-term risk and outcomes of glaucoma in eyes with intermediate, posterior, and panuveitis managed with systemic or fluocinolone acetonide (0.59 mg, “implant”) therapy. DESIGN: Prospective Follow-up of the Multicenter Uveitis Steroid Treatment (MUST) Clinical Trial Cohort METHODS: Patients with intermediate, posterior or panuveitis randomized to implant or systemic therapy (corticosteroid plus immunosuppression in >90%) were followed prospectively for glaucoma incidence and outcome. RESULTS: Among 405 uveitic at-risk eyes of 232 patients (median follow-up=6.9 years), 40% (79/196) of eyes assigned and treated with implant and 8% (17/209) of eyes assigned and treated with systemic therapy (censoring eyes receiving an implant upon implantation) developed glaucoma (Hazard Ratio (HR)=5.9 (95% CI: 3.2, 10.8); p

Background Hyperalgesia is a heightened pain response to a noxious stimulus and is a hallmark of many common neuropathic and chronic pain conditions. In a double-blind placebo-controlled drug-crossover trial, the effects of concomitant and delayed minocycline treatment on the initiation and resolution of muscle hyperalgesia were tested. Methods An initial cohort (n = 10) received repeated injections (5 mu g: days 0, 2 and 4) of nerve growth factor (NGF) in the flexor carpi ulnaris muscle of the forearm and pressure pain thresholds were collected at day 0 (control), day 7 (peak) and day 14 (recovery). A second cohort (n = 18) underwent an identical procedure, however, half received a placebo between days 0 and 7 before switching to minocycline from days 7 to 14 (P1/M2), while the remaining subjects received minocycline (day 0: 200mg then 100mg b.i.d. for 7 days) before switching to placebo (M1/P2). Results The initial cohort exhibited a diffuse muscular pain hypersensitivity with a decrease in pressure pain thresholds at day 7 before a partial return to normalcy at day 14. The P1/M2 treatment group exhibited an identical peak in hypersensitivity at day 7, however, after switching to minocycline in week 2 showed a significant reduction in muscle hyperalgesia compared with the initial cohort at day 14. The M1/P2 treatment group had significantly less (similar to 43%) hyperalgesia at day 7 compared with the other groups. Conclusions The study indicates that the administration of minocycline can reduce experimentally induced muscle pain regardless of the time of administration. Significance In a double-blind placebo-controlled drug-crossover study, the common antibiotic minocycline was found to reduce the muscle hyperalgesia induced by intramuscular injection of nerve growth factor. The results of the study showed that both concomitant (pre-emptive) and delayed administration of minocycline can ameliorate the onset and facilitate the resolution of experimentally induced muscle hyperalgesia. Funding Agencies|Western Sydney University School of Medicine under the Research Training Program (RTP)

Neuroblastoma is a deadly pediatric solid tumor with infrequent recurrent somatic mutations. Particularly, the pathophysiology of tumors without MYCN amplification remains poorly defined. Utilizing an unbiased approach, we performed gene set enrichment analysis of RNA-sequencing data from 498 patients with neuroblastoma and revealed a differentially overexpressed gene signature in MYCN nonamplified neuroblastomas with telomerase reverse transcriptase (TERT) gene overexpression and coordinated activation of oncogenic signaling pathways, including E2Fs, Wnt, Myc, and the DNA repair pathway. Promoter rearrangement of the TERT gene juxtaposes the coding sequence to strong enhancer elements, leading to TERT overexpression and poor prognosis in neuroblastoma, but TERT-associated oncogenic signaling remains unclear. ChIP-seq analysis of the human CLB-GA neuroblastoma cells harboring TERT rearrangement uncovered genome-wide chromatin co-occupancy of Brd4 and H3K27Ac and robust enrichment of H3K36me3 in TERT and multiple TERT-associated genes. Brd4 and cyclin-dependent kinases (CDK) had critical regulatory roles in the expression and chromatin activation of TERT and multiple TERT-associated genes. Epigenetically targeting Brd4 or CDKs with their respective inhibitors suppressed the expression of TERT and multiple TERT-associated genes in neuroblastoma with TERT overexpression or MYCN amplification. ChIP-seq and ChIP-qPCR provided evidence that the CDK inhibitor directly inhibited Brd4 recruitment to activate chromatin globally. Therefore, inhibiting Brd4 and CDK concurrently with AZD5153 and dinaciclib would be most effective in tumor growth suppression, which we demonstrated in neuroblastoma cell lines, primary human cells, and xenografts. In summary, we describe a unique mechanism in neuroblastoma with TERT overexpression and an epigenetically targeted novel therapeutic strategy. Significance: Epigenetically cotargeting Brd4 and Cdks suppresses human neuroblastoma with TERT overexpression by inhibiting the TERT-associated gene expression networks.

Background The Streptococcus anginosus group (SAG, S. anginosus, S. intermedius and S. constellatus) are often associated with severe disease and abscess formation. In our institution, we observed an apparent increase in frequency of intraorbital and intracranial infections resulting from SAG at Texas Children's Hospital. We undertook a retrospective review to describe the frequency and clinical features of these infections. Methods We reviewed the database of the microbiology laboratory at Texas Children's Hospital from 2011 to 2018 for SAG-positive cultures. Cases included were those associated with (1) either otitis media or sinusitis and (2) Pott's puffy tumor, orbital abscesses, mastoiditis, epidural abscesses, subdural empyema, brain parenchymal abscesses or dural enhancement by imaging. The number of overall diagnoses were determined using diagnostic codes and used to estimate the proportion of disease caused by SAG. Results Ninety-five cases were identified meeting inclusion criteria. The median age of patients was 11.4 years, and 75.8% were previously healthy. S. intermedius was most commonly isolated (80%) followed by S. constellatus (12.6%) and S. anginosus (7.4%); 50.5% of cases were polymicrobial. Among polymicrobial cases, Staphylococcus aureus was most frequently isolated. All patients underwent surgical intervention. 8.4% of patients experienced persistent neurologic deficits. We observed a significant increase in disease incidence during the study period; in addition, the overall proportion of all intracranial infections caused by SAG increased. Conclusions Complications of otitis media and sinusitis caused by SAG are associated with substantial morbidity. These infections are becoming increasingly common at our center although the precise reason for this temporal trend is unclear.

Matching the identity of unfamiliar faces is important in applied identity verification tasks, for example when verifying photo ID at border crossings, in secure access areas, or when issuing identity credentials. In these settings, other biographical details—such as name or date of birth on an identity document—are also often compared to existing records, but the impact of these concurrent checks on decisions has not been examined. Here, we asked participants to sequentially compare name, then face information between an ID card and digital records to detect errors. Across four experiments (combined n = 274), despite being told that mismatches between written name pairs and face image pairs were independent, participants were more likely to say that face images matched when names also matched. Across all experiments, we found that this bias was unaffected by the image quality, suggesting that the source of the bias is somewhat independent of perceptual processes. In a final experiment, we show that this decisional bias was found only for name checks, but not when participants were asked to check ID card expiration dates or unrelated object names. We conclude that the bias arises from processing identity information and propose that it operates at the level of unfamiliar person identity representations. Results are interpreted in the context of theoretical models of face processing, and we discuss applied implications.

To identify geographic and socioeconomic variables associated with residential proximity to Phase 3 ophthalmology clinical trial sites.The geographic location of clinical trial sites for Phase 3 clinical trials in ophthalmology was identified using ClinicalTrials.gov. Driving time from each United States (US) census tract centroid to nearest clinical trial site was calculated using real traffic patterns. Travel data were crosslinked to census-tract level public datasets from United States Census Bureau American Community Survey (ACS). Cross-sectional multivariable regression was used to identify associations between census-tract sociodemographic factors and driving time (60 min) from each census tract centroid to the nearest clinical trial site.There were 2330 unique clinical trial sites and 71,897 census tracts. Shortest median time was to retina sites [33.7 min (18.7, 70.1 min)]. Longest median time was to neuro-ophthalmology sites [119.8 min (48.7, 240.4 min)]. Driving60 min was associated with rural tracts [adjusted odds ratio (aOR) 7.60; 95% CI (5.66-10.20), p 0.0001]; Midwest [aOR 1.84(1.15-2.96), p = 0.01], South [aOR 2.57 (1.38-4.79), p 0.01], and West [aOR 2.52 (1.52-4.17), p 0.001] v. Northeast; and tracts with higher visual impairment [aOR 1.07 (1.03-1.10), p 0.001)]; higher poverty levels [4th v.1st Quartile of population below poverty, aOR 2.26 (1.72-2.98), p 0.0001]; and lower education levels [high school v. Bachelor's degree or higher aOR 1.02 (1.00-1.03), p = 0.0072].There are significant geographic and socioeconomic disparities in access to ophthalmology clinical trial sites for rural, non-Northeastern, poorer, and lower education level census tracts, and for census tracts with higher levels of self-reported visual impairment.

For decades, it has been assumed that the foreign body response (FBR) to biomedical implants is primarily a reaction to the chemical and mechanical properties of the implant. Here, we show for the first time that a third independent variable, allometric tissue-scale forces (which increase exponentially with body size), can drive the biology of FBR in humans. We first demonstrate that pathological FBR in humans is mediated by immune cell-specific Rac2 mechanotransduction signaling, independent of implant chemistry or mechanical properties. We then show that mice, which are typically poor models of human FBR, can be made to induce a strikingly human-like pathological FBR by altering these extrinsic tissue forces. Altering these extrinsic tissue forces alone activates Rac2 signaling in a unique subpopulation of immune cells and results in a human-like pathological FBR at the molecular, cellular, and local tissue levels. Finally, we demonstrate that blocking Rac2 signaling negates the effect of increased tissue forces, dramatically reducing FBR. These findings highlight a previously unsuspected mechanism for pathological FBR and may have profound implications for the design and safety of all implantable devices in humans.One-Sentence SummaryAllometric tissue-scale forces at the implant-tissue interface drive pathological foreign body response.